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A Review-Ceftriaxone for Life

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DOI: 10.5958/2231-5691.2017.00007.7

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Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

ISSN- 2231–5683 (Print) www.asianpharmaonline.org

ISSN- 2231–5691 (Online) www.asianjpr.com

REVIEW ARTICLE

A Review- Ceftriaxone for Life

Mohd. Yaqub Khan*, Maryada Roy, Raj Kumar Rawal, Umesh Kumar Bansal
Prosperity 6 Pharmaceutics, Plot No. 23, EPIP Phase 2, Thana, Baddi, Himachal Pradesh-173205, India
*Corresponding Author E-mail: mohdyaqubkhan19@gmail.com

ABSTRACT:
Ceftriaxone for injection, USP 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-zabicyclo
[4.2.0] oct-2-ene-2-carboxylic acid, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate. Ceftriaxone is a
third-generation of cephalosporins which is used for community acquired infections such as pneumonia and
urinaly tract infections. It showed great advantage of once-daily administration based on pharmacological
manner and need no renal impairment. It is stable for β-lactamases against first- or second- generations of
cephalosporins. Ceftriaxone is also used for streptococcal endocarditis as alternative first-line therapeutic
regimen and used for Sexually Transmited Disease (STD) such as syphilis and chancoroid.

KEY WORDS: Ceftriaxone, Cephalosporin, β-lactamases

INTRODUCTION: However, the recent spread of derepressed mutants,

The aminothiazol-cephalosporin ceftriaxone sodium
(ceftriaxone) is a third-generation cephalosporin. The
product name for this drug is Rocephin throughout the
world, including the USA, Canada and Japan, but is
Cefaxona in Mexico and Peru. This agent is used for the
treatment of various community-acquired infections and
is also used for the treatment of infections with Neisseria
gonorrhoeae and Salmonella typhi. Ceftriaxone was
developed by Roche in 1978; it has the advantages of
only requiring a once-daily administration and can be
used as an intravenous or intramuscular injection for
outpatients in an appropriate pharmacological manner. It
has been used extensively because of its improved
stability against traditional β-lactamases, compared with
first or second generations of cephalosporins.1
which hyper produce chromosomal β-lactamases and
extended-spectrum β-lactamases (ESBLs), during the
past decade has diminished the activity of all third-
generation cephalosporins against Enterobacteriaceae,
necessitating careful attention to sensitivity studies.
Outpatient management for the treatment of infectious
diseases is increasing because of medical economics.
The outpatient use of ceftriaxone is based on
pharmacokinetics and pharmacodynamics theory. It is
also justified for medical economic reasons because it
can reduce the length of hospital stay. Home intravenous
antibiotics therapy (HIAT) or outpatient parenteral
antimicrobial therapy (OPAT) are possible using
ceftriaxone because of its pharmacological
characterization.

Ceftriaxone has a good tolerability profile, the most

well-known adverse events being diarrhea, nausea,
vomiting, hematopoietic disturbance, and rash. However,
these are common adverse events for beta lactam
antibiotics. Ceftriaxone may cause biliary
Received on 04.11.2016 Accepted on 05.12.2016 pseudolithiasis, notably at higher dosages and/or after
© Asian Pharma Press All Right Reserved long-term administration (more than 2 g/day for more
Asian J. Pharm. Res. 2017; 7(1): 35-48. than 28 days), although the incidence of pseudolithiasis
DOI: 10.5958/2231-5691.2017.00007.7 is less than 0.1%.2
35
Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

The chemical formula of ceftriaxone sodium is The color of ceftriaxone sodium solutions ranges from
C18H16N8Na2O7S3•3.5H2O. It has a calculated light yellow to amber, depending on the length of
molecular weight of 661.60 and the following structural storage, concentration and diluent used.
formula:
Each vial contains ceftriaxone sodium equivalent to 250
mg, 500 mg, 1 gram or 2 grams of ceftriaxone activity.
Ceftriaxone sodium contains approximately 83 mg (3.6
mEq) of sodium per gram of ceftriaxone activity.3

Clinical Pharmacology & Pharmacokinetic

Average plasma concentrations of ceftriaxone following
a single 30-minute intravenous (IV) infusion of a 0.5, 1
Figure 1: Chemical Structure of Ceftriaxone or 2 gm dose and intramuscular (IM) administration of a
single 0.5 (250 mg/mL or 350 mg/mL concentrations) or
Ceftriaxone sodium is a white to yellowish crystalline 1 gm dose in healthy subjects are presented in Table 1.
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.

Table 1. Ceftriaxone Plasma Concentrations after Single Dose Administration 4, 5

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 IV* 82 59 48 37 29 23 15 10 5
0.5 gm IM 22 33 38 35 30 26 16 ND 5
250 mg/mL
0.5 gm IM 20 32 38 34 31 24 16 ND 5
350 mg/mL
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
ND = Not determined
* IV doses were infused at a constant rate over 30 minutes.

