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Ceftriaxone: Adverse Reactions

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Ceftriaxone
The following is a brief summary CefTRIaxONE for Injection and Dextrose Injection

Rx only
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftriaxone for Injection and Dextrose Injection and other antibacterial drugs, Ceftriaxone for Injection and Dextrose Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION
Ceftriaxone for Injection and Dextrose Injection is a sterile, nonpyrogenic, single use, packaged combination of Ceftriaxone Sodium and
Dextrose Injection (diluent) in the DUPLEX sterile container. The DUPLEX Container is a flexible dual chamber container. The drug chamber is filled with ceftriaxone sodium, a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous
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.

Ceftriaxone Sodium has the following structural formula:
The chemical formula of ceftriaxone sodium is C18H16N8Na2O7S3•3.5H2O,
representing a molecular weight of 661.60.
Ceftriaxone Sodium is supplied as a dry powder form equivalent to either 1 g or 2 g of ceftriaxone. 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 and concentration.

Ceftriaxone Sodium contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity.
The diluent chamber contains Dextrose Injection. The concentration of Hydrous Dextrose in Water for Injection USP has been adjusted to
render the reconstituted drug product iso-osmotic. Dextrose USP has been added to adjust osmolality (approximately 1.87 g and 1.11 g to 1 g
and 2 g dosages, respectively). Dextrose Injection is sterile, nonpyrogenic, and contains no bacteriostatic or antimicrobial agents.
Hydrous Dextrose USP has the following structural (molecular) formula:
The molecular weight of Hydrous Dextrose USP is 198.17.
After removing the peelable foil strip, activating the seals, and thoroughly mixing, the reconstituted drug product is intended for single
intravenous use. When reconstituted, the approximate osmolality for the reconstituted solution for Ceftriaxone for Injection and Dextrose
Injection is 290 mOsmol/kg.

The DUPLEX Container is Latex-free, PVC-free, and DEHP-free.
The DUPLEX dual chamber container is made from a specially formulated material. The product (diluent and drug) contact layer is a mixture
of thermoplastic rubber and a polypropylene ethylene copolymer that contains no plasticizers. The safety of the container system is supported
by USP biological evaluation procedures.
INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftriaxone for Injection and Dextrose Injection and
other antibacterial drugs, Ceftriaxone for Injection and Dextrose Injection should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered
in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to
the empiric selection of therapy.

Ceftriaxone for Injection and Dextrose Injection is indicated for the treatment of the following infections when caused by susceptible
organisms:

LOWER RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae,
Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.
SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes,
Viridans group streptococci, Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella
morganii*, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis* or Peptostreptococcus species.
URINARY TRACT INFECTIONS (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella
morganii or Klebsiella pneumoniae.

PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae. Ceftriaxone Sodium, like other cephalosporins, has no activity
against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and
Chlamydia trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added.
BACTERIAL SEPTICEMIA caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or
Klebsiella pneumoniae.

BONE AND JOINT INFECTIONS caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis,
Klebsiella pneumoniae or Enterobacter species.

INTRA-ABDOMINAL INFECTIONS caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most
strains of Clostridium difficile are resistant) or Peptostreptococcus species.
MENINGITIS caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae. Ceftriaxone Sodium has also been
used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis* and Escherichia coli.*
*Efficacy for this organism in this organ system was studied in fewer than ten infections.

SURGICAL PROPHYLAXIS: The preoperative administration of a single 1 g dose of Ceftriaxone for Injection and Dextrose Injection may
reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially
contaminated (e.g., vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous cholecystitis in high-risk patients, such as
those over 70 years of age, with acute cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common duct bile stones)
and in surgical patients for whom infection at the operative site would present serious risk (e.g., during coronary artery bypass surgery).
Although Ceftriaxone Sodium has been shown to have been as effective as cefazolin in the prevention of infection following coronary artery
bypass surgery, no placebo-controlled trials have been conducted to evaluate any cephalosporin antibiotic in the prevention of infection
following coronary artery bypass surgery.

When administered prior to surgical procedures for which it is indicated, a single 1 g dose of Ceftriaxone for Injection and Dextrose
Injection provides protection from most infections due to susceptible organisms throughout the course of the procedure.
Before instituting treatment with Ceftriaxone for Injection and Dextrose Injection, 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.

