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Ceftriaxone Sodium

Ceftriaxone is a semisynthetic, third generation cephalosporin antibiotic.

Uses

Ceftriaxone is used for the treatment of bone and joint infections, endocarditis, intra-abdominal infections, meningitis and other CNS infections, otitis media, respiratory tract infections,septicemia, skin and skin structure infections, and urinary tract infections caused by susceptible bacteria.

The drug also is used for the treatment of chancroid, gonorrhea and associated infections, pelvic inflammatory disease,infections caused by Neisseria meningitidis, infections caused by Shigella, and typhoid fever and other infections caused by Salmonella. In addition, ceftriaxone is used for the treatment of Lyme disease and for empiric anti-infective therapy in febrile neutropenic patients, and has been used for perioperative prophylaxis.

Ceftriaxone has a wide spectrum of activity and is effective for the treatment of infections caused by a variety of gram-positive and gram-negative bacteria. Like other parenteral third generation cephalosporins (cefoperazone, cefotaxime, ceftazidime, ceftizoxime), ceftriaxone is less active than first and second generation cephalosporins against some gram- positive aerobic bacteria (e.g., staphylococci) and generally should not be used in the treatment of infections caused by these organisms when a penicillin or first or second generation cephalosporin could be used.

However, ceftriaxone may be a drug of choice for serious infections caused by certain other gram-positive bacteria, including some streptococci. Ceftriaxone is considered a drug of choice for many infections caused by gram-negative bacteria, and a principal use of the drug is for the treatment of serious gram-negative bacterial infections, especially nosocomial infections, when other anti-infectives are ineffective or contraindicated.

Because ceftriaxone has a long serum half-life and can be administered once daily, the drug has been used for community-based parenteral anti-infective therapy for the treatment of infections that require prolonged therapy (e.g., community-acquired pneumonia, osteomyelitis, endocarditis) and for empiric anti-infective therapy in febrile neutropenic patients. Ceftriaxone has been administered parenterally to adults and children in outpatient settings such as the clinician’s office, outpatient clinics, infusion centers, skilled nursing facilities, rehabilitation centers, or the patient’s home.

Outpatient parenteral anti-infective therapy generally is used to complete a course of ceftriaxone therapy initiated during hospitalization, but ceftriaxone therapy also has been initiated on an outpatient basis in patients who were clinically stable. When considering use of community-based ceftriaxone therapy, the benefits and risks of such therapy should be considered. Prior to initiation of ceftriaxone therapy, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests. Ceftriaxone therapy may be started pending results of susceptibility tests, but should be discontinued if the organism is found to be resistant to the drug.

Bone and Joint Infections

Ceftriaxone is used in adults and pediatric patients for the treatment of bone and joint infections (e.g., osteomyelitis, septic arthritis) caused by susceptible Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, or Klebsiella pneumoniae.

Endocarditis

Ceftriaxone is used for the treatment of native valve endocarditis caused by penicillin-susceptible viridans streptococci (e.g., S. milleri group, S. mitis, S. mutans, S. salivarius, S. sanguis) or S. bovis ( nonenterococcal group D streptococcus). The drug also is used for the treatment of native valve or prosthetic valve endocarditis caused by slow-growing fastidious gram-negative bacilli termed the HACEK group (i.e., Haemophilus parainfluenzae, H. aphrophilus, Actinobacillus actinomycetemcomitans,Cardiobacterium hominis, Eikenella corrodens, Kingella kingae). Ceftriaxone has been administered on an outpatient basis for the treatment of endocarditis caused by susceptible bacteria. Ceftriaxone is not indicated for the treatment of enterococcal or staphylococcal endocarditis.

Endocarditis Caused by Viridans Streptococci or Streptococcus bovis

For the treatment of native valve endocarditis caused by penicillin-susceptible viridans streptococci or S. bovis (i.e., penicillin MIC 0.1 mcg/mL or less), the American Heart Association (AHA) recommends use of a 4-week regimen of IV penicillin G; a 4-week regimen of IM or IV ceftriaxone; or a 2-week regimen of IV penicillin G given in conjunction with IM or IV gentamicin. All 3 regimens are highly effective and can be expected to result in a bacteriologic cure in up to 98% of patients.

There is some evidence that a 2-week regimen of IM or IV ceftriaxone given in conjunction with IM or IV netilmicin (no longer commercially available in the US) may be equivalent to the 2-week regimen of IV penicillin G and IM or IV gentamicin. In addition, results of one study in patients with endocarditis caused by penicillin-susceptible viridans streptococci or S. bovis indicate that a 2-week regimen of IV ceftriaxone and IV gentamicin is as effective as a 4-week regimen of IV ceftriaxone since the bacteriologic cure rate was 95.7% with either regimen.

The AHA suggests that a 2-week combination regimen may be appropriate for uncomplicated cases of native valve endocarditis in patients at low risk for adverse effects related to aminoglycoside therapy, but is not recommended for patients with complications such as extracardiac foci of infection or intracardiac abscess. The 4-week monotherapy regimens are preferred in most patients older than 65 years of age and in patients with eighth cranial nerve function impairment, renal impairment, or other conditions that contraindicate use of aminoglycosides.

Ceftriaxone is not included in the AHA recommendations for the treatment of endocarditis caused by penicillin-susceptible viridans streptococci or S. bovis when prosthetic valves or other prosthetic material are involved; the AHA recommends a combination regimen of IV penicillin G and gentamicin for these infections. A combination regimen of IV penicillin G and gentamicin also is recommended for the treatment of native valve endocarditis caused by viridans streptococci or S. bovis that are relatively resistant to penicillin (i.e., penicillin MIC greater than 0.1 mcg/mL and less than 0.5 mcg/mL).

Endocarditis caused by nutritionally variant viridans streptococci or viridans streptococci with penicillin MICs of 0.5 mcg/mL or greater requires treatment with an IV penicillin G or IV ampicillin sodium combination regimen recommended for the treatment of enterococcal endocarditis. (See Endocarditis under Uses: Gram-positive Aerobic Bacterial Infections in the Natural Penicillins General Statement 8:12.16.04.)

Endocarditis Caused by the HACEK Group

The slow-growing fastidious gram-negative bacilli known as the HACEK group (i.e., Haemophilus parainfluenzae, H. aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) account for up to 10% of cases of native valve endocarditis in patients who are not IV drug abusers and also rarely cause prosthetic valve endocarditis. While only limited clinical data are available regarding the efficacy of third generation cephalosporins in these infections, the AHA states that the treatment of choice for HACEK endocarditis is a regimen of IM or IV ceftriaxone or, alternatively, cefotaxime or another third generation cephalosporin. A combination regimen of IV penicillin G or IV ampicillin sodium given with an aminoglycoside (e.g., gentamicin) also may be effective in the treatment of these infections; however, HACEK organisms generally should be considered ampicillin-resistant. The AHA states that patients with HACEK endocarditis who are hypersensitive to b-lactam antibiotics should be treated in consultation with an infectious disease specialist.

Intra-abdominal Infections

Ceftriaxone is used for the treatment of intra-abdominal infections caused by susceptible E. coli, K. pneumoniae, Bacteroides fragilis, Clostridium, or Peptostreptococcus. The drug also has been used for the treatment of various gynecologic infections, including pelvic inflammatory disease. (See Uses: Pelvic Inflammatory Disease.) While ceftriaxone monotherapy may be effective in some patients for the treatment of mixed aerobic-anaerobic intra-abdominal infections and generally is associated with less toxicity than combination regimens that include an aminoglycoside (e.g., clindamycin and gentamicin), ceftriaxone has been ineffective in the treatment of intra-abdominal infections when B. fragilis was present and superinfection with this organism has been reported occasionally. Therefore, some clinicians recommend that ceftriaxone monotherapy not be used for the treatment of serious intra-abdominal infections when B. fragilis may be present.

Meningitis and Other CNS Infections

Ceftriaxone is used in neonates, children, or adults for the treatment of meningitis caused by susceptible strains of H. influenzae, N. meningitidis, or S. pneumoniae. The drug also has been used for the treatment of meningitis and other CNS infections caused by susceptible Enterobacteriaceae (e.g., E. coli, Klebsiella). Ceftriaxone should not be used alone for empiric treatment of meningitis when Listeria monocytogenes, enterococci, staphylococci, or Pseudomonas aeruginosa may be involved.

Empiric Treatment of Meningitis

Pending results of CSF culture and in vitro susceptibility testing, the most appropriate anti-infective regimen for empiric treatment of suspected bacterial meningitis should be selected based on results of CSF Gram stain and antigen tests, age of the patient, the most likely pathogen(s) and source of infection, and current patterns of bacterial resistance within the hospital and local community. When results of culture and susceptibility tests become available and the pathogen is identified, the empiric anti-infective regimen should be modified (if necessary) to ensure that the most effective regimen is being administered.