Ceftriaxone was completely absorbed following IM Thirty-three percent to 67% of a ceftriaxone dose was
administration with mean maximum plasma excreted in the urine as unchanged drug and the
concentrations occurring between 2 and 3 hours post- remainder was secreted in the bile and ultimately found
dose. Multiple IV or IM doses ranging from 0.5 to 2 gm in the feces as microbiologically inactive compounds.
at 12- to 24-hour intervals resulted in 15% to 36% After a 1 gm IV dose, average concentrations of
accumulation of ceftriaxone abovesingle dose values. ceftriaxone, determined from 1 to 3 hours after dosing,
Ceftriaxone concentrations in urine are shown in Table were 581 mcg/mL in the gallbladder bile, 788 mcg/mL
2. in the common duct bile, 898 mcg/mL in the cystic duct
bile, 78.2 mcg/gm in the gallbladder wall and 62.1
Table 2. Urinary Concentrations of Ceftriaxone after Single Dose mcg/mL in the concurrent plasma.7
6
Administration
Dose/ Average Urinary Concentrations (mcg/mL)
Route 0 to 2 2 to 4 4 to 8 to 12 to 24 to
Over a 0.15 to 3 gm dose range in healthy adult subjects,
hr hr 8 hr 12 hr 24 hr 48 hr the values of elimination half-life ranged from 5.8 to 8.7
0.5 gm 526 366 142 87 70 15 hours; apparent volume of distribution from 5.78 to 13.5
IV L; plasma clearance from 0.58 to 1.45 L/hour; and renal
0.5 gm 115 425 308 127 96 28
IM
clearance from 0.32 to 0.73 L/hour. Ceftriaxone is
1 gm IV 995 855 293 147 132 32 reversibly bound to human plasma proteins, and the
1 gm IM 504 628 418 237 ND ND binding decreased from a value of 95% bound at plasma
2 gm IV 2692 1976 757 274 198 40 concentrations of < 25 mcg/mL to a value of 85% bound
ND = Not Determined at 300 mcg/mL. Ceftriaxone crosses the blood placenta
barrier.

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Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

The average values of maximum plasma concentration, The elimination of ceftriaxone is not altered when
elimination half life, plasma clearance and volume of ceftriaxone is coadministered with probenecid.
distribution after a 50 mg/kg IV dose and after a 75
mg/kg IV dose in pediatric patients suffering from Pharmacokinetics in the Middle Ear Fluid:
bacterial meningitis are shown in Table 3. Ceftriaxone In one study, total ceftriaxone concentrations (bound and
penetrated the inflamed meninges of infants and unbound) were measured in middle ear fluid obtained
pediatric patients; CSF concentrations after a 50 mg/kg during the insertion of tympanostomy tubes in 42
IV dose and after a 75 mg/kg IV dose are also shown in pediatric patients with otitis media. Sampling times were
Table 3. from 1 to 50 hours after a single intramuscular injection
of 50 mg/kg of ceftriaxone. Mean (±SD) ceftriaxone
Table 3. Average Pharmacokinetic P arameters of Ceftriaxone in levels in the middle ear reached a peak of 35 (±12)
Pediatric Patients With Meningitis 8 mcg/mL at 24 hours, and remained at 19 (±7) mcg/mL at
50 mg/kg IV 75 mg/kg IV
Maximum Plasma 216 275 48 hours. Based on middle ear fluid ceftriaxone
Concentrations (mcg/mL) concentrations in the 23 to 25 hour and the 46 to 50 hour
Elimination Half-life (hr) 4.6 4.3 sampling time intervals, a half-life of 25 hours was
Plasma Clearance 49 60 calculated. Ceftriaxone is highly bound to plasma
(mL/hr/kg)
proteins. The extent of binding to proteins in the middle
Volume of Distribution 338 373
(mL/kg) ear fluid is unknown. 10
CSF Concentration – 5.6 6.4
inflamed meninges Interaction with Calcium:
(mcg/mL) Two in vitro studies, one using adult plasma and the
Range (mcg/mL) 1.3 to 18.5 1.3 to 44
Time after dose (hr) 3.7 (±1.6) 3.3 (±1.4)
other neonatal plasma from umbilical cord blood have
been carried out to assess interaction of ceftriaxone and
Compared to that in healthy adult subjects, the calcium. Ceftriaxone concentrations up to 1 mM (in
pharmacokinetics of ceftriaxone were only minimally excess of concentrations achieved in vivo following
altered in elderly subjects and in patients with renal administration of 2 grams ceftriaxone infused over 30
impairment or hepatic dysfunction (Table 4); therefore, minutes) were used in combination with calcium
dosage adjustments are not necessary for these patients concentrations up to 12 mM (48 mg/dL). Recovery of
with ceftriaxone dosages up to 2 gm per day. Ceftriaxone ceftriaxone from plasma was reduced with calcium
was not removed to any significant extent from the concentrations of 6 mM (24 mg/dL) or higher in adult
plasma by hemodialysis. In 6 of 26 dialysis patients, the plasma or 4 mM (16 mg/dL) or higher in neonatal
elimination rate of ceftriaxone was markedly reduced. plasma. This may be reflective of ceftriaxone-calcium
precipitation.
Table 4. Average Pharmacokinetic Parameters of Ceftriaxone in
Humans 9 Microbiology:
Subject Group Elimination Plasma Volume of Mechanism of Action:
Half-Life Clearance Distribution
(hr) (L/hr) (L) Ceftriaxone is a bactericidal agent that acts by inhibition
Healthy Subjects 5.8 to 8.7 0.58 to 1.45 5.8 to 13.5 of bacterial cell wall synthesis. Ceftriaxone has activity
Elderly Subjects 8.9 0.83 10.7 in the presence of some beta-lactamases, both
(mean age, 70.5 penicillinases and cephalosporinases, of Gram-negative
yr)
Patients With
and Gram-positive bacteria. 11
Renal Impairment
Hemodialysis Mechanism of Resistance:
Patients 14.7 0.65 13.7 Resistance to ceftriaxone is primarily through hydrolysis
(0 to 5 mL/min)* 15.7 0.56 12.5
Severe (5 to 15
by beta-lactamase, alteration of penicillin-binding
mL/min) 11.4 0.72 11.8 proteins (PBPs), and decreased permeability. Interaction
Moderate (16 to with Other Antimicrobials In an in vitro study
30 mL/min) 12.4 0.70 13.3 antagonistic effects have been observed with the
Mild (31 to 60
mL/min)
combination of chloramphenicol and ceftriaxone 12.
Patients With 8.8 1.1 13.6 Ceftriaxone has been shown to be active against most
Liver Disease isolates of the following bacteria, both in vitro and in
* Creatinine clearance. clinical infections as described in the Indications and
Usage section:

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Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