CONTRAINDICATIONS

Ceftriaxone for Injection and Dextrose Injection is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.
Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn products.

WARNINGS

BEFORE THERAPY WITH CEFTRIAXONE FOR INJECTION AND DEXTROSE INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF
ALLERGY, PARTICULARLY TO DRUGS. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE THE USE OF SUBCUTANEOUS EPINEPHRINE AND OTHER EMERGENCY MEASURES.


Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftriaxone, and may range in severity
from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent
to the administration of antibacterial agents.


Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a
toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis". After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

PRECAUTIONS


General
Prescribing Ceftriaxone for Injection and Dextrose Injection in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Although transient elevations of BUN and serum creatinine have been observed, at the recommended dosages, the nephrotoxic
potential of Ceftriaxone Sodium is similar to that of other cephalosporins.
Ceftriaxone is excreted via both biliary and renal excretion (see CLINICAL PHARMACOLOGY). Therefore, patients with renal failure normally
require no adjustment in dosage when usual doses of Ceftriaxone for Injection and Dextrose Injection are administered, but concentrations of
drug in the serum should be monitored periodically. If evidence of accumulation exists, dosage should be decreased accordingly.
Dosage adjustments should not be necessary in patients with hepatic dysfunction; however, in patients with both hepatic dysfunction and
significant renal disease, Ceftriaxone for Injection and Dextrose Injection dosage should not exceed 2 g daily without close monitoring of
serum concentrations.
Alterations in prothrombin times have occurred rarely in patients treated with Ceftriaxone Sodium. Patients with impaired vitamin K synthesis
or low vitamin K stores (e.g., chronic hepatic disease and malnutrition) may require monitoring of prothrombin time during Ceftriaxone for
Injection and Dextrose Injection treatment. Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged
before or during therapy.
Prolonged use of Ceftriaxone for Injection and Dextrose Injection may result in overgrowth of nonsusceptible organisms. Careful observation
of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Ceftriaxone for Injection and Dextrose Injection should be prescribed with caution in individuals with a history of gastrointestinal disease,
especially colitis.
There have been reports of sonographic abnormalities in the gallbladder of patients treated with Ceftriaxone Sodium; some of
these patients also had symptoms of gallbladder disease. These abnormalities appear on sonography as an echo without acoustical
shadowing suggesting sludge or as an echo with acoustical shadowing which may be misinterpreted as gallstones. The chemical nature of
the sonographically detected material has been determined to be predominantly a ceftriaxone-calcium salt. The condition appears to be
transient and reversible upon discontinuation of Ceftriaxone Sodium and institution of conservative management. Therefore,
Ceftriaxone for Injection and Dextrose Injection should be discontinued in patients who develop signs and symptoms suggestive of
gallbladder disease and/or the sonographic findings described above.
As with other dextrose-containing solutions, Ceftriaxone for Injection and Dextrose Injection should be prescribed with caution in patients
with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason.
If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air
embolism may result.


Use only if solution is clear and container and seals are intact.

Information for Patients

Patients should be counseled that antibacterial drugs including Ceftriaxone for Injection and Dextrose Injection should only be used to treat
bacterial infections. They do not treat viral infections (e.g., the common cold). When Ceftriaxone for Injection and Dextrose 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 should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the
effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by
Ceftriaxone for Injection and Dextrose Injection or other antibacterial drugs in the future.


Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Considering the maximum duration of treatment and the class of the compound, carcinogenicity studies with ceftriaxone in
animals have not been performed. The maximum duration of animal toxicity studies was 6 months.
Mutagenesis: Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human
lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies.
Impairment of Fertility: Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day,
approximately 20 times the recommended clinical dose of 2 g/day.

Pregnancy: Teratogenic Effects:

Pregnancy Category B. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and
have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a
dose approximately 3 times the human dose.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects: In rats, in the Segment I (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.

Nursing Mothers

Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone for Injection and Dextrose
Injection is administered to a nursing woman.
Pediatric Use
Ceftriaxone for Injection and Dextrose Injection in the DUPLEX ®


Container is designed to deliver a 1 g or 2 g dose of ceftriaxone. To prevent
unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of ceftriaxone.
Safety and effectiveness of Ceftriaxone for Injection and Dextrose Injection 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 for Injection and Dextrose Injection should not be administered to
hyperbilirubinemic neonates, especially prematures.