There is some evidence that short-term adjunctive therapy with IV dexamethasone may decrease the incidence of audiologic and/or neurologic sequelae in infants and children with H. influenzae meningitis and possibly may provide some benefit in patients with S. pneumoniae meningitis. While such therapy is controversial, the American Academy of Pediatrics (AAP) and other clinicians suggest that use of adjunctive dexamethasone therapy should be considered during the initial 2-4 days of anti-infective therapy in infants and children 6-8 weeks of age or older with known or suspected bacterial meningitis, and is recommended in those with suspected or proven H. influenzaeinfection. (See Uses: Bacterial Meningitis in the Corticosteroids General Statement 68:04 and see Dexamethasone 68:04.)

Bacterial meningitis in neonates usually is caused by S. agalactiae (group B streptococci), L. monocytogenes, or aerobic gram-negative bacilli (e.g., E. coli, K. pneumoniae). The AAP recommends that neonates 4 weeks of age or younger with suspected bacterial meningitis receive an empiric regimen of IV ampicillin and an aminoglycoside pending results of CSF culture and susceptibility testing.

Alternatively, neonates can receive an empiric regimen of IV ampicillin and IV cefotaxime or IV ceftazidime with or without gentamicin. Because frequent use of cephalosporins in neonatal units may result in rapid emergence of resistant strains of some gram-negative bacilli (e.g., Enterobacter cloacae, Klebsiella, Serratia), the AAP cautions that cephalosporins should be used for empiric treatment of meningitis in neonates only if gram-negative bacterial meningitis is strongly suspected. Consideration should be given to including IV vancomycin in the empiric regimen if S. pneumoniae, enterococci, or Staphylococci is suspected.

Although IV ceftriaxone can be used for empiric therapy in neonates, the drug should be used with caution in neonates who are hyperbilirubinemic (especially those born prematurely).

Because premature, low-birthweight neonates are at increased risk for nosocomial infection caused by staphylococci or gram-negative bacilli, some clinicians suggest that these neonates receive an empiric regimen of IV ceftazidime and IV vancomycin. In infants beyond the neonatal stage who are younger than 3 months of age, bacterial meningitis may be caused by S. agalactiae, L. monocytogenes, H. influenzae, S. pneumoniae, N. meningitidis, or aerobic gram-negative bacilli (e.g., E. coli, K. pneumoniae).

The empiric regimen recommended for infants in this age group is IV ampicillin and either IV ceftriaxone or IV cefotaxime. Consideration should be given to including IV vancomycin in the empiric regimen if S. pneumoniae is suspected. In children 3 months through 17 years of age, bacterial meningitis usually is caused by N. meningitidis, S. pneumoniae, or H. influenzae, and the most common cause of bacterial meningitis in adults 18-50 years of age is N. meningitidis or S. pneumoniae. An empiric regimen of IV ceftriaxone or IV cefotaxime usually is used for empiric therapy of suspected bacterial meningitis in children 3 months through 17 years of age and in adults 18-50 years of age. Although an empiric regimen of IV ampicillin and IV chloramphenicol can be used as an alternative regimen in children 3 months through 17 years of age, most clinicians prefer a cephalosporin regimen unless the drugs are contraindicated.

Because of the increasing prevalence of penicillin-resistant S. pneumoniae that also are resistant to or have reduced susceptibility to cephalosporins, the AAP and others recommend that the initial empiric cephalosporin regimen include IV vancomycin (with or without rifampin) pending results of in vitro susceptibility tests; vancomycin and rifampin should be discontinued if the causative organism is found to be susceptible to the cephalosporin.

The US Centers for Disease Control and Prevention (CDC) and some clinicians have recommended that vancomycin be added to the empiric regimen in areas where there have been reports of highly penicillin-resistant strains of S. pneumoniae, but other clinicians suggest that use of ceftriaxone or cefotaxime in conjunction with vancomycin provides the optimal initial empiric regimen. While L. monocytogenes meningitis is relatively rare in this age group, the empiric regimen should include ampicillin if L. monocytogenes is suspected. In adults older than 50 years of age, bacterial meningitis usually is caused by S. pneumoniae, L. monocytogenes, N. meningitidis, or aerobic gram-negative bacilli, and the empiric regimen recommended for this age group is IV ampicillin given in conjunction with IV cefotaxime or IV ceftriaxone. Because of the increasing prevalence of penicillin-resistant S. pneumoniae, some clinicians suggest that the empiric regimen also should include IV vancomycin.

Meningitis Caused by Streptococcus pneumoniae

IV ceftriaxone and IV cefotaxime are considered drugs of choice for the treatment of meningitis caused by susceptible S. pneumoniae. While cefotaxime and ceftriaxone generally have been considered the drugs of choice for the treatment of meningitis caused by penicillin-resistant S. pneumoniae, treatment failures have been reported when the drugs were used alone for the treatment of meningitis caused by strains of S. pneumoniae with intermediate or high-level penicillin resistance (i.e., penicillin MIC 0.1 mcg/mL or greater). In addition, strains of S. pneumoniae with reduced susceptibility to cephalosporins have been reported with increasing frequency, and use of cefotaxime or ceftriaxone alone may be ineffective for the treatment of meningitis caused by these strains.

The prevalence of S. pneumoniae with reduced susceptibility to penicillin and/or cephalosporins varies geographically, and clinicians should be aware of the prevalence and pattern of S. pneumoniae drug resistance in the local community to optimize empiric regimens and initial therapy for serious pneumococcal infections.

Because susceptibility can no longer be assumed, S. pneumoniae isolates should be routinely tested for in vitro susceptibility. If anti-infective therapy in a patient with meningitis is initiated with an empiric regimen of IV ceftriaxone and IV vancomycin (with or without rifampin) and results of culture and in vitro susceptibility testing indicate that pathogen involved is a strain of S. pneumoniae susceptible to ceftriaxone and susceptible or resistant to penicillin, vancomycin and rifampin can be discontinued and therapy completed using ceftriaxone alone. If the isolate is found to have reduced susceptibility to ceftriaxone and penicillin, both IV ceftriaxone and IV vancomycin usually are continued.

If the patient’s condition does not improve or worsens or results of a second repeat lumbar puncture (performed 24-48 hours after initiation of anti-infective therapy) indicate that the anti-infective regimen has not eradicated or substantially reduced the number of pneumococci in CSF, rifampin probably should be added to the regimen or vancomycin discontinued and replaced with rifampin. If meningitis is caused by S. pneumoniae highly resistant to ceftriaxone (i.e., MIC 4 mcg/mL or greater), consultation with an infectious disease expert is recommended.

Meningitis Caused by Haemophilus influenzae

IV ceftriaxone and IV cefotaxime are considered drugs of choice for the initial treatment of meningitis caused by susceptible H. influenzae (including penicillinase-producing strains). The AAP suggests that children with meningitis possibly caused by H. influenzae can receive an initial treatment regimen of ceftriaxone, cefotaxime, or a regimen of ampicillin given in conjunction with chloramphenicol; most clinicians prefer ceftriaxone or cefotaxime for the initial treatment of meningitis caused by H. influenzae since these cephalosporins are active against both penicillinase-producing and nonpenicillinase-producing strains. Because of the prevalence of ampicillin-resistant H. influenzae, ampicillin should not be used alone for empiric treatment of meningitis when H. influenzae may be involved. The incidence of H. influenzae meningitis in the US has decreased considerably since H. influenzae type b conjugate vaccines became available for immunization of infants.

Meningitis Caused by Neisseria meningitidis

While both IV ampicillin and IV penicillin G may be used for the treatment of meningitis caused by N. meningitidis, the AAP and other clinicians suggest that IV penicillin G is the drug of choice for the treatment of these infections and IV ceftriaxone and IV cefotaxime are acceptable alternatives. Chloramphenicol is recommended for the treatment of N. meningitidis meningitis in patients with a history of anaphylactoid-type hypersensitivity reactions to penicillin.

Meningitis Caused by Enterobacteriaceae

Some clinicians recommend that meningitis caused by Enterobacteriaceae (e.g., E. coli, K. pneumoniae) be treated with a third generation cephalosporins (i.e., cefotaxime, ceftazidime, ceftriaxone) with or without an aminoglycoside. Because ceftazidime (but not cefotaxime or ceftriaxone) is effective for the treatment of meningitis caused by Ps. aeruginosa, some clinicians suggest that a regimen of ceftazidime and an aminoglycoside may be preferred for the treatment of meningitis caused by gram-negative bacilli pending results of culture and susceptibility testing.

Meningitis Caused by Streptococcus agalactiae

For the initial treatment of meningitis or other severe infection caused by S. agalactiae (group B streptococci), a regimen of IV ampicillin or IV penicillin G given in conjunction with an aminoglycoside is recommended. Some clinicians suggest that IV ampicillin is the drug of choice for the treatment of group B streptococcal meningitis and that an aminoglycoside (IV gentamicin) should be used concomitantly in the first 72 hours until in vitro susceptibility testing is completed and a clinical response is observed; thereafter, ampicillin can be given alone.