• Gram-negative bacteria 13 • Gram-positive bacteria

Acinetobacter calcoaceticus Streptococcus agalactiae
Enterobacter aerogenes
Enterobacter cloacae • Anaerobic bacteria
Escherichia coli Porphyromonas (Bacteroides) melaninogenicus
Haemophilus influenzae Prevotella (Bacteroides) bivius
Haemophilus parainfluenzae
Klebsiella oxytoca Susceptibility Test Methods: 15
Klebsiella pneumoniae When available, the clinical microbiology laboratory
Moraxella catarrhalis should provide the results of in vitro susceptibility test
Morganella morganii results for antimicrobial drug products used in resident
Neisseria gonorrhoeae hospitals to the physician as periodic reports that
Neisseria meningitidis describe the susceptibility profile of nosocomial and
Proteus mirabilis community-acquired pathogens. These reports should aid
Proteus vulgaris the physician in selecting an antibacterial drug product
Pseudomonas aeruginosa for treatment.
Serratia marcescens
Dilution techniques:
• Gram-positive bacteria 14 Quantitative methods are used to determine
Staphylococcus aureus antimicrobial minimal inhibitory concentrations (MICs).
Staphylococcus epidermidis These MICs provide estimates of the susceptibility of
Streptococcus pneumoniae bacteria to antimicrobial compounds. The MICs should
Streptococcus pyogenes be determined using a standardized test method 1,3. The
Viridans group streptococci MIC values should be interpreted according to criteria
provided in Table 5.
• Anaerobic bacteria
Bacteroides fragilis Diffusion techniques:
Clostridium species Quantitative methods that require measurement of zone
Peptostreptococcus species diameters also provide reproducible estimates of the
susceptibility of bacteria to antimicrobial compounds.
The zone size provides an estimate of the susceptibility
The following in vitro data are available, but their of bacteria to antimicrobial compounds. The zone size
clinical significance is unknown. At least 90 percent of should be determined using a standardized test
the following microorganisms exhibit an in vitro method.2,3 .This procedure uses paper disks
minimum inhibitory concentration (MIC) less than or impregnated with 30 mcg ceftriaxone to test the
equal to the susceptible breakpoint for ceftriaxone. susceptibility of microorganisms to ceftriaxone. The disk
However, the efficacy of ceftriaxone in treating clinical diffusion interpretive criteria are provided in Table 5. 16
infections due to these microorganisms has not been
established in adequate and well-controlled clinical Anaerobic techniques:
trials. For anaerobic bacteria, the susceptibility to ceftriaxone
as MICs can be determined by a standardized agar test
• Gram-negative bacteria method 3, 4. The MIC values obtained should be
Citrobacter diversus interpreted according to the criteria provided in Table 5.
Citrobacter freundii
Providencia species (including Providencia rettgeri)
Salmonella species (including Salmonella typhi )
Shigella species

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Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

Table 5. Susceptibility Test Interpretive Criteria for Ceftriaxone. 17, 18

Pathogen Minimum Inhibitory Concentrations (mcg/ml) Disk Diffusion Zone Diameters (mm)
(S) (I) (R) (S) (I) (R)
Susceptible Intermediate Resistant Susceptible Intermediate Resistant
Enterobacteriaceae ≤1 2 ≥4 ≥23 20 to 22 ≤19
Haemophilus ≤2 - - ≥26 - -
influenzae*
Neisseria gonorrhoeae* ≤ 0.25 - - ≥ 35 - -
Neisseria meningitidis* ≤ 0.12 - - ≥ 34 - -
Streptococcus ≤ 0.5 1 ≥2 - - -
pneumoniae†
meningitis isolates
Streptococcus ≤1 2 ≥4 - - -
pneumoniae† nonmeningitis
isolates
Streptococcus ≤0.5 - - ≥ 24 - -
species betahemolytic
group*
Viridans group ≤1 2 ≥4 ≥27 25 to 26 ≤24
Streptococci
Anaerobic bacteria ≤16 32 ≥64 - - -
(agar method)
Susceptibility of staphylococci to ceftriaxone may be deduced from testing only penicillin and either cefoxitin or oxacillin.
* The current absence of data on resistant isolates precludes defining any category other than ‘Susceptible’. If isolates yield MIC results other
than susceptible, they should be submitted to a reference laboratory for additional testing.
† 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.

Quality Control: performing the test 1,2,3,4. Standard ceftriaxone powder

Standardized susceptibility test procedures require the should provide the following range of MIC values noted
use of laboratory controls to monitor and ensure the in Table 6. For the diffusion technique using the 30 mcg
accuracy and precision of supplies and reagents used in disk, the criteria in Table 6 should be achieved.
the assay, and the techniques of the individual

Table 6. Acceptable Quality Control Ranges for Ceftriaxone 19

QC Strain Minimum Inhibitory Concentrations Disk Diffusion Zone diameters
(mcg/mL) (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 ---------

INDICATIONS AND USAGE: caused by susceptible bacteria. When culture and

Before instituting treatment with ceftriaxone, appropriate
specimens should be obtained for isolation of the
causative organism and for determination of its
susceptibility to the drug. Therapy may be instituted
prior to obtaining results of susceptibility testing. To
reduce the development of drug-resistant bacteria and
maintain the effectiveness of ceftriaxone for injection,
USP and other antibacterial drugs, ceftriaxone for
injection, USP should be used only to treat or prevent
infections that are proven or strongly suspected to be
39
susceptibility information are available, they should be
considered in selecting or modifying antibacterial
therapy 20. In the absence of such data, local
epidemiology and susceptibility patterns may contribute
to the empiric selection of therapy. Ceftriaxone for
injection, USP is indicated for the treatment of the
following infections when caused by susceptible
organisms:
Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

Lower Respiratory Tract Infections: Caused by Proteus mirabilis, Klebsiella pneumoniae or