ADVERSE REACTIONS

Ceftriaxone Sodium is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to
Ceftriaxone Sodium therapy or of uncertain etiology, were observed:

LOCAL REACTIONS—Phlebitis was reported in <1% after IV administration.

HYPERSENSITIVITY—rash (1.7%). Less frequently reported (<1%) were pruritus, fever or chills.

HEMATOLOGIC—eosinophilia (6%), thrombocytosis (5.1%) and leukopenia (2.1%). Less frequently reported (<1%) were anemia, hemolytic
anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.

GASTROINTESTINAL—diarrhea (2.7%). Less frequently reported (<1%) were nausea or vomiting, and dysgeusia. The onset of
pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS).

HEPATIC—elevations of SGOT (3.1%) or SGPT (3.3%). Less frequently reported (<1%) were elevations of alkaline phosphatase and bilirubin.

RENAL—elevations of the BUN (1.2%). Less frequently reported (<1%) were elevations ofcreatinine 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%).

MISCELLANEOUS—diaphoresis and flushing were reported occasionally (<1%).

Other rarely observed adverse reactions (<0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia,
biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis,
lymphocytosis, monocytosis, nephrolithiasis, palpitations, a decrease in the prothrombin time, renal precipitations, seizures, and serum
sickness.


OVERDOSAGE

In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote.
Treatment of overdosage should be symptomatic.

Issued: April 2005 (566) DUPLEX ® is a registered trademark of B. Braun Medical Inc.
U.S. Patent Nos. D388,168, D397,789, D402,366, D407,816, 5,944,709, and 6,165,161; additional patents pending.
Made in USA

http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v15n1_e.html#6

Canadian Adverse Reaction Newsletter, Volume 15 . Issue 1 . January 2005
Health Products and Food Branch, Marketed Health Products Directorate

Ceftriaxone (Rocephin) and immune hemolytic anemia in children

Ceftriaxone (Rocephin), marketed in Canada since Dec. 31, 1987, is a third-generation cephalosporin indicated for the treatment of susceptible strains of bacteria, as well as for prophylaxis against infections in patients undergoing hysterectomy, coronary artery bypass surgery or biliary tract surgery.1 Immune hemolytic anemia (IHA) is a hypersensitivity adverse reaction (AR) known to occur in adults and children. The Rocephin product monograph describes autoimmune hemolytic anemia as a rare AR (< 0.1% of cases),1 but does not mention IHA.

Ceftriaxone antibodies appear to be induced by an immune complex mechanism during a sensitization phase after initial exposure to the drug. 2 Intravascular hemolysis may be triggered after subsequent re-exposure. The signs and symptoms of drug-induced IHA include severe hemolytic anemia, hemoglobinuria, hypotension, acute renal failure, fever and back pain.3

From Jan. 1, 1988, to Sept. 15, 2004, Health Canada received 1 report of acute hemolysis suspected of being associated with ceftriaxone. A young child with sickle cell disease had been given a single dose of ceftriaxone (80 mg/kg body weight) intravenously for fever and cough, and within 30 minutes developed a rash, pallor and decreased level of consciousness. Laboratory examination showed a positive direct Coomb's test result, a hemoglobin level of 7 g/L (the pre-infusion level was 110 g/L) and hemolyzed red blood cells. The following day, the patient died despite resuscitation attempts. The only concomitant medication was a single oral dose of erythromycin. The patient had been exposed to ceftriaxone in the past.

Nine pediatric cases of IHA associated with exposure to ceftriaxone were identified in the literature, 6 of which were fatal.4-12One child with sickle cell anemia received ceftriaxone on several occasions and experienced 6 episodes of unexplained transient hemoglobinuria before the onset of the IHA.10

Drug-induced IHA is associated with a high mortality rate.3 Other than supportive care and red blood cell transfusion, there are few effective treatment options. Reintroduction of the drug is contraindicated because of the high risk of recurrence of hemolysis, which is often more severe.3

IHA associated with ceftriaxone is rare and has been reported to occur with repetitive, intermittent use of this drug. Children with underlying conditions such as hemoglobinopathies and immunodeficiencies are likely to require frequent treatment or prophylaxis with ceftriaxone, which may place them at increased risk of IHA. The development of signs and symptoms of IHA, including hemoglobinuria or unexplained anemia, should prompt health care professionals to consider this diagnosis and the discontinuation of the suspect drug.3

Lise Watters, MD, FRCPC; Debra Willcox, BSP, Health Canada

References

1. Rocephin (ceftriaxone) [product monograph]. Mississauga (ON): Hoffman-La Roche Limited; 1997.

2. Arndt PA, Leger RM, Garratty G. Serology of antibodies to second- and third-generation cephalosporins associated with immune hemolytic anemia and/or positive direct antiglobulin tests. Transfusion 1999;39(11-12):1239-46.