Meningitis Caused by Listeria monocytogenes

The optimal regimen for the treatment of meningitis caused by Listeria monocytogenes has not been established. Ceftriaxone is ineffective in and should not be used alone for the treatment of meningitis caused by L. monocytogenes. The AAP and other clinicians generally recommend that meningitis or other severe infection caused by L. monocytogenes be treated with a regimen of IV ampicillin with or without an aminoglycoside (usually gentamicin); alternatively, a regimen of penicillin G used in conjunction with gentamicin can be used. In patients hypersensitive to penicillin, the alternative regimen for treatment of meningitis caused by L. monocytogenes is co-trimoxazole.

Brain Abscess and Other CNS Infections

Bacterial brain abscesses and other CNS infections (e.g., subdural empyema, intracranial epidural abscesses) often are polymicrobial and can be caused by gram-positive aerobic cocci, Enterobacteriaceae (e.g., E. coli, Klebsiella), and/or anaerobic bacteria (e.g., Bacteroides, Fusobacterium). The choice of anti-infectives for empiric therapy of these infections should be based on the predisposing condition and site of primary infection.

Some clinicians suggest that the empiric anti-infective regimen in patients who develop the CNS infections after respiratory tract infection (e.g., otitis media, mastoiditis, paranasal sinusitis, pyogenic lung disease) should consist of an appropriate third generation IV cephalosporin (e.g., ceftriaxone, cefotaxime, ceftazidime) given in conjunction with metronidazole; employing one of these cephalosporins rather than a penicillin provides coverage against Haemophilus and facultative anaerobic gram-negative bacteria. If presence of staphylococci is suspected, a penicillinase-resistant penicillin (e.g., nafcillin, oxacillin) or vancomycin should be added to the empiric regimen. In patients who develop brain abscess, subdural empyema, or intracranial epidural abscess after trauma or neurosurgery, the empiric regimen should consist of an appropriate third generation IV cephalosporin (e.g., ceftriaxone, cefotaxime, ceftazidime) given in conjunction with a penicillinase-resistant penicillin or vancomycin. Prolonged anti-infective therapy (e.g., 3-6 weeks or longer) usually is required for the treatment of brain abscess, subdural empyema, or intracranial epidural abscess.

Otitis Media

Acute Otitis Media

A single 50-mg/kg IM dose of ceftriaxone is used for the treatment of acute otitis media caused by S. pneumoniae, H. influenzae (including b- lactamase-producing strains), or Moraxella (formerly Branhamella) catarrhalis (including b-lactamase-producing strains).

Results of several controlled clinical studies in pediatric patients with acute otitis media indicate that the short-term clinical response rate to the single-dose IM ceftriaxone regimen is similar to that of a 10-day regimen of oral cefaclor (40 mg/kg daily), a 7- or 10-day regimen of oral amoxicillin (40 mg/kg daily), a 10-day regimen of oral co-trimoxazole (8 mg/kg trimethoprim and 40 mg/kg of sulfamethoxazole daily), or a 10-day regimen of oral amoxicillin and clavulanate potassium; however, in one study, the single-dose IM ceftriaxone regimen had a lower clinical cure rate than a 10-day regimen of oral amoxicillin and clavulanate potassium.

The single-dose IM ceftriaxone regimen offers some practical advantages over 5- to 10-day oral anti-infective regimens usually recommended for the treatment of acute otitis media since it provides a more convenient dosing schedule, ensures compliance, and can be administered to patients who have nausea and vomiting. However, the manufacturer cautions that the potentially lower clinical cure rate reported with the single-dose ceftriaxone regimen should be considered when weighing the potential advantages of the regimen. Some clinicians suggest that further study of the single-dose ceftriaxone regimen is needed to more fully assess the bacteriologic eradication rate, long-term efficacy, and rate of relapse and to determine whether the single-dose regimen contributes to emergence of resistant organisms. In addition, some clinicians caution that short-term anti-infective regimens (i.e., 5 days or less) may not be appropriate for the treatment of acute otitis media in children with underlying disease or recurrent or chronic infections or for children younger than 2 years of age.

Persistent or Recurrent Otitis Media

A 3-day regimen of ceftriaxone (50 mg/kg IM once daily) has been effective for the treatment of persistent or recurrent acute otitis media in pediatric patients 3 months of age or older with infections that failed to respond to treatment with other anti-infectives (e.g., amoxicillin, amoxicillin and clavulanate potassium, cefaclor, cefuroxime axetil). The 3-day ceftriaxone regimen has been effective for the treatment of persistent or relapsing otitis media caused by H. influenzae, M. catarrhalis, S. pyogenes, or penicillin-susceptible S. pneumoniae; however, treatment failures have been reported when the causative agent was S. pneumoniae with reduced susceptibility to penicillin.

Respiratory Tract Infections

Ceftriaxone is used in adults and pediatric patients for the treatment of respiratory tract infections (including pneumonia) caused by susceptible gram-positive cocci (e.g., S. pneumoniae, S. aureus) or gram-negative bacteria (e.g., H. influenzae, H. parainfluenzae, K. pneumoniae, E. coli, Enterobacter aerogenes, Proteus mirabilis, Serratia marcescens). Ceftriaxone generally has been effective in the treatment of pneumonia caused by some strains of S. pneumoniae with intermediate resistance to penicillin (i.e., penicillin MIC less than 0.1-2 mcg/mL), treatment failures have been reported when the drug was used alone in the treatment of severe infections (e.g., meningitis) caused by strains of S. pneumoniae with intermediate or high-level penicillin resistance (i.e., penicillin MIC 0.12 mcg/mL or greater). (See Uses: Meningitis and Other CNS Infections.) Although other drugs are preferred, ceftriaxone has been administered on an outpatient basis for empiric anti-infective therapy in adults with community-acquired pneumonia who did not require hospitalization.

Community-acquired Pneumonia

The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) suggest that certain parenteral cephalosporins (cefotaxime, ceftriaxone) can be used in inpatient regimens for the treatment of community-acquired pneumonia (CAP).

Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens; therapy may then be changed (if possible) to a pathogen-specific regimen based on results of in vitro culture and susceptibility testing, especially in hospitalized patients. The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation and whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., penicillin- or multidrug-resistant S. pneumoniae, enteric gram-negative bacilli, Ps. aeruginosa).

Most experts recommend that an empiric regimen for the inpatient treatment of CAP include an anti-infective active against S. pneumoniae since this organism is the most commonly identified cause of bacterial pneumonia and causes more severe disease than many other common CAP pathogens; some other pathogens often involved in inpatient CAP are H. influenzae, enteric gram-negative bacilli, S. aureus, Legionella, Mycoplasma pneumoniae, Chlamydia pneumoniae, and viruses.

Patients with severe CAP admitted into the ICU may have Ps. aeruginosainfections (especially those with underlying bronchiectasis or cystic fibrosis) and Enterobacteriaceae often are involved. In addition, anaerobic infection should be suspected in patients with aspiration pneumonia or lung abscess. Inpatient treatment of CAP is initiated with a parenteral regimen, although therapy may be changed to an oral regimen if the patient is improving clinically, is hemodynamically stable, and able to ingest drugs.

CAP patients usually have a clinical response within 3-5 days after initiation of therapy and failure to respond to the initial empiric regimen generally indicates an incorrect diagnosis, host failure, inappropriate anti-infective regimen (drug selection, dosage, route), unusual pathogen, adverse drug reaction, or complication (e.g., pulmonary superinfection, empyema).

For empiric inpatient treatment of CAP in immunocompetent adults who require hospitalization in a general patient-care setting (not an ICU), the IDSA recommends a 2-drug regimen consisting of a parenteral b-lactam anti-infective (e.g., cefotaxime, ceftriaxone, ampicillin and sulbactam, piperacillin and tazobactam) and a macrolide (e.g., azithromycin, clarithromycin, erythromycin) or monotherapy with a fluoroquinolone active against S. pneumoniae (e.g., gatifloxacin, levofloxacin, moxifloxacin).

For empiric inpatient treatment of CAP in immunocompetent adults who are hospitalized in a general patient-care setting and have cardiopulmonary disease (congestive heart failure or chronic obstructive pulmonary disease [COPD]) and/or other modifying factors that increase the risk for multidrug-resistant S. pneumoniae or gram-negative bacteria, the ATS recommends a 2-drug regimen consisting of a parenteral b-lactam anti-infective (cefotaxime, ceftriaxone, ampicillin and sulbactam, high-dose ampicillin) and an oral or IV macrolide (azithromycin or clarithromycin; doxycycline can be used in those with macrolide sensitivity or intolerance) or, alternatively, monotherapy with an IV fluoroquinolone active against S. pneumoniae. If anaerobes are documented or lung abscess is present, clindamycin or metronidazole should be added to the regimen.

For CAP patients admitted to a general patient-care setting who do not have cardiopulmonary disease or other modifying factors, the ATS suggests an empiric regimen of monotherapy with IV azithromycin; for those with macrolide sensitivity or intolerance, a 2-drug regimen of doxycycline and a b-lactam or monotherapy with a fluoroquinolone active against S. pneumoniae can be used.