Streptococcus pneumoniae, Staphylococcus aureus, Enterobacter species.
Haemophilus influenzae, Haemophilus parainfluenzae,
Klebsiella pneumoniae, Escherichia coli, Enterobacter Intra-abdominal Infections: Caused by Escherichia
aerogenes, Proteus mirabilis or Serratia marcescens. coli, Klebsiella pneumoniae, Bacteroides fragilis,
Clostridium species (Note: most strains of Clostridium
Acute Bacterial Otitis Media: Caused by Streptococcus difficile are resistant) or Peptostreptococcus species. 24
pneumoniae, Haemophilus influenzae (including beta-
lactamase producing strains) or Moraxella catarrhalis Meningitis: Caused by Haemophilus influenzae,
(including beta-lactamase producing strains). NOTE: In Neisseria meningitidis or Streptococcus pneumoniae.
one study lower clinical cure rates were observed with a Ceftriaxone has also been used successfully in a limited
single dose of ceftriaxone compared to 10 days of oral number of cases of meningitis and shunt infection caused
therapy. In a second study comparable cure rates were by Staphylococcus epidermidis* and Escherichia coli.*
observed between single dose ceftriaxone and the
comparator. The potentially lower clinical cure rate of Surgical Prophylaxis: The preoperative administration
ceftriaxone should be balanced against the potential of a single 1 gm dose of ceftriaxone may reduce the
advantages of parenteral therapy. 21 incidence of postoperative infections in patients
undergoing surgical procedures classified as
Skin and Skin Structure Infections: Caused by contaminated or potentially contaminated (e.g., vaginal
Staphylococcus aureus, Staphylococcus epidermidis, or abdominal hysterectomy or cholecystectomy for
Streptococcus pyogenes, Viridans group streptococci, chronic calculous cholecystitis in high-risk patients, such
Escherichia coli, Enterobacter cloacae, Klebsiella as those over 70 years of age, with acute cholecystitis
oxytoca, Klebsiella pneumoniae, Proteus mirabilis, not requiring therapeutic antimicrobials, obstructive
Morganella morganii,* Pseudomonas aeruginosa, jaundice or common duct bile stones) and in surgical
Serratia marcescens, Acinetobacter calcoaceticus, patients for whom infection at the operative site would
Bacteroides fragilis* or Peptostreptococcus species. present serious risk (e.g., during coronary artery bypass
surgery) 25. Although ceftriaxone has been shown to
Urinary Tract Infections (complicated and have been as effective as cefazolin in the prevention of
uncomplicated): Caused by Escherichia coli, Proteus infection following coronary artery bypass surgery, no
mirabilis, Proteus vulgaris, Morganella morganii or placebo controlled trials have been conducted to evaluate
Klebsiella pneumoniae. 22 any cephalosporin antibiotic in the prevention of
infection following coronary artery bypass surgery.
Uncomplicated Gonorrhea (cervical/urethral and When administered prior to surgical procedures for
rectal): Caused by Neisseria gonorrhoeae, including which it is indicated, a single 1 gm dose of ceftriaxone
both penicillinase- and nonpenicillinase- producing provides protection from most infections due to
strains, and pharyngeal gonorrhea caused by susceptible organisms throughout the course of the
nonpenicillinase-producing strains of Neisseria procedure.
gonorrhoeae.
* Efficacy for this organism in this organ system was
Pelvic Inflammatory Disease: Caused by Neisseria studied in fewer than ten infections.
gonorrhoeae. Ceftriaxone sodium, like other
cephalosporins, has no activity against Chlamydia CONTRAINDICATIONS: 26, 27
trachomatis. Therefore, when cephalosporins are used in Ceftriaxone for injection is contraindicated in patients
the treatment of patients with pelvic inflammatory with known allergy to the cephalosporin class of
disease and Chlamydia trachomatis is one of the antibiotics.
suspected pathogens, appropriate antichlamydial
coverage should be added. 23 Neonates (≤28 days): Hyperbilirubinemic neonates,
especially prematures, should not be treated with
Bacterial Septicemia: Caused by Staphylococcus ceftriaxone for injection. In vitro studies have shown that
aureus, Streptococcus pneumoniae, Escherichia coli, ceftriaxone can displace bilirubin from its binding to
Haemophilus influenzae or Klebsiella pneumoniae. serum albumin, leading to a possible risk of bilirubin
encephalopathy in these patients.
Bone and Joint Infections: Caused by Staphylococcus
aureus, Streptococcus pneumoniae, Escherichia coli,

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Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

Ceftriaxone is contraindicated in neonates if they require
(or are expected to require) treatment with calcium-
containing IV solutions, including continuous calcium-
containing infusions such as parenteral nutrition because
of the risk of precipitation of ceftriaxone-calcium.
thoroughly flushed between infusions with a compatible
fluid. In vitro studies using adult and neonatal plasma
from umbilical cord blood demonstrated that neonates
have an increased risk of precipitation of ceftriaxone-
calcium.

A small number of cases of fatal outcomes in which a Clostridium difficile:

crystalline material was observed in the lungs and Clostridium difficile associated diarrhea (CDAD) has
kidneys at autopsy have been reported in neonates been reported with use of nearly all antibacterial agents,
receiving ceftriaxone and calcium-containing fluids. In including ceftriaxone, and may range in severity from
some of these cases, the same intravenous infusion line mild diarrhea to fatal colitis. Treatment with antibacterial
was used for both ceftriaxone and calcium-containing agents alters the normal flora of the colon leading to
fluids and in some a precipitate was observed in the overgrowth of C. difficile.
intravenous infusion line. At least one fatality has been
reported in a neonate in whom ceftriaxone and calcium- C. difficile produces toxins A and B which contribute to
containing fluids were administered at different time the development of CDAD. Hypertoxin producing
points via different intravenous lines; no crystalline strains of C. difficile cause increased morbidity and
material was observed at autopsy in this neonate. There mortality, as these infections can be refractory to
have been no similar reports in patients other than antimicrobial therapy and may require colectomy.
neonates. CDAD must be considered in all patients who present
with diarrhea following antibiotic use. Careful medical
WARNINGS: 28 history is necessary since CDAD has been reported to
Hypersensitivity: occur over two months after the administration of
Before therapy with ceftriaxone is instituted, careful antibacterial agents. 29
inquiry should be made to determine whether the patient
has had previous hypersensitivity reactions to If CDAD is suspected or confirmed, ongoing antibiotic
cephalosporins, penicillins or other drugs. This product use not directed against C. difficile may need to be
should be given cautiously To Penicillin-Sensitive discontinued. Appropriate fluid and electrolyte
Patients. management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should
Antibiotics should be administered with caution to any be instituted as clinically indicated.
patient w who has demonstrated some form of allergy,
particularly to drugs. Serious acute hypersensitivity Hemolytic Anemia:
reactions may require the use of subcutaneous An immune mediated hemolytic anemia has been
epinephrine and other emergency measures. observed in patients receiving cephalosporin class
antibacterials including ceftriaxone. Severe cases of
As with other cephalosporins, anaphylactic reactions hemolytic anemia, including fatalities, have been
with fatal outcome have been reported, even if a patient reported during treatment in both adults and children. If
is not known to be allergic or previously exposed. a patient develops anemia while on ceftriaxone, the
diagnosis of a cephalosporin associated anemia should
Interaction with Calcium-Containing Products: be considered and ceftriaxone stopped until the etiology
Do not use diluents containing calcium, such as Ringer’s is determined.
solution or Hartmann’s solution, to reconstitute
ceftriaxone vials or to further dilute a reconstituted vial PRECAUTIONS:
for IV administration because a precipitate can form. General:
Precipitation of ceftriaxone-calcium can also occur when Prescribing ceftriaxone for injection in the absence of a
ceftriaxone is mixed with calcium-containing solutions proven or strongly suspected bacterial infection or a
in the same IV administration line. Ceftriaxone must not prophylactic indication is unlikely to provide benefit to
be administered simultaneously with calcium-containing the patient and increases the risk of the development of
IV solutions, including continuous calcium-containing drug-resistant bacteria. Although transient elevations of
infusions such as parenteral nutrition via a Y-site. BUN and serum creatinine have been observed, at the
recommended dosages, the nephrotoxic potential of
However, in patients other than neonates, ceftriaxone ceftriaxone is similar to that of other cephalosporins.
and calcium-containing solutions may be administered Ceftriaxone is excreted via both biliary and renal
sequentially of one another if the infusion lines are excretion. Therefore, patients with renal failure normally

41
Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

require no adjustment in dosage when usual doses of should be taken exactly as directed. Skipping doses or
ceftriaxone are administered. 30 not completing the full course of therapy may (1)
decrease the effectiveness of the immediate treatment
Dosage adjustments should not be necessary in patients and (2) increase the likelihood that bacteria will develop
with hepatic dysfunction; however, in patients with both resistance and will not be treatable by ceftriaxone for
hepatic dysfunction and significant renal disease, caution injection or other antibacterial drugs in the future.
should be exercised and the ceftriaxone dosage should Diarrhea is a common problem caused by antibiotics
not exceed 2 gm daily. Alterations in prothrombin times which usually ends when the antibiotic is discontinued.
have occurred rarely in patients treated with ceftriaxone. Sometimes after starting treatment with antibiotics,
Patients with impaired vitamin K synthesis or low patients can develop watery and bloody stools (with or
vitamin K stores (e.g., chronic hepatic disease and without stomach cramps and fever) even as late as two or
malnutrition) may require monitoring of prothrombin more months after having taken the last dose of the
time during ceftriaxone treatment. Vitamin K antibiotic. If this occurs, patients should contact their
administration (10 mg weekly) may be necessary if the physician as soon as possible. 33
prothrombin time is prolonged before or during therapy.
Prolonged use of ceftriaxone may result in overgrowth of Carcinogenesis, Mutagenesis, Impairment of
nonsusceptible organisms. Careful observation of the Fertility:
patient is essential. If superinfection occurs during Carcinogenesis: Considering the maximum duration of
therapy, appropriate measures should be taken. treatment and the class of the compound, carcinogenicity
studies with ceftriaxone in animals have not been
Ceftriaxone for injection should be prescribed with performed. The maximum duration of animal toxicity
caution in individuals with a history of gastrointestinal studies was 6 months. 34
disease, especially colitis. There have been reports of
sonographic abnormalities in the gallbladder of patients Mutagenesis: Genetic toxicology tests included the
treated with ceftriaxone; some of these patients alsohad Ames test, a micronucleus test and a test for
symptoms of gallbladder disease. These abnormalities chromosomal aberrations in human lymphocytes
appear on sonography as an echo without acoustical cultured in vitro with ceftriaxone. Ceftriaxone showed
shadowing suggesting sludge or as an echo with no potential for mutagenic activity in these studies. 35
acoustical shadowing which may be misinterpreted as
gallstones.31 The chemical nature of the sonographically Impairment of Fertility: Ceftriaxone produced no
detected material has been determined to be impairment of fertility when given intravenously to rats
predominantly a ceftriaxone-calcium salt. The condition at daily doses up to 586 mg/kg/day, approximately 20
appears to be transient and reversible upon times the recommended clinical dose of 2 gm/day. 36
discontinuation of ceftriaxone for injection and
institution of conservative management. Pregnancy: 37, 38
Teratogenic Effects: Pregnancy Category B:
Therefore, ceftriaxone should be discontinued in patients Reproductive studies have been performed in mice and
who develop signs and symptoms suggestive of rats at doses up to 20 times the usual human dose and
gallbladder disease and/or the sonographic findings have no evidence of embryotoxicity, fetotoxicity or
described above. Cases of pancreatitis, possibly teratogenicity. In primates, no embryotoxicity or
secondary to biliary obstruction, have been reported teratogenicity was demonstrated at a dose approximately
rarely in patients treated with ceftriaxone. Most patients 3 times the human dose. There are, however, no
presented with risk factors for biliary stasis and biliary adequate and well-controlled studies in pregnant women.
sludge (preceding major therapy, severe illness, and total Because animal reproductive studies are not always
parenteral nutrition). A cofactor role of ceftriaxone- predictive of human response, this drug should be used
related biliary precipitation cannot be ruled out.32 during pregnancy only if clearly needed.