3. Solal-Celigny P. Abnormal hematologic values. In: Benichou C, editor. Adverse drug reactions. A practical guide to diagnosis and management. Chichester: John Wiley and Sons Ltd.; 1994. p. 13-30.

4. Mattis LE, Saavedra JM, Shan H, Shirey RS, Powell E, Oliva-Hemker MM. Life-threatenting ceftriaxone-induced immune hemolytic anemia in a child with Crohn's disease. Clin Pediatr (Phila) 2004;43(2):175-8.

5. Citak A, Garratty G, Ucsel R, Karabocuoglu M, Uzel N. Ceftriaxone-induced haemolytic anaemia in a child with no immune deficiency or haematological disease. J Paediatr Child Health 2002;38(2):209-10.

6. Viner Y, Hashkes PJ, Yakubova R, Segal-Kupershmit D, Luder AS. Severe hemolysis induced by ceftriaxone in a child with sickle-cell anemia. Pediatr Infect Dis J 2000;19(1):83-5.

7. Meyer O, Hackstein H, Hoppe B, Gobel FJ, Bein G, Salama A. Fatal immune haemolysis due to a degradation product of ceftriaxone. Br J Haematol 1999;105(4):1084-5.

8. Scimeca PG, Weinblatt ME, Boxer R. Hemolysis after treatment with ceftriaxone. J Pediatr 1996;128(1):163.

9. Moallem HJ, Garratty G, Wakeham M, Dial S, Oligario A, Gondi A, et al. Ceftriaxone-related fatal hemolysis in an adolescent with perinatally acquired human immunodeficiency virus infection. J Pediatr 1998;133(2):279-81.

10. Bernini JC, Mustafa MM, Sutor LJ, Buchanan GR. Fatal hemolysis induced by ceftriaxone in a child with sickle cell anemia. J Pediatr 1995;126(5 Pt 1):813-5.

11. Lascari AD, Amyot K. Fatal hemolysis caused by ceftriaxone. J Pediatr 1995;126(5 Pt 1):816-7.

12. Borgna-Pignatti C, Bezzi TM, Reverberi R. Fatal ceftriaxone-induced hemolysis in a child with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1995;14(12):1116-7.


http://www.docguide.com/news/content.nsf/news/852571020057CCF6852573100075672D
Rocephin (Ceftriaxone Sodium) - Contraindications, Warnings, Precautions, Adverse Reactions, Dosage and Administration Sections of Labeling Revised

BETHESDA, MD -- July 6, 2007 -- Roche and FDA informed healthcare professionals of revisions to the Contraindications, Warnings, Precautions, Adverse Reactions and Dosage and Administration sections of the prescribing information for Rocephin for Injection.

The revisions are based on new information that describes the potential risk associated with concomitant use of Rocephin with calcium or calcium containing solutions or products. Cases of fatal reactions with calcium-ceftriaxone precipitates in the lungs and kidneys in both term and premature neonates were reported. Hyperbilirubinemic neonates, especially prematures, should not be treated with Rocephin.

The drug must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines. Additionally, calcium-containing solutions or products must not be administered within 48-hours of the last administration of ceftriaxone.

SOURCE: U.S. Food and Drug Administration

http://www.medscape.com/viewarticle/513823_3
Am J Health-Syst Pharm. 2005;62(19):2006-2010. ©2005 American Society of Health-System Pharmacists

Overview of Ceftriaxone-Induced Hepatic Panel Abnormalities

Hepatocellular Enzyme Elevations in a Patient Receiving Ceftriaxone

Posted 10/07/2005

Anastasia M. Rivkin
Case Report

A 31-year-old man arrived at the emergency department (ED) with a one-week history of sinus infection, headache, decreased oral intake, and ear pain. He reported taking ibuprofen and pseudoephedrine, with partial relief of his symptoms. On the day of admission, he developed a severe headache, nausea, vomiting, and confusion.