For inpatient treatment of CAP in immunocompetent adults who require hospitalization in an ICU, the IDSA recommends an empiric 2-drug regimen consisting of a b-lactam anti-infective (cefotaxime, ceftriaxone, ampicillin and sulbactam, piperacillin and tazobactam) and either a macrolide or a fluoroquinolone. For inpatient treatment of severe CAP in patients hospitalized in an ICU, the ATS recommends that those not at risk for Ps. aeruginosa infection receive a 2-drug empiric regimen consisting of an IV b-lactam anti-infective (cefotaxime, ceftriaxone) and either an IV macrolide (azithromycin) or IV fluoroquinolone. If risk factors for Ps. aeruginosa are present in patients with severe CAP admitted to an ICU, the ATS recommends an empiric regimen that includes 2 antipseudomonal agents and provides coverage for multidrug-resistant S. pneumonia and Legionella. Therefore, the ATS recommends that these patients receive a 2-drug empiric regimen that includes an IV antipseudomonal b-lactam anti-infective (e.g., cefepime, piperacillin and tazobactam, imipenem, meropenem) and an IV antipseudomonal fluoroquinolone (e.g., ciprofloxacin) or, alternatively, a 3-drug empiric regimen that includes one of the IV antipseudomonal ?-lactams, an IV aminoglycoside, and either an IV macrolide (e.g., azithromycin) or an IV nonpseudomonal quinolone.

Septicemia

Ceftriaxone is used in adults and pediatric patients for the treatment of septicemia caused by S. aureus, S. pneumoniae, E. coli, H. influenzae, or K. pneumoniae. The choice of anti-infective agent for the treatment of sepsis syndrome should be based on the probable source of infection, gram-stained smears of appropriate clinical specimens, the immune status of the patient, and current patterns of bacterial resistance within the hospital and local community. Certain parenteral cephalosporins (i.e., cefepime, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime) are good choices for the treatment of gram-negative sepsis.

For the initial treatment of life-threatening sepsis in adults, some clinicians suggest that a parenteral cephalosporin (i.e., cefepime, cefotaxime, ceftriaxone) given in conjunction with an aminoglycoside (amikacin, gentamicin, tobramycin) is one of several preferred regimens.

Skin and Skin Structure Infections

Ceftriaxone is used for the treatment of skin and skin structure infections caused by susceptible S. aureus, S. epidermidis, S. pyogenes (group A β- hemolytic streptococci), viridans streptococci, E. coli, E. cloacae, K. oxytoca, K. pneumoniae, P. mirabilis, Morganella morganii, S. marcescens, Acinetobacter calcoaceticus, B. fragilis, or Peptostreptococcus.

Urinary Tract Infections

Ceftriaxone is used in adult and pediatric patients for the treatment of complicated and uncomplicated urinary tract infections caused by E. coli, K. pneumoniae, M. morganii, P. mirabilis, or P. vulgaris. The most appropriate anti-infective for the treatment of urinary tract infections should be selected based on the severity of the infection and results of culture and in vitro susceptibility testing. It has been suggested that certain parenteral cephalosporins (i.e., cefepime, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime) may be drugs of choice for the treatment of infections caused by susceptible Enterobacteriaceae, including susceptible strains of E. coli, K. pneumoniae, P. rettgeri, M. morganii, P. vulgaris, or P. stuartii; an aminoglycoside usually is used concomitantly in severe infections. Ceftriaxone may be particularly useful as initial therapy for the treatment of nosocomial urinary tract infections known or suspected to be caused by multidrug-resistant Enterobacteriaceae. However, ceftriaxone, like other third generation cephalosporins, generally should not be used in the treatment of uncomplicated urinary tract infections when other anti-infectives with a narrower spectrum of activity could be used.

Chancroid

A single 250-mg IM dose of ceftriaxone generally is effective for the treatment of chancroid, genital ulcers caused by H. ducreyi. The CDC167 and many clinicians state that a single IM dose of ceftriaxone, a single oral dose of azithromycin, a 3-day regimen of oral ciprofloxacin (contraindicated in pregnant or lactating women), or a 7-day regimen of oral erythromycin are the regimens of choice for the treatment of chancroid.

All 4 regimens generally are effective for the treatment of chancroid; however, patients with human immunodeficiency virus (HIV) infection and patients who are uncircumcised may not respond to treatment as well as those who are HIV-negative or circumcised.

Treatment failures that have occurred in HIV-infected individuals who received the single-dose ceftriaxone regimen do not appear to be related to ceftriaxone resistance since isolates of H. ducreyi obtained from these individuals were susceptible to ceftriaxone in vitro. Because data on efficacy of the single-dose ceftriaxone or single-dose azithromycin regimen for the treatment of chancroid in patients with HIV infection are limited, the CDC recommends that these regimens be used in HIV patients only if follow-up can be ensured; some experts recommend that HIV-infected individuals with chancroid receive the multiple-dose erythromycin regimen. In the US, chancroid usually occurs in discrete outbreaks, but the disease is endemic in some areas.

Approximately 10% of patients with chancroid acquired in the US also are coinfected with Treponema pallidum or herpes simplex virus (HSV); this percentage is higher in individuals who acquired the infection outside the US. In addition, high rates of HIV infection have been reported in patients with chancroid, and the disease appears to be a cofactor for HIV transmission.

Evaluation of the physical features of genital ulcers (without laboratory evaluation and testing) usually is inadequate to provide a differential diagnosis between chancroid, primary syphilis, and genital HSV infection. Ideally, diagnostic evaluation of patients with genital ulcers include a serologic test for syphilis and either darkfield examination or direct immunofluorescence test for T. pallidum, culture for H. ducreyi, and culture or antigen test for HSV.

A definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that is not widely available. However, a probable diagnosis of chancroid can be made if the patient has one or more painful genital ulcers, there is no evidence of T. pallidum infection based on a negative darkfield examination of ulcer exudate or a negative serologic test for syphilis (performed at least 7 days after onset of ulcers), culture or antigen test for HSV is negative, and the clinical presentation, appearance of genital ulcers, and regional lymphadenopathy (if present) are typical for chancroid.

While the presence of a painful ulcer and tender inguinal adenopathy occur in about one-third of chancroid patients and suggests a diagnosis of chancroid, the additional presence of suppurative inguinal adenopathy is a clearer indication of the disease.

Patient Follow-up and Management of Sexual Partners

The CDC recommends that all patients diagnosed with chancroid be tested for HIV and, if initial tests for syphilis and HIV are negative, the tests repeated 3 months later. Patients with chancroid should be examined 3-7 days after initiation of anti-infective therapy. If the regimen was effective, symptomatic improvement in the ulcers is evident within 3 days and objective improvement is evident within 7 days. If clinical improvement is not evident within 3-7 days, consideration should be given to the possibility that the diagnosis was incorrect, there is coinfection with another sexually transmitted disease, the patient was noncompliant with the regimen, the strain of H. ducreyi is resistant to the anti-infective agent used, or the patient is HIV seropositive.

The time required for complete healing is related to the size of the ulcer; large ulcers may require more than 2 weeks to heal. Healing of ulcers may be slower in uncircumcised men who have ulcers under the foreskin. Resolution of fluctuant lymphadenopathy is slower than that of ulcers, and needle aspiration or incisional drainage may be necessary even during otherwise effective anti-infective therapy. While needle aspiration of buboes is a simpler procedure, incision and drainage of buboes may be preferred. Any individual who had sexual contact with a patient with chancroid within 10 days before the onset of the patient’s symptoms should be examined and treated for the disease, even if no symptoms are present.

Gonorrhea and Associated Infections

Ceftriaxone is used in adults and pediatric patients for the treatment of uncomplicated gonorrhea, disseminated gonorrhea, and various other gonococcal infections caused by penicillinase-producing strains of N. gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism.

Ceftriaxone has been considered a drug of choice for the treatment of uncomplicated and disseminated gonococcal infections since 1989 when the CDC first altered their guidelines for the treatment of the disease based on the increasing prevalence of antibiotic-resistantstrains of N. gonorrhoeae, including penicillinase-producing N. gonorrhoeae (PPNG), strains with plasmid-mediated resistance to tetracyclines (TRNG), and strains with chromosomally mediated resistance to multiple anti-infectives (CMRNG). Anti-infective regimens for the treatment of gonococcal infections should be selected based on the anatomic site of infection, prevalence of resistant N. gonorrhoeae in the community, and the relative efficacy, adverse effects, and costs of the various regimens.

While many anti-infective agents have been shown to be safe and effective for the treatment of uncomplicated and disseminated gonococcal infections, ceftriaxone has remained a drug of choice for the treatment of these infections since ceftriaxone-resistant strains of N. gonorrhoeae have not been reported, clinical experience with ceftriaxone is fairly extensive, and the drug provides sustained, high bactericidal concentrations in blood. When used in the treatment of uncomplicated urogenital or anorectal gonorrhea in clinical studies, ceftriaxone has been associated with a cure rate of about 99%.