Information for Patients: Nonteratogenic Effects: In rats, in the Segment I

Patients should be counseled that antibacterial drugs
including ceftriaxone for injection should only be used to
treat bacterial infections. They do not treat viral
infections (e.g., the common cold). When ceftriaxone for
injection is prescribed to treat a bacterial infection,
patients should be told that although it is common to feel
better early in the course of therapy, the medication
(fertility and general reproduction) and Segment III
(perinatal and postnatal) studies with intravenously
administered ceftriaxone, no adverse effects were noted
on various reproductive parameters during gestation and
lactation, including postnatal growth, functional
behavior and reproductive ability of the offspring, at
doses of 586 mg/kg/day or less.

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Nursing Mothers: Low concentrations of ceftriaxone Hepatic: Elevations of SGOT (3.1%) or SGPT (3.3%).
are excreted in human milk. Caution should be exercised Less frequently reported (<1%) were elevations of
when ceftriaxone is administered to a nursing woman. alkaline phosphatase and bilirubin.

Pediatric Use: Safety and effectiveness of ceftriaxone in
neonates, infants and pediatric patients have been
established for the dosages described in the DOSAGE
AND ADMINISTRATION section. In vitro studies
have shown that ceftriaxone, like some other
cephalosporins, can displace bilirubin from serum
albumin. Ceftriaxone should not be administered to
hyperbilirubinemic neonates, especially prematures (see
CONTRAINDICATIONS).
Renal: Elevations of the BUN (1.2%). Less frequently
reported (<1%) were elevations of creatinine and the
presence of casts in the urine.
Central Nervous System: Headache or dizziness were
reported occasionally (<1%).
Genitourinary: Moniliasis or vaginitis were reported
occasionally (<1%).

Geriatric Use: Of the total number of subjects in Miscellaneous: Diaphoresis and flushing were reported
clinical studies of ceftriaxone, 32% were 60 and over. occasionally (<1%). Other rarely observed adverse
No overall differences in safety or effectiveness were reactions (<0.1%) include abdominal pain,
observed between these subjects and younger subjects, agranulocytosis, allergic pneumonitis, anaphylaxis,
and other reported clinical experience has not identified basophilia, biliary lithiasis, bronchospasm, colitis,
differences in responses between the elderly and younger dyspepsia, epistaxis, flatulence, gallbladder sludge,
patients, but greater sensitivity of some older individuals glycosuria, hematuria, jaundice, leukocytosis,
cannot be ruled out. The pharmacokinetics of ceftriaxone lymphocytosis, monocytosis, nephrolithiasis,
were only minimally altered in geriatric patients palpitations, a decrease in the prothrombin time, renal
compared to healthy adult subjects and dosage precipitations, seizures, and serum sickness.
adjustments are not necessary for geriatric patients with
ceftriaxone dosages up to 2 grams per day. Postmarketing Experience: In addition to the adverse
reactions reported during clinical trials, the following
ADVERSE REACTIONS:39, 40 adverse experiences have been reported during clinical
Ceftriaxone is generally well tolerated. In clinical trials, practice in patients treated with ceftriaxone. Data are
the following adverse reactions, which were considered generally insufficient to allow an estimate of incidence
to be related to ceftriaxone therapy or of uncertain or to establish causation. A small number of cases of
etiology, were observed: fatal outcomes in which a crystalline material was
observed in the lungs and kidneys at autopsy have been
Local Reactions: Pain, induration and tenderness was reported in neonates receiving ceftriaxone and calcium-
1% overall. Phlebitis was reported in <1% after IV containing fluids.
administration. The incidence of warmth, tightness or In some of these cases, the same intravenous infusion
induration was 17% (3/17) after IM administration of line was used for both ceftriaxone and calcium-
350 mg/mL and 5% (1/20) after IM administration of containing fluids and in some a precipitate was observed
250 mg/mL. in the intravenous infusion line. At least one fatality has
been reported in a neonate in whom ceftriaxone and
Hypersensitivity: Rash (1.7%). Less frequently reported calcium-containing fluids were administered at different
(<1%) were pruritus, fever or chills. time points via different intravenous lines; no crystalline
material was observed at autopsy in this neonate. There
Hematologic: Eosinophilia (6%), thrombocytosis (5.1%) have been no similar reports in patients other than
and leukopenia (2.1%). Less frequently reported (<1%) neonates.
were anemia, hemolytic anemia, neutropenia,
lymphopenia, thrombocytopenia and prolongation of the Gastrointestinal: Stomatitis and glossitis.
prothrombin time.
Genitourinary: Oliguria.
Gastrointestinal: Diarrhea (2.7%). Less frequently
reported (<1%) were nausea or vomiting, and dysgeusia. Dermatologic: Exanthema, allergic dermatitis, urticaria,
The onset of pseudomembranous colitis symptoms may edema. As with many medications, isolated cases of
occur during or after antibacterial treatment. severe cutaneous adverse reactions (erythema
multiforme, Stevens-Johnson syndrome or Lyell’s