He had no significant past medical history, was physically fit, and reported taking multivitamins and calcium supplements. The patient was also taking bisacodyl and caffeine tablets and drank an energy drink daily. He denied taking hormonal or protein supplements.

The patient reported having penicillin allergy, described as facial hives, and sulfonamide allergy (reaction unknown). Physical examination in the ED revealed a blood pressure of 118/73 mm Hg, a heart rate of 88 beats/min, a respiration rate of 18 breaths/min, a temperature of 101.2 °F, and an oxygen saturation rate of 98% on room air. His neck was not rigid, lungs were clear, and abdominal examination was normal. Neurologic examination revealed extreme agitation and an inability to follow commands.

His white blood cell (WBC) count was 27.5 x 103/mm3, with 92% neutrophils. His other laboratory values (chemistry and hematologic values) were within normal limits. Initial chest radiograph and electrocardiogram were normal. The results of liver function tests on admission were normal, with an albumin concentration of 3.6 g/dL; total bilirubin (TB), 0.6 mg/dL; direct bilirubin (DB), 0.0 mg/dL; alkaline phosphatase (ALP), 68 IU/L; aspartate transaminase (AST), 22 IU/L; alanine transaminase (ALT), 9 IU/L; and total protein, 6 g/dL.

Computed tomography (CT) of the head without a contrast agent demonstrated bilateral maxillary sinus mucosal thickening, suggesting acute sinusitis, with no intracranial hemorrhage or mass effect. Lumbar puncture showed 100 red blood cells, 2400 WBCs with 98% neutrophils, a glucose concentration of 54 mg/dL (serum glucose, 139 mg/dL), and a protein concentration of 272 mg/dL. The direct antigen test for Streptococcus pneumoniae was positive.

Stat doses of vancomycin 1 g i.v., ceftriaxone sodium 2 g i.v., and dexamethasone 10 mg i.v. were given in the ED to treat what was presumed to be meningitis, and the patient was admitted to the medical intensive care unit (ICU). Other medications administered to the patient in the ED included midazolam 4 mg i.v., fentanyl 100 µg i.v., lorazepam 4 mg i.v., and haloperidol 5 mg i.v.

His blood culture was positive for S. pneumoniae susceptible to penicillin and ceftriaxone. A diagnosis of pneumococcal meningitis was made, and the patient continued to receive ceftriaxone sodium 2 g i.v. every 12 hours. Vancomycin was discontinued after sensitivities of the bacterium were reported.

On the second day of his ICU stay, the patient required intubation for desaturation and the inability to clear secretions. A chest radiograph on the same day showed infiltrate in the lower lobe of his right lung. He remained febrile during days 1-4 of his ICU stay.

Other medications administered during hospitalization included metronidazole 500 mg i.v. every 8 hours, cortisporin otic solution, oxymetazoline nasal spray, heparin 5000 IU s.c. every 8 hours, two packets of potassium phosphate and sodium phosphate p.o. daily, sliding-scale insulin, a continuous infusion of propofol 5-25 µg/kg/min (during the 48 hours of intubation), and acetaminophen rectal suppositories 650 mg every 4 hours as needed (three doses were administered).

Repeat head and sinus CT scan showed sinusitis and no dural sinus thrombosis or hydrocephalus. Surgical intervention for sinusitis was not required. The patient's mental status improved, and he was extubated after 48 hours (on day 4 of his ICU stay). He remained afebrile for 24 hours after extubation and was transferred to a medical floor.

His AST and ALT levels started rising on day 2 of admission (275 and 56 IU/L, respectively) and peaked on days 7-9 (638 and 442 IU/L, respectively). The decision was made to discontinue ceftriaxone and restart vancomycin on day 7. His ALP level remained normal throughout the treatment period. His AST and ALT levels began to decrease on days 8 and 10, respectively, and had significantly decreased at his outpatient follow-up visit on day 20 ( Table 1 ).

The patient denied abdominal pain or anorexia, and there was no abdominal tenderness on examination. His hepatitis A, B, and C serologic tests were negative, and his abdominal ultrasound was normal.