Although other parenteral or oral cephalosporins may be as effective as ceftriaxone in the treatment of some gonococcal infections, clinical experience with these agents is more limited and they do not appear to offer any clear advantage over ceftriaxone. In addition, unlike some other drugs, ceftriaxone is effective for the treatment of uncomplicated gonorrhea at all sites, including cervical, urethral, rectal, and pharyngeal gonococcal infections.

Gonorrhea frequently is associated with coexisting chlamydial infection. Ceftriaxone, like other cephalosporins, penicillins, spectinomycin, and most single-dose quinolone regimens, is ineffective for the treatment of chlamydial infection. Because of the risks associated with untreated coexisting chlamydial infection, the CDC and most clinicians recommend that patients being treated for uncomplicated gonorrhea or disseminated gonococcal infection also receive an anti-infective regimen effective for presumptive treatment of uncomplicated genital chlamydial infection.

For presumptive treatment of chlamydia in adults and adolescents being treated for uncomplicated or disseminated gonococcal infections, the CDC and many clinicians recommend use of a single dose of oral azithromycin or a 7-day regimen of oral doxycycline.

For presumptive treatment of chlamydia in pregnant women, the CDC recommends a 7-day regimen of oral erythromycin or oral amoxicillin. The strategy of routine administration of a regimen effective against chlamydia in patients being treated for gonococcal infection has been recommended by the CDC for more than 10 years and appears to have resulted in decreases in the prevalence of genital chlamydial infection in some populations. In addition, since most N. gonorrhoeae isolated in the US are susceptible to doxycycline and azithromycin, dual therapy possibly may delay the development of resistance in N. gonorrhoeae.

Since the cost of presumptive treatment of chlamydia is less than the cost of testing for presence of chlamydia, routine dual therapy without chlamydial testing can be cost-effective for populations in which coinfection with chlamydia has been reported in 10-30% of gonococcal infections. In areas where the rate of coinfection with chlamydia is low and chlamydial testing is widely available, some clinicians may prefer to test for chlamydia rather than treat presumptively; however, presumptive treatment is indicated for patients who may not return for test results.

Ceftriaxone

Patients being treated for gonorrhea should be instructed to refer their sexual partner(s) for evaluation and treatment, and to avoid sexual intercourse until therapy has been completed and they and their partner(s) no longer have symptoms. Sexual partners of individuals with disseminated gonorrhea often have asymptomatic gonococcal infection. Individuals who had their last sexual contact with the gonorrhea patient within 60 days before the onset of symptoms or diagnosis in the patient should be evaluated and treated for both N. gonorrhoeae and chlamydia. If the patient reports that the last sexual contact occurred more than 60 days prior to the onset of symptoms or diagnosis, their most recent sexual partner should be treated. Individuals with HIV infection who also are infected with N. gonorrhoeae should receive the same treatment regimens recommended for other individuals with gonococcal infections. The single-dose ceftriaxone regimen used for the treatment of uncomplicated gonorrhea is not effective for the treatment of syphilis. (See Syphilis under Uses: Spirochetal Infections.)

Gonococcal Infections in Adults and Adolescents

Uncomplicated Cervical, Urethral, and Rectal Gonorrhea A single IM dose of ceftriaxone is one of several effective regimens for the treatment of uncomplicated cervical, urethral, or rectal infections caused by PPNG or nonpenicillinase-producing N. gonorrhoeae. The CDC and many clinicians recommend that uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents be treated with a single IM dose of ceftriaxone, a single oral dose of cefixime, or a single oral dose of certain fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline).

However, fluoroquinolones should not be used for the treatment of gonorrhea acquired in Asia or the pacific islands (including Hawaii) and may be inadvisable for infections acquired in other areas when N. gonorrhoeae with quinolone resistance have been reported (including California). (See Uses: Gonorrhea and Associated Infections, in Ciprofloxacin 8:12.18.) Alternative regimens that are recommended by the CDC for the treatment of uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents include a single IM dose of spectinomycin, a single IM dose of certain cephalosporins (ceftizoxime, cefotaxime, cefoxitin), or a single oral dose of certain fluoroquinolones (gatifloxacin, lomefloxacin, norfloxacin), given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia. Either a single 125- or 250-mg IM dose of ceftriaxone appears to be effective for the treatment of uncomplicated gonorrhea; however, the 125-mg dose is preferred by the CDC and many clinicians because of reduced cost and a smaller volume of solution for IM injection.

While the 250-mg ceftriaxone dose was recommended in the past because of concern that the lower dosage might accelerate the development of strains of N. gonorrhoeae resistant to the drug, the 125-mg dose provides sustained, high bactericidal concentrations in blood. Because quinolones and tetracyclines are contraindicated during pregnancy, pregnant women with uncomplicated gonorrhea should receive a single IM dose of ceftriaxone (or a single oral dose of cefixime or a single IM dose of another cephalosporin recommended for the treatment of uncomplicated gonorrhea) given in conjunction with a 7-day regimen of oral erythromycin or amoxicillin for the treatment of presumptive or diagnosed chlamydial infection.

A single IM dose of spectinomycin should be used in to treat uncomplicated gonorrhea in pregnant women who are hypersensitive to cephalosporins. Although patients receiving any of the currently recommended regimens for the treatment of uncomplicated gonorrhea do not need to return for a test of cure, patients should be advised to return for reevaluation if symptoms persist after treatment.

Reevaluation should include cultures and any N. gonorrhoeae isolated should be tested for in vitro susceptibility; if susceptibility testing cannot be performed locally, isolates should be forwarded to a reference laboratory for testing. Infections identified in patients who have received a recommended regimen for the treatment of gonorrhea usually reflect reinfection rather than treatment failure and indicate a need for improved patient education and referral of sexual partners. Persistent urethritis, cervicitis, or proctitis also may be caused by C. trachomatis or other organisms.

Uncomplicated Pharyngeal Gonorrhea

Pharyngeal gonococcal infections are more difficult to eradicate than cervical, urethral, or rectal infections. Ceftriaxone generally has been effective in the treatment of pharyngeal gonococcal infections whereas spectinomycin and many other currently available cephalosporins may be ineffective. The CDC and many clinicians state that uncomplicated pharyngeal gonococcal infections should be treated with a single IM dose of ceftriaxone or, alternatively, a single oral dose of ciprofloxacin given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia. Although chlamydial coinfection of the pharynx is rare, coinfection at genital sites sometimes occurs in patients with pharyngeal gonococcal infection.

Disseminated Gonococcal Infections

A multiple-dose regimen of IM or IV ceftriaxone (1 g once daily) is recommended by the CDC and many clinicians as the treatment of choice for the initial treatment of disseminated gonococcal infections in adults and adolescents. Alternatively, a multiple-dose parenteral regimen of certain IV cephalosporins (cefotaxime, ceftizoxime) or certain IV fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin), or IM spectinomycin can be used for the initial treatment of disseminated gonococcal infections in adults and adolescents. The initial parenteral regimen should be continued for 24-48 hours after improvement begins; therapy can then be switched to oral cefixime, oral ciprofloxacin, or oral ofloxacin, or oral levofloxacin and continued to complete at least 1 week of treatment. Unless the presence of coexisting chlamydial infection has been excluded by appropriate testing, individuals being treated for disseminated gonococcal infections also should receive an anti-infective regimen effective for presumptive treatment of chlamydia.

The CDC recommends that the patient be hospitalized for initial treatment of disseminated gonorrhea, especially when compliance may be a problem, when the diagnosis is uncertain, or when the patient has purulent synovial effusions or other complications. Disseminated gonococcal infection results from gonococcal bacteremia and often results in petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthritis; strains of N. gonorrhoeae that cause disseminated infections usually cause minimal genital inflammation.

Disseminated infections can result in perihepatitis and, rarely, endocarditis or meningitis. All patients with disseminated gonococcal infections should be examined for clinical evidence of endocarditis and meningitis; the recommended regimen for these infections is IV ceftriaxone. The CDC recommends that treatment of individuals with complicated disseminated gonococcal infections be undertaken in consultation with an expert.

Patients being treated for disseminated gonococcal infections should be instructed to refer their sexual partner(s) for evaluation and treatment. Partners of patients with disseminated infection often have asymptomatic gonococcal infections.

Gonococcal Conjunctivitis

The regimen of choice for the treatment of gonococcal conjunctivitis in adults and adolescents is a single 1-g IM dose of ceftriaxone. As an adjunct to anti-infective therapy, the infected eye can be irrigated once with sterile sodium chloride solution.