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syndrome/toxic epidermal necrolysis) have

been Neonates: Hyperbilirubinemic neonates, especially
reported. prematures, should not be treated with ceftriaxone for
injection. Ceftriaxone is contraindicated in neonates if
Cephalosporin Class Adverse Reactions: In addition to they require (or are expected to require) treatment with
the adverse reactions listed above which have been calcium-containing IV solutions, including continuous
observed in patients treated with ceftriaxone, the calcium-containing infusions such as parenteral nutrition
following adverse reactions and altered laboratory test because of the risk of precipitation of ceftriaxone-
results have been reported for cephalosporin class calcium.
antibiotics:
Pediatric Patients: For the treatment of skin and skin
Adverse Reactions: Allergic reactions, drug fever, serum structure infections, the recommended total daily dose is
sickness-like reaction, renal dysfunction, toxic 50 to 75 mg/kg given once a day (or in equally divided
nephropathy, reversible hyperactivity, hypertonia, doses twice a day). The total daily dose should not
hepatic dysfunction including cholestasis, aplastic exceed 2 grams. For the treatment of acute bacterial
anemia, hemorrhage, and superinfection. otitis media, a single intramuscular dose of 50 mg/kg
(not to exceed 1 gram) is recommended.
Altered Laboratory Tests: Positive direct Coombs’ test, For the treatment of serious miscellaneous infections
false-positive test for urinary glucose, and elevated other than meningitis, the recommended total daily dose
LDH. Several cephalosporins have been implicated in is 50 to 75 mg/kg, given in divided doses every 12 hours.
triggering seizures, particularly in patients with renal The total daily dose should not exceed 2 grams. In the
impairment when the dosage was not reduced. If seizures treatment of meningitis, it is recommended that the
associated with drug therapy occur, the drug should be initial therapeutic dose be 100 mg/kg (not to exceed 4
discontinued. Anticonvulsant therapy can be given if grams). Thereafter, a total daily dose of 100 mg/kg/day
clinically indicated. (not to exceed 4 grams daily) is recommended. The daily
dose may be administered once a day (or in equally
OVERDOSAGE: In the case of overdosage, drug divided doses every 12 hours). The usual duration of
concentration would not be reduced by hemodialysis or therapy is 7 to 14 days.
peritoneal dialysis. There is no specific antidote.
Treatment of overdosage should be symptomatic.41 Adults: The usual adult daily dose is 1 to 2 grams given
once a day (or in equally divided doses twice a day)
DOSAGE AND ADMINISTRATION: 42 depending on the type and severity of infection. For
Ceftriaxone may be administered intravenously or infections caused by Staphylococcus aureus (MSSA),
intramuscularly. Do not use diluents containing calcium, the recommended daily dose is 2 to 4 grams, in order to
such as Ringer’s solution or Hartmann’s solution, to achieve >90% target attainment. The total daily dose
reconstitute ceftriaxone vials or to further dilute a should not exceed 4 grams. If Chlamydia trachomatis is
reconstituted vial for IV administration because a a suspected pathogen, appropriate anti chlamydial
precipitate can form. Precipitation of ceftriaxone- coverage should be added, because ceftriaxone sodium
calcium can also occur when ceftriaxone is mixed with has no activity against this organism.
calcium-containing solutions in the same IV
administration line. Ceftriaxone must not be For the treatment of uncomplicated gonococcal
administered simultaneously with calcium-containing IV infections, a single intramuscular dose of 250 mg is
solutions, including continuous calcium-containing recommended. For preoperative use (surgical
infusions such as parenteral nutrition via a Y-site. prophylaxis), a single dose of 1 gram administered
intravenously 1/2 to 2 hours before surgery is
However, in patients other than neonates, ceftriaxone recommended. Generally, ceftriaxone therapy should be
and calcium-containing solutions may be administered continued for at least 2 days after the signs and
sequentially of one another if the infusion lines are symptoms of infection have disappeared. The usual
thoroughly flushed between infusions with a compatible duration of therapy is 4 to 14 days; in complicated
fluid. There have been no reports of an interaction infections, longer therapy may be required. When
between ceftriaxone and oral calcium-containing treating infections caused by Streptococcus pyogenes,
products or interaction between intramuscular therapy should be continued for at least 10 days. No
ceftriaxone and calcium-containing products (IV or dosage adjustment is necessary for patients with
oral). impairment of renal or hepatic function.

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Directions for Use: 43 aminoglycosides, and fluconazole are physically

Intramuscular Administration: Reconstitute ceftriaxone incompatible with ceftriaxone in admixtures. When any
sodium powder with the appropriate diluent. Inject of these drugs are to be administered concomitantly with
diluent into vial, shake vial thoroughly to form solution. ceftriaxone by intermittent intravenous infusion, it is
Withdraw entire contents of vial into syringe to equal recommended that they be given sequentially, with
total labeled dose. After reconstitution, each 1 mL of thorough flushing of the intravenous lines (with one of
solution contains approximately 250 mg or 350 mg the compatible fluids) between the administrations.
equivalent of ceftriaxone according to the amount of
diluent indicated below. If required, more dilute Do not use diluents containing calcium, such as Ringer’s
solutions could be utilized. A 350 mg/mL concentration solution or Hartmann’s solution, to reconstitute
is not recommended for the 250 mg vial since it may not ceftriaxone for injection or to further dilute a
be possible to withdraw the entire contents. As with all reconstituted vial for IV administration. Particulate
intramuscular preparations, ceftriaxone should be formation can result. Ceftriaxone for injection solutions
injected well within the body of a relatively large should not be physically mixed with or piggybacked into
muscle; aspiration helps to avoid unintentional injection solutions containing other antimicrobial drugs or into
into a blood vessel. diluent solutions other than those listed above, due to
possible incompatibility.
Table 7: Amount of diluents to be added
Vial Dosage Size Amount of Diluent to be Added Ceftriaxone sodium sterile powder should be stored at
250 mg/mL 350 mg/mL
250 mg 0.9 mL -
20° to 25°C (68° to 77°F) [see USP Controlled Room
500 mg 1.8 mL 1 mL Temperature] and protected from light. After
1 gm 3.6 mL 2.1 mL reconstitution, protection from normal light is not
2 gm 7.2 mL 4.2 mL necessary. The color of solutions ranges from light
yellow to amber, depending on the length of storage,
Intravenous Administration: concentration and diluent used. Ceftriaxone
Ceftriaxone should be administered intravenously by intramuscular solutions remain stable (loss of potency
infusion over a period of 30 minutes. Concentrations less than 10%) for the following time periods:
between 10 mg/mL and 40 mg/mL are recommended;
however, lower concentrations may be used if desired. Table 9: Storage of Diluent
Reconstitute vials with an appropriate IV diluent. Diluent Concentration Storage
mg/mL Room Refrigerated
Temp. (4°C)
Table 8: Amount of diluents to be added
(25°C)
Vial Dosage Size Amount of Diluent to be
Sterile Water for 100 2 days 10 days
Added
Injection 250, 350 24 hours 3 days
250 mg 2.5 mL
0.9% Sodium 100 2 days 10 days
500 mg 4.8 mL Chloride 250, 350 24 hours 3 days
1 gm 9.6 mL Solution
2 gm 19.2 mL 5% Dextrose 100 2 days 10 days
Solution 250, 350 24 hours 3 days
After reconstitution, each 1 mL of solution contains Bacteriostatic 100 24 hours 10 days
approximately 100 mg equivalent of ceftriaxone. Water + 250, 350 24 hours 3 days
Withdraw entire contents and dilute to the desired 0.9% Benzyl
Alcohol
concentration with the appropriate IV diluent. 1% Lidocaine 100 24 hours 10 days
Solution 250, 350 24 hours 3 days
Compatibility and Stability: 44 (without
Ceftriaxone has been shown to be compatible with Flagy epinephrine)
IV (metronidazole hydrochloride). The concentration
should not exceed 5 to 7.5 mg/mL metronidazole
hydrochloride with ceftriaxone 10 mg/mL as an
admixture. The admixture is stable for 24 hours at room Ceftriaxone intravenous solutions, at concentrations of
temperature only in 0.9% sodium chloride injection or 10, 20 and 40 mg/mL, remain stable (loss of potency less
5% dextrose in water (D5W). No compatibility studies than 10%) for the following time periods stored in glass
have been conducted with the Flagy IV RTUR or PVC containers:
(metronidazole) formulation or using other diluents.
Metronidazole at concentrations greater than 8 mg/mL
will precipitate. Do not refrigerate the admixture as
precipitation will occur. Vancomycin, amsacrine,
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Asian J. Pharm. Res. 2017; Vol. 7: Issue 1 [AJPRes.]