Use of the Naranjo probability scale indicated a possible relationship between ceftriaxone administration and elevated hepatic transaminases (score = 4).[1] Use of the Roussel Uclaf Causality Assessment method (RUCAM), developed specifically for causality assessment for hepatocellular reactions, indicated a probable relationship between ceftriaxone administration and elevated hepatic transaminases.[2,3] Other clinical diagnostic scales have been developed specifically for causality assessment for hepatocellular reactions (i.e., the Council for International Organizations of Medical Sciences scale and the Maria & Victorino clinical scale) but have been demonstrated to be inferior to RUCAM in a scale comparison analysis.[4] Thus, our patient's AST and ALT abnormalities were attributed to ceftriaxone sodium administration, as they resolved after ceftriaxone discontinuation.

Ceftriaxone sodium is a third-generation cephalosporin and widely used for a variety of infections caused by gram-positive and gram-negative aerobic organisms. It is reversibly bound to plasma proteins, but the unbound fraction increases with higher dosages of ceftriaxone. It has an elimination half-life of 5.8-8.7 hours and is primarily eliminated in the urine (67%), with the remainder secreted in the bile and eliminated in the feces.[5] Ceftriaxone sodium causes hepatotoxicity infrequently, with AST, ALT, and ALP elevations reported in 3.1%, 3.3%, and <1% of patients, respectively.[6]

Hepatocellular Enzyme Transaminase Elevations

Mechanisms by which ceftriaxone increases hepatic transaminase levels independently of ALP are unknown; however, many cephalosporins have been associated with hepatocellular and cholestatic abnormalities.[7] Mild, transient elevations in hepatic transaminase levels have been associated with cephalosporin use.[5,7-9] Because hepatotoxicity is rare with the use of cephalosporins, the mechanism of toxicity is most likely idiosyncratic.[10] According to some estimations, idiosyncratic drug reactions comprised 20% of all cases of severe liver injury in the United States.[11] These unpredictable idiosyncratic reactions may have metabolic or immunologic sources. Metabolic idiosyncratic reactions usually result in direct toxic damage to hepatocytes throughout the hepatic lobule, leading to apoptosis and variable degrees of necrosis. Hepatitis symptoms may occur within days to weeks of exposure to the offending agent and may worsen after the agent is discontinued.[11,12] In some cases, immunologic idiosyncracy, or hypersensitivity reactions involving an abnormal hepatic panel and hallmark signs of hypersensitivity (e.g., fever, rash, lymphocytosis, eosinophilia), may also explain the hepatotoxic properties of cephalosporin antibiotics.[10] However, an initial exposure period of one to five weeks is usually necessary for immunologic idiosyncracy to develop.[12]

A search of the medical literature revealed two case reports of ceftriaxone-induced elevations in hepatic transaminase levels. The first report described a 43-year-old man treated with ceftriaxone 2 g twice daily for three weeks for presumed "seronegative Lyme disease."[13] Four days after stopping ceftriaxone, he developed a sore throat, fever, tongue ulceration, granulocytopenia, and Clostridium difficile colitis. His hepatic transaminase levels were seven times the upper limit of normal (ULN). The patient reported taking ibuprofen for headaches but took no other medications. His abnormal laboratory test values improved over 72 hours.

Another case report described an 80-year-old man who was hospitalized with painless cholestatic jaundice 3 days after his previous discharge from the hospital.[14] During that previous admission he had received a 12-day course of ceftriaxone 2 g p.o. daily. Three days after completing the course, his AST level was 9 times the ULN, ALT was 11 times the ULN, TB was 22 times the ULN, conjugated bilirubin was 15 times the ULN, and ALP was 6 times the ULN. The patient was diagnosed with drug-induced acute hepatitis. His hepatic transaminase levels declined but his bilirubin levels continued to rise. He was readmitted with a hemoglobin concentration of 5.8 g/dL and had a positive reaction to a direct Coombs' IgG test. The final diagnosis was an autoimmune hemolytic anemia secondary to drug-induced acute hepatitis. His hepatic transaminase levels normalized within three weeks and bilirubin values returned to normal within four months.