Gonococcal Epididymitis

A single 250-mg IM dose of ceftriaxone given in conjunction with a 10-day regimen of oral doxycycline is recommended by the CDC and many clinicians for the treatment of epididymitis most likely to be caused by N. gonorrhoeae and/or C. trachomatis (e.g., in those younger than 35 years of age). For epididymitis most likely to be caused by enteric bacteria (e.g., E. coli), for those allergic to cephalosporins and/or tetracyclines, or for patients 35 years of age or older, the CDC recommends a 10-day regimen of oral ofloxacin or oral levofloxacin. Empiric treatment of epididymitis is indicated before culture results are available. As an adjunct to therapy, bed rest, scrotal elevation, and analgesics are recommended until fever and local inflammation have subsided.

Although most patients can be treated as outpatients, hospitalization should be considered when severe pain suggests other diagnoses (e.g., torsion, testicular infarction, or abscess) or when patients are febrile or might be noncompliant.

Gonococcal Proctitis

A single 125-mg IM dose of ceftriaxone given in conjunction with a 7-day regimen of oral doxycycline is recommended by the CDC for the treatment of proctitis likely to be caused by N. gonorrhoeae and/or C. trachomatis.

Gonococcal Infections in Neonates and Infants

Gonococcal infections in neonates usually occur as the result of exposure to the mother’s infected cervical exudate and are apparent 2-5 days after birth. The most serious manifestations of N. gonorrhoeae infection in neonates are ophthalmia neonatorum and sepsis, arthritis, and meningitis; less serious manifestations include rhinitis, vaginitis, urethritis, and inflammation at sites of fetal monitoring (e.g., scalp). Because a neonate with gonococcal infection usually has acquired the organism from their mother, both the mother and her sexual partner(s) should be evaluated and treated for gonorrhea.

Prophylaxis of Gonococcal Infections in Neonates

While universal topical prophylaxis using 0.5% erythromycin ophthalmic ointment, silver nitrate 1% ophthalmic solution, or 1% tetracycline ophthalmic ointment (no longer commercially available in the US) is recommended for all neonates as soon as possible after birth to prevent gonococcal ophthalmia neonatorum, these topical anti-infectives are inadequate for prophylaxis of gonococcal infections at other sites, and may be ineffective in preventing chlamydial ocular infections.

Because neonates born to mothers with untreated gonorrhea are at high risk of infection with N. gonorrhoeae, these neonates also should receive parenteral prophylaxis against the disease. The CDC and AAP recommend that neonates born to mothers with documented peripartum gonococcal infection receive parenteral prophylaxis with a single IM or IV dose of ceftriaxone (25-50 mg/kg not to exceed 125 mg). Alternatively, the AAP states that these neonates can receive a single IM or IV dose of cefotaxime (100 mg/kg).

Gonococcal Ophthalmia Neonatorum

For the treatment of ophthalmia neonatorum caused by N. gonorrhoeae, the CDC, AAP, and many clinicians recommend that neonates receive a single IM or IV dose of ceftriaxone (25-50 mg/kg not to exceed 125 mg). Alternatively, the AAP states that a single IM or IV dose of cefotaxime (100 mg/kg) can be used for the treatment of gonococcal ophthalmia neonatorum. The single-dose ceftriaxone regimen is adequate therapy for gonococcal conjunctivitis, but infants with ophthalmia neonatorum should be hospitalized and evaluated for signs of disseminated infection (e.g., sepsis, arthritis, meningitis).

The AAP recommends that, as an adjunct to parenteral therapy in the treatment of gonococcal ophthalmia neonatorum, the neonate’s eyes should be irrigated with sterile sodium chloride solution immediately and at frequent intervals until the discharge is eliminated. Topical anti-infectives are inadequate for the treatment of gonococcal ophthalmia neonatorum and are unnecessary when appropriate systemic anti-infective therapy is given. Infants born to mothers with untreated gonorrhea are at increased risk for gonococcal ophthalmia neonatorum if they do not receive ophthalmic prophylaxis at birth.

Other neonates at increased risk for gonococcal ophthalmia neonatorum are those with mothers who received no prenatal care, have a history of sexually transmitted diseases, or a history of substance abuse. In all cases of neonatal conjunctivitis, conjunctival exudate should be cultured for N. gonorrhoeae and tested for anti-infective susceptibility and both mother and infant should be tested for chlamydial infection with appropriate tests.

The presence of typical gram-negative diplococci in gram-stained conjunctival exudate is strongly suggestive of gonococcal ophthalmia and justifies presumptive treatment for gonococcal infection after appropriate cultures have been obtained. Presumptive treatment for gonococcal infection also may be indicated for neonates with conjunctivitis who are at increased risk for gonococcal ophthalmia even if gram-negative diplococci are not identified in conjunctival exudate. Ophthalmia neonatorum also can be caused by M. catarrhalis or Neisseria other than N. gonorrhoeae. Simultaneous ophthalmic infection with C. trachomatis has been reported and should be considered in neonates who do not respond satisfactorily to ceftriaxone therapy.

Disseminated Gonococcal Infections

Neonates and infants with a documented gonococcal infection at any site (including the eyes or scalp) should be evaluated for the possibility of disseminated infection (e.g., sepsis, arthritis, meningitis). If disseminated gonococcal infection is present, the CDC, AAP, and many clinicians recommend a multidose regimen of IV or IM ceftriaxone or IV or IM cefotaxime. While either ceftriaxone or cefotaxime can be used for the treatment of disseminated gonococcal infections in neonates, ceftriaxone should be used with caution in neonates who are hyperbilirubinemic (especially those born prematurely) and the AAP suggests that cefotaxime may be preferred in these neonates.

Gonococcal Infections in Children

Uncomplicated Gonorrhea

For the treatment of uncomplicated gonococcal vulvovaginitis, cervicitis, epididymitis, urethritis, proctitis, or pharyngitis in prepubertal children who weigh less than 45 kg, the CDC and AAP recommend a single 125-mg IM dose of ceftriaxone given in conjunction with an anti-infective regimen effective for the presumptive treatment of chlamydia (e.g., a single oral dose of azithromycin or a 7-day regimen of oral erythromycin). Prepubertal children who weigh less than 45 kg and are allergic to cephalosporins can receive a single IM dose of spectinomycin (40 mg/kg not to exceed 2 g) for the treatment of uncomplicated gonorrhea; however, this drug is ineffective for pharyngeal infections.

The AAP suggests that a 5-day regimen of co-trimoxazole can be used for the treatment of pharyngeal infections in these children when cephalosporins and fluoroquinolones cannot be used. The CDC recommends that children with uncomplicated gonorrhea who weigh 45 kg or more should receive an anti-infective agent recommended for the treatment of these infections in adults and adolescents. The AAP recommends that children with uncomplicated gonococcal endocervicitis, urethritis, epididymitis, proctitis, or pharyngitis who weigh 45 kg or more and are 8 years of age or older receive a single-dose regimen of IM ceftriaxone, oral cefixime, oral ciprofloxacin, or oral ofloxacin given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (a single oral dose of azithromycin or a 7-day regimen of oral doxycycline).

Alternative regimens recommended by the AAP for these children are spectinomycin (a single IM dose), ceftizoxime, cefotaxime, cefotetan, or cefoxitin; spectinomycin is not recommended for pharyngeal infections. While follow-up cultures for test of cure generally are unnecessary in adolescents and adults who are asymptomatic after treatment of uncomplicated gonorrhea or in children treated with ceftriaxone, the CDC and AAP recommend that follow-up cultures be performed in children who receive other regimens to ensure that treatment was effective.

Disseminated Gonococcal Infections

For the treatment of disseminated gonococcal infections (e.g., bacteremia, arthritis) in prepubertal children weighing less than 45 kg, the CDC and AAP recommend a 7-day regimen of IM or IV ceftriaxone (50 mg/kg once daily not to exceed 1 g daily). For the treatment of gonococcal meningitis or endocarditis in these children, the same dosage (but up to 2 g daily, given in 2 divided doses) of IM or IV ceftriaxone should be given for 10-14 days or at least 4 weeks, respectively.

These children should also receive an anti-infective regimen effective for the presumptive treatment of chlamydia. The CDC recommends that children with disseminated gonococcal infections (e.g., bacteremia, arthritis) who weigh 45 kg or more receive a 10- to 14-day regimen of IM or IV ceftriaxone (50 mg/kg once daily not to exceed 2 g). The AAP suggests that disseminated gonococcal infections in children who weigh 45 kg or more and are 8 years of age or older can be treated with a 7-day regimen of IM or IV ceftriaxone or IV cefotaxime; however, a 10- to 14-day regimen of IV ceftriaxone should be used for the treatment of meningitis or endocarditis.

Alternative regimens recommended by the AAP for the treatment of disseminated gonococcal infections in these children are spectinomycin, ciprofloxacin, or ofloxacin; spectinomycin is not recommended for pharyngeal infections.