Table 10: Storage of Diluent in Glass or PVC containers Vials containing 2 gm equivalent to ceftriaxone. Package
Diluent Storage of 10.
Room Temp. Refrigerated
(25°C) (4°C)
Vials containing 250 mg equivalent to ceftriaxone.
Sterile Water 2 days 10 days Package of 1.
0.9% Sodium 2 days 10 days Vials containing 500 mg equivalent to ceftriaxone.
Chloride Solution Package of 1.
5% Dextrose Solution 2 days 10 days Vials containing 1 gm equivalent to ceftriaxone. Package
10% Dextrose Solution 2 days 10 days
5% Dextrose + 0.9% 2 days Incompatible
of 1.
Sodium Chloride
Solution* Storage Prior to Reconstitution:
5% Dextrose + 0.45% 2 days Incompatible Store at 20° to 25°C (68° to 77°F) [see USP Controlled
Sodium Chloride
Solution
Room Temperature]. Protect from light.
* Data available for 10 to 40 mg/mL concentrations in this diluent in
PVC containers only.
CLINICAL STUDIES: 45
HOW SUPPLIED: Clinical Trials in Pediatric Patients with Acute
Ceftriaxone for injection, USP is supplied as a sterile Bacterial Otitis Media:
crystalline powder in glass vials. The following packages In two adequate and well-controlled US clinical trials a
are available: single IM dose of ceftriaxone was compared with a 10
Vials containing 250 mg equivalent to ceftriaxone. day course of oral antibiotic in pediatric patients between
Package of 10. the ages of 3 months and 6 years. The clinical cure rates
Vials containing 500 mg equivalent to ceftriaxone. and statistical outcome appear in the table below:
Package of 10.
Vials containing 1 gm equivalent to ceftriaxone. Package
of 10.

Table 11: Clinical Efficacy in Evaluable Population

Study Day Ceftriaxone Comparator- 95% Statistical
Single Dose 10 Days of Confidence Outcome
Oral Therapy Interval
Study 1– US amoxicillin/ clavulanate Ceftriaxone is lower
14 74% 82% (-14.4%, than control at study day
(220/296) (247/302) -0.5%) 14 And 28.
28 58% 67% (-17.5%,
(167/288) (200/297) -1.2%)
Study 2 – US5 TMP-SMZ Ceftriaxone is
14 54% 60% (-16.4%, equivalent to control at
(113/210) (124/206) 3.6%) study day 14 And 28.
28 35% 45% (-19.9%,
(73/206) (93/205) 0.0%)

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

Table 12: Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by Pathogen
Organism Study Day Study Day
13 to 15 30+2
No. No. Erad. No. No. Erad.
Analyzed (%) Analyzed (%)
Streptococcus pneumonia 38 32 (84) 35 25 (71)
Haemophilus influenza 33 28 (85) 31 22 (71)
Moraxella catarrhalis 15 12 (80) 15 9 (60)

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Asian J. Pharm. Res. 2017; Vol. 7: Issue 1
CONCLUSION:
Ceftriaxone is recognized as a ‘traditional’ antibiotic,
similar to PCG. Indeed, the development of new
antibiotics is decelerating, but the spread of multi-drug-
resistant pathogens has accelerated throughout the world
over the past decade. Although new fifth-generations of
cephalosporins, such as ceftaroline are now available, 20
ceftriaxone continues to have an important place in the
treatment of many infectious diseases. Of note,
ceftriaxone is becoming a first-line alternative regimen
for the treatment of streptococcal endocarditis. The
reappraisal of ‘traditional antibiotics’, such as
ceftriaxone, has triggered a review of adequate antibiotic
treatment. In addition, the use of them requires no
developmental costs and no clinical experiments. No
new adverse events will be observed. Such topics of
study can be considered as ‘antibiotic-ecology.’ 46
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