A major early study of ceftriaxone's adverse effects was published by Oakes et al.[9] Their study examined 2640 neonates, infants, children, and adults who participated in 153 clinical studies of various dosages of ceftriaxone. The study found an overall 5% incidence of hepatic abnormalities with ceftriaxone therapy, with abnormal AST and ALT levels in 3.1% and 3.3% of study participants, respectively. Similar data appear in the drug's package insert, including all values that fell outside the normal range.[6] Hepatic function abnormalities were equally distributed among all age groups, with patients over age 50 years having fewer abnormal values. Higher dosages were associated with higher percentages of hepatocellular enzyme elevations. Three patients had discontinued therapy after hepatic transaminase levels became elevated. In all cases, hepatic transaminase elevations resolved; however, the initial degree of hepatic enzyme elevation and the time to resolution were not described in this review.[9]

According to the Center for Drug Evaluation and Research, of the 3852 individual safety reports collected by the agency between November 1997 and September 2004, 159 reported "abnormal liver function tests," which may include hepatocellular or cholestatic abnormalities or both.[15]
Biliary Sludge and Pseudolithiasis

Ceftriaxone's ability to cause drug-induced gallstones or sludge is well-known. Multiple case reports[16-33] and prospective studies[34-42] in the medical literature describe the relationship between ceftriaxone and the development of biliary pseudolithiasis or gallbladder sludge in adults and children.

Ceftriaxone concentrations may become very high within the biliary tree, leading to the passive influx of calcium ions.[43] In turn, certriaxone binds to calcium ions, and a ceftriaxone-calcium product precipitates in the gallbladder and biliary tree as soon as the concentration of ceftriaxone exceeds its saturation level in the bile, causing gallbladder sludge or pseudolithiasis.[8] Shiffman et al.[44] suggested that higher dosages of ceftriaxone (>2 g daily), as well as conditions impairing gallbladder contractility, may predispose patients to ceftriaxone-induced sludge. Biliary precipitation is usually self-limiting, and gallstones generally resolve after ceftriaxone discontinuation.[8,34]

Discussion

Our patient's AST value was 17 times the ULN, and his ALT level was 11 times the ULN. While this is considered clinically significant, it is unknown how often ceftriaxone induces such substantial increases in hepatic transaminase levels.

Other possibilities that might have caused this reaction include ischemic hepatitis or adverse reactions associated with the use of propofol, ibuprofen, or metronidazole. Ischemic hepatitis is unlikely because our patient was never in shock and maintained normal blood pressure throughout his ICU stay. Propofol has rarely been related to elevated hepatic transaminase levels.[45] In our patient, propofol was started after AST and ALT values had already started to rise, and, despite its discontinuation within 48 hours, a progressive rise in hepatic transaminase levels was observed. Metronidazole rarely causes acute hepatitis and severe liver injury.[46-48] In our patient, however, metronidazole was initiated after AST and ALT had already started to rise and was discontinued after three days of therapy with a progressive rise in hepatic transaminase levels. Ibuprofen intake before admission could have caused hepatotoxicity on its own, but that is exceedingly rare and commonly associated with other hallmarks of an immunologic reaction (e.g., Stevens-Johnson syndrome), although metabolic idiosyncracy may also occur.[12,48] No reports of liver injury caused by low doses (=200 mg) of ibuprofen have been reported.[12,49]

Our patient's slow decrease of hepatic enzymes over 11-13 days after their peak on days 6-8 is consistent with ceftriaxone-induced injury. According to the Maria & Victorino clinical scale for grading drug-induced hepatitis, it can take up to two months for AST and ALT levels to normalize after drug-induced liver injury with hepatocellular abnormalities.[50] Using RUCAM, ALT decreases of >50% from peak concentration within 8 days is highly suggestive of drug-induced hepatocellular injury, and ALT decreases of >50% from peak concentration within 30 days is suggestive of drug-induced hepatocellular injury.[2] Our patient's peak ALT concentration was 442 IU/L on day 9 and subsequently decreased to 127 IU/L on day 20 (a decrease of more than 50% within 11 days).

Our patient had severe meningitis, and his prognosis was deemed poor on the basis of his condition upon arrival at the ED. Ceftriaxone was initially continued despite the rising hepatic transaminase levels because it is considered superior to vancomycin for the treatment of meningitis and because the patient had a penicillin allergy. The decision to discontinue ceftriaxone and resume vancomycin on day 7 was based on the patient's excellent clinical response and the continued rise in hepatic enzyme levels. The decision to discontinue ceftriaxone would have been more difficult had the patient not exhibited such marked improvement.