Pelvic Inflammatory Disease

Ceftriaxone is used for the treatment of pelvic inflammatory disease (PID) caused by N. gonorrhoeae. Ceftriaxone, like other cephalosporins, generally is inactive against C. trachomatis and should not be used alone in the treatment of PID. PID is an acute or chronic inflammatory disorder in the upper female genital tract and can include any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. PID generally is a polymicrobial infection most frequently caused by N. gonorrhoeae and/or Chlamydia trachomatis; however, organisms that can be part of the normal vaginal flora (e.g., anaerobic bacteria, Gardnerella vaginalis, H. influenzae, enteric gram-negative bacilli, S. agalactiae) or mycoplasma (e.g., Mycoplasma hominis, Ureaplasma urealyticum) also may be involved. PID is treated with an empiric regimen that provides broad-spectrum coverage. The regimen should be effective against N. gonorrhoeae and C. trachomatis and also probably should be effective against anaerobes, gram-negative facultative bacteria, and streptococci. The optimum empiric regimen for the treatment of PID has not been identified.

A wide variety of parenteral and oral regimens have been shown to achieve clinical and microbiologic cure in randomized studies with short-term follow-up; however, only limited data are available to date regarding elimination of the infection in the endometrium and fallopian tubes or intermediate or long-term outcomes, including the impact of these regimens on the incidence of long-term sequelae of PID (e.g., tubal infertility, ectopic pregnancy, pain). While many clinicians previously recommended that all patients with acute PID be hospitalized so that bedrest and supervised treatment with parenteral anti-infectives could be initiated, the CDC currently states that decisions regarding the necessity for hospitalization and whether an oral or parenteral regimen are most appropriate should be made on an individual basis since data are not available to date comparing efficacy of parenteral or oral therapy or inpatient or outpatient therapy.

Based on observational data and theoretical concerns, the CDC states that hospitalization is indicated if surgical emergencies such as appendicitis cannot be excluded; the patient is pregnant; the patient is unable to follow or tolerate an outpatient oral regimen; the patient has severe illness, nausea and vomiting, or high fever; the patient has a tubo-ovarian abscess; or a clinical response was not obtained with an oral anti-infective regimen.

Parenteral Regimens for PID

When a parenteral regimen is indicated for the treatment of patients with PID, the CDC and other clinicians generally recommend a 2-drug regimen of cefotetan (2 g IV every 12 hours) or cefoxitin (2 g IV every 6 hours) given in conjunction with doxycycline (100 mg IV or orally every 12 hours) or a 2-drug regimen of clindamycin (900 mg IV every 8 hours) and gentamicin (usually a 2-mg/kg IV or IM loading dose followed by 1.5 mg/kg every 8 hours). While there is some evidence that certain parenteral cephalosporins (e.g., ceftizoxime, cefotaxime, ceftriaxone) also may be effective for the treatment of PID, the CDC states that there is less experience with use of these cephalosporins in patients with PID and these drugs may be less active than cefotetan or cefoxitin against anaerobic bacteria.

The CDC states that limited data support the use of several alternative parenteral regimens for the treatment of acute PID, including IV levofloxacin (with or without IV metronidazole) or IV ampicillin sodium and sulbactam sodium with oral or IV doxycycline. Traditionally, parenteral regimens for the treatment of PID have been continued for at least 48 hours after the patient demonstrates substantial clinical improvement and then an oral regimen continued to complete a total of 14 days of therapy; however, the CDC states that a transition to oral therapy may occur within 24 hours after the patient demonstrates clinical improvement and that decisions regarding such a transition should be guided by clinical experience. Most clinicians recommend at least 24 hours of direct inpatient observation for patients with tubo-ovarian abscesses, after which time anti-infective therapy at home is adequate.

Oral Regimens for PID

When PID is treated with an oral regimen, the CDC recommends a 14-day regimen that consists of oral ofloxacin (400 mg twice daily) or oral levofloxacin (500 mg once daily) given in conjunction with or without oral metronidazole (500 mg twice daily for 14 days) or a regimen that consists of a single dose of a parenteral cephalosporin (e.g., cefoxitin, ceftriaxone, ceftizoxime, cefotaxime) given in conjunction with a 14-day regimen of oral doxycycline with or without oral metronidazole (500 mg twice daily for 14 days). Although ofloxacin is effective against both N. gonorrhoeae and C. trachomatis, the addition of metronidazole to the fluoroquinolone regimen may be necessary to provide adequate coverage against anaerobes.

The optimal parenteral cephalosporin for the second regimen is unclear; however, cefoxitin or ceftriaxone usually is preferred. Data are not available to date regarding use of oral cephalosporins for the treatment of PID. There is evidence from clinical trials that IM cefoxitin (given with probenecid) effectively produces a short-term clinical response in women with PID; however, because of theoretical limitations in cefoxitin’s coverage of anaerobes, the addition of metronidazole to the regimen may be necessary. In addition, metronidazole should be effective in the treatment of bacterial vaginosis, which is frequently associated with PID.

There are limited data suggesting that use of oral doxycycline and oral metronidazole after primary parenteral therapy is safe and effective.

Patient Follow-up and Management of Sexual Partners

Regardless of whether an oral or parenteral regimen is used, patients with PID should demonstrate substantial clinical improvement (e.g., defervescence; reduction in direct or rebound abdominal tenderness; reduction in uterine, adnexal, and cervical motion tenderness) within 72 hours after initiation of anti-infective therapy, and patients being treated on an outpatient basis should receive a follow-up examination within this period to ensure that a response is obtained. Patients who do not respond to oral therapy within 72 hours should be reevaluated to confirm the diagnosis and then given a parenteral regimen on either an outpatient or inpatient basis.

If clinical improvement is not evident within 72 hours, additional diagnostic tests and/or surgical intervention usually are indicated. In women who have documented infections with N. gonorrhoeae or C. trachomatis, some experts recommend rescreening for these organisms 4-6 weeks after therapy is completed. Sexual partners of women with PID should be examined and treated if they had sexual contact during the 60 days preceding the onset of symptoms in the patients. Evaluation and treatment are imperative because of the risk for reinfection and the strong likelihood of urethral gonococcal or chlamydial infection in the partner.

Male partners of women with PID caused by either organism often are asymptomatic. Sex partners should be treated empirically with regimens effective against these organisms, regardless of the apparent etiology of PID or pathogens isolated from the infected woman.

Actinomycosis

Ceftriaxone has been used in a limited number of patients to treat infections caused by Actinomyces. IV ceftriaxone has been effective when given on an outpatient basis for the treatment of thoracic actinomycosis and also has been effective when used for follow-up outpatient treatment after IV ceftizoxime in patients with endocarditis caused by Actinomyces viscosus. However, IV penicillin G generally is the drug of choice for the treatment of all forms of actinomycosis, including thoracic, abdominal, CNS, and cervicofacial infections. While an oral regimen of penicillin V or a tetracycline (e.g., doxycycline) may be effective for the treatment of mild cervicofacial infections, severe actinomycosis should be treated for 4-6 weeks with parenteral penicillin G followed by 6-12 months of therapy with oral penicillin V or amoxicillin. Alternative agents that can be used in patients hypersensitive to penicillin include tetracyclines, erythromycins, chloramphenicol, clindamycin, and third generation cephalosporins.

Bartonella Infections

IM or IV ceftriaxone has been used in conjunction with oral erythromycin or oral azithromycin for the treatment of bacteremia caused by Bartonella quintana (formerly Rochalimaea quintana). B. quintana, a gram-negative bacilli, can cause cutaneous bacillary angiomatosis, trench fever, bacteremia, endocarditis, and chronic lymphadenopathy. B. quintana infections have been reported most frequently in immunocompromised patients (e.g., individuals with HIV infection), homeless individuals in urban areas, and chronic alcohol abusers. Optimum anti-infective regimens for the treatment of infections caused by B. quintana have not been identified, and various drugs have been used to treat these infections, including doxycycline, erythromycin, azithromycin, chloramphenicol, or cephalosporins.

There is evidence that these infections tend to persist or recur and prolonged therapy (several months or longer) usually is necessary. The possible role of ceftriaxone in the treatment of infections caused by Bartonella henselae (formerly Rochalimaea henselae) (e.g., cat scratch disease, bacillary angiomatosis, peliosis hepatitis) has not been determined. Cat scratch disease generally is a self-limited illness in immunocompetent individuals and may resolve spontaneously in 2-4 months; however, some clinicians suggest that anti-infective therapy be considered for acutely or severely ill patients with systemic symptoms, particularly those with hepatosplenomegaly or painful lymphadenopathy, and such therapy probably is indicated in immunocompromised patients.

Anti-infectives also are indicated in patients with B. henselae infections who develop bacillary angiomatosis, neuroretinitis, or Parinaud’s oculoglandular syndrome. While the optimum anti-infective regimen for the treatment of cat scratch disease or other B. henselae infections has not been identified, some clinicians recommend use of azithromycin, erythromycin, doxycycline, ciprofloxacin, rifampin, co-trimoxazole, gentamicin, or third generation cephalosporins.

Capnocytophaga Infections

Based on results of in vitro susceptibility tests that indicate that Capnocytophaga generally are inhibited by ceftriaxone, some clinicians suggest that ceftriaxone can be used in the treatment of infections caused by this organism.

Capnocytophaga is a gram-negative bacilli that can cause life-threatening septicemia, meningitis, and/or endocarditis and often is associated with disseminated intravascular coagulation; splenectomized and immunocompromised individuals are at particularly high risk for serious Capnocytophaga infections. C. canimorsus (formerly CDC group DF-2) infection usually occurs as the result of a dog bite or other close contact with a dog. The optimum regimen for the treatment of infections caused by Capnocytophaga has not been identified, but some clinicians recommend use of penicillin G197, 463 or, alternatively, a third generation cephalosporin (cefotaxime, ceftizoxime, ceftriaxone), a carbapenem (imipenem and cilastatin sodium, meropenem), vancomycin, a fluoroquinolone, or clindamycin.

Neisseria meningitidis Infections

Ceftriaxone is used in the treatment of invasive infections caused by Neisseria meningitidis and also is used to eliminate nasopharyngeal carriage of N. meningitidis and for chemoprophylaxis to prevent meningococcal disease in close contacts of patients with invasive disease. Although IV penicillin G generally is considered the drug of choice for the treatment of meningitis caused by N. meningitidis, ceftriaxone and cefotaxime are considered acceptable alternatives. Patients with invasive meningococcal disease who have been treated with penicillin G or any anti-infective agent other than ceftriaxone or another third-generation cephalosporin may still be carriers of N. meningitidis and should receive an anti-infective regimen to eradicate nasopharyngeal carriage of the organism prior to hospital discharge.

Ceftriaxone, rifampin, or ciprofloxacin can be used to eradicate nasopharyngeal carriage of N. meningitidis. A single IM dose of ceftriaxone (125 mg in pediatric patients or 250 mg in adults) appears to be 97-100% effective in eliminating meningococci from the nasopharynx of carriers. While further study is needed to evaluate the relative efficacy of the drugs, there is some evidence that a single IM dose of ceftriaxone may be more effective than rifampin in eliminating pharyngeal carriage of N. meningitidis serogroup A.

Chemoprophylaxis in Household and Other Close Contacts of Individuals with Invasive Meningococcal Disease

When sporadic or cluster cases of meningococcal disease occur in the US, chemoprophylaxis is the principal means of preventing secondary cases in household and other close contacts of individuals with invasive disease. Recommended regimens for chemoprophylaxis against meningococcal disease include a single IM dose of ceftriaxone, 2 days of oral rifampin therapy (not recommended in pregnant women), or a single oral dose of ciprofloxacin (not recommended in individuals younger than 18 years of age unless no other regimen can be used and not recommended for pregnant or lactating women).

Although the AAP suggests that rifampin is the drug of choice for chemoprophylaxis in most instances, the CDC states that rifampin, ciprofloxacin, or ceftriaxone are all 90-95% effective and are all acceptable regimens for chemoprophylaxis. The attack rate for household contacts who do not receive chemoprophylaxis has been estimated to be 4 cases per 1000 individuals exposed, which is 500-800 times greater than that for the general population. A decision to administer chemoprophylaxis to close contacts of an individual with invasive meningococcal disease is based on the degree of risk.

Throat and nasopharyngeal cultures are not useful in determining the need for chemoprophylaxis and may unnecessarily delay administration of the regimen. The CDC and AAP currently recommend that chemoprophylaxis be administered to contacts of individuals with invasive meningococcal disease who are considered at high risk of infection. These high risk individuals include household contacts (especially young children) and any individual who has slept or eaten frequently in the same dwelling with the index case; child care and nursery school contacts who were exposed during the 7 days before the onset of disease in the index case; individuals exposed directly to oropharyngeal secretions of the index case (e.g., through kissing or sharing toothbrushes, eating utensils, or drinking containers) during the 7 days before the onset of disease in the index case; and medical personnel and others who had intimate exposure (e.g., through mouth to mouth resuscitation or unprotected contact during endotracheal intubation or suctioning) to the index case during the 7 days before the onset of disease.

Chemoprophylaxis is not routinely recommended for contacts considered at low risk of infection. Individuals considered in most circumstances as being at low risk include casual contacts with no history of direct exposure to the index case’s oral secretions (e.g., school or work contacts); individuals who had only indirect contact with the index case (only contact was with a high-risk contact of the index case); and medical personnel who had no direct exposure to the index case’s oral secretions. When chemoprophylaxis is indicated in high-risk contacts, it must be administered promptly (ideally within 24 hours after identification of the index case) since the attack rate of secondary disease is greatest in the few days following disease onset in the index case.

All high-risk contacts should be informed that even if chemoprophylaxis is taken or started, the development of any suspicious clinical manifestation warrants early, rapid medical attention. Chemoprophylaxis probably is of limited or no value if administered more than 2 weeks after contact with the index case. If high-risk exposure to a new index case occurs more than 2 weeks after initial chemoprophylaxis, additional chemoprophylaxis is indicated.

Outbreak Control

When an outbreak of meningococcal disease occurs in the US and the outbreak is caused by a vaccine-preventable meningococcal strain (i.e., serogroups A, C, Y, or W-135), large-scale vaccination programs with meningococcal polysaccharide vaccine in the appropriate target group is the principal control measure. (See Uses: Outbreak Control in Meningococcal Polysaccharide Vaccine 80:12.)

Mass chemoprophylaxis programs (e.g., with rifampin, ceftriaxone, ciprofloxacin) in large population groups is not effective in most settings in which organization- or community-based outbreaks have occurred and disadvantages of such programs (e.g., costs, difficulty in ensuring simultaneous administration of the drugs to large populations, adverse effects of the drugs, emergence of resistant organisms) probably outweigh any possible benefit in disease prevention. However, when outbreaks involve small populations (e.g., a small organization such as a single school), administration of chemoprophylaxis to all individuals in the population may be considered. The CDC states that other measures, such as restricting travel to areas with a suspected meningococcal outbreak, closing schools or universities, or canceling sporting or social events, are not recommended to control meningococcal outbreaks in the US.

While the vast majority of cases of meningococcal disease in the US are sporadic, the frequency of outbreaks of group C meningococcal disease has increased in the US and Canada since 1991 and there also have been small outbreaks as well as statewide epidemics caused by serogroup B. As a result, the CDC has published guidelines for the evaluation and management of suspected meningococcal outbreaks that can be used by US public health professionals (e.g., epidemiologists in state and local health departments), and these guidelines can be consulted for further information. In addition, the Childhood and Respiratory Diseases Branch, Division of Bacteria and Mycotic Diseases, National Center for Infectious Diseases, CDC can be consulted on these and other issues regarding meningococcal disease 404-639-2215 or 404-639-3311).

Pseudomonas aeruginosa Infections

Although ceftriaxone has been used in the treatment of infections caused by Pseudomonas aeruginosa and the manufacturer recommends its use in skin and skin structure infections caused by the organism, treatment failures have been reported when ceftriaxone was used alone in the treatment of urinary tract infections or respiratory tract infections caused by Ps. aeruginosa.

Some of these failures occurred because superinfection with resistant strains of Ps. aeruginosa occurred during therapy with the drug. Because many strains of Ps. aeruginosa are only susceptible to high concentrations of ceftriaxone in vitro and because resistant strains of the organism have developed during therapy with the drug, many clinicians state that ceftriaxone should not be used alone in the treatment of any infection where Ps. aeruginosa may be present.

Shigella Infections

Ceftriaxone has been effective when used in children for the treatment of shigellosis caused by susceptible Shigella sonnei or S. flexneri and, in one study, was more effective than ampicillin for the treatment of these infections. Anti-infective therapy generally is indicated in addition to fluid and electrolyte replacement for the treatment of severe cases of shigellosis since anti-infectives appear to shorten the duration of diarrhea and the period of fecal excretion of Shigella. Although ampicillin previously was considered the anti-infective of first choice for the treatment of shigellosis, especially in children, strains of S. flexneri and S. sonnei resistant to ampicillin have been reported with increasing frequency. Although ampicillin or co-trimoxazole may be effective when the strain is known to be susceptible to these drugs, a fluoroquinolone or ceftriaxone are considered the agents of choice for the treatment of shigellosis when the susceptibility of the isolate is unknown, especially in areas where ampicillin-resistant Shigella have been reported.

Typhoid Fever and Other Salmonella Infections

Typhoid Fever

Ceftriaxone has been effective when used in adults or children for the treatment of typhoid fever (enteric fever) or septicemia caused by Salmonella typhi or S. paratyphi, including multidrug-resistant strains. Ceftriaxone also has been used for the treatment of infections caused by nontyphi Salmonella, including bacteremia or osteomyelitis caused by S. typhimurium. IV ceftriaxone (3 or 4 g once daily in adults or 75 mg/kg once daily in children) given for 5-7 days is as effective as a 14-day course of oral or IV chloramphenicol in the treatment of typhoid fever caused by susceptible S. typhi. Although bacteremia resolved sooner with ceftriaxone in some of these patients, the time to defervescence was faster with chloramphenicol. Multidrug-resistant strains of S. typhi