Acknowledgements

Janet Shapiro, M.D., is acknowledged for her valuable suggestions in preparation of this article.
Reprint Address

Dr. Rivkin at Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201-5497. anastasia.rivkin@liu.edu .

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Author Information
Anastasia M. Rivkin, Pharm.D., BCPS, is Assistant Professor of Pharmacy Practice, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, and St. Luke's/Roosevelt Hospital Center, New York

Rprint Address

Dr. Rivkin at Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201-5497. anastasia.rivkin@liu.edu .

http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=2584749&cmd=showdetailview&indexed=google

1: J Infect Dis. 1989 Dec;160(6):1005-11.Links
Comment in:
J Infect Dis. 1990 Oct;162(4):991-3.
Cerebrospinal fluid endotoxin levels in children with H. influenzae meningitis before and after administration of intravenous ceftriaxone.
Arditi M, Ables L, Yogev R.

Department of Pediatrics, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614.

Total, cell-free, and cell-bound endotoxin and bacterial density were measured in cerebrospinal fluid (CSF) of 22 children with Hemophilus influenzae meningitis. Also the effect of ceftriaxone on CSF endotoxin levels was investigated in eight patients by reexamining their CSF 2-6 h after the initial dose. Initial CSF bacterial density correlated with initial CSF endotoxin levels (P less than .001). Ceftriaxone induced a marked increase of free endotoxin in CSF, from an initial (mean +/- SE) 0.75 +/- 0.21 to 1.29 +/- 0.23 log10 ng/ml (P less than .01). This increase correlated positively with the number of bacteria killed in the CSF (P less than .01). The increase in free endotoxin was associated with an increase in mean CSF lactate levels from 8.5 to 9.7 units/l (P less than .05) and mean lactate dehydrogenase levels from 102 to 180 mmol/l (P less than .02) and a decrease in mean CSF glucose from 1.17 to 0.46 mmol/l (P less than .05). Initial CSF total endotoxin concentrations correlated both with the Herson-Todd clinical severity score (P less than .001) and with the number of febrile hospital days (P less than .001). These findings suggest that highly bactericidal agents initially lead to release of free endotoxin from gram-negative organisms into CSF, with associated enhanced inflammatory response by the host.

http://md1.csa.com/partners/viewrecord.php?requester=gs&collection=ENV&recid=
3962692&q=Ceftriaxone+%2B+endotoxin&uid=791990964&setcookie=yes


Different endotoxin release and IL-6 plasma levels after antibiotic administration in surgical intensive care patients
Holzheimer, RG; Hirte, JF; Reith, B; Engelhardt, W; Horak, KH; Leppert, R; Aasen, A; Capel, P; Urbaschek, R; Karch, H; Thiede, A
Journal of Endotoxin Research [J. ENDOTOXIN RES.]. Vol. 3, no. 3. 1996.

Despite the use of broad-spectrum antibiotics, aggressive fluid resuscitation, vasopressor support, the mortality associated with Gram-negative sepsis and septic shock has not decreased significantly in the last two decades. The consequences of host exposure to endotoxin and the relationship of antibiotic administration to endotoxin release have become important areas of intense interest. In vitro studies have demonstrated that there was a difference in endotoxin release between PBP-3 specific antibiotics ( beta -lactam antibiotics) and PBP-2 specific antibiotics (carbapenems). This is the first clinical report of surgical patients admitted to the surgical and anaesthesiology intensive care unit on the missing endotoxin release after imipenem treatment; however cefotaxime and ceftriaxone showed significantly more positive endotoxin tests in the plasma when compared to imipenem. Ciprofloxacin and vancomycin were intermediate in endotoxin release and tobramycin did not cause endotoxin release. There were also significant differences in endotoxin neutralizing capacity. IL-6 levels were decreased after imipenem faster than after ceftriaxone or cefotaxime; ciprofloxacin seemed to increase IL-6. Endotoxin may be harmful in patients where the immune system has been continuously challenged. Timing, dosage, or combination with other compounds as well as the effect of antibiotics on macrophages need to be tested in larger clinical trials. In this respect a consecutive study was started.

Descriptors: {Q1}; endotoxins; gram-negative bacteria; intensive care units; interleukin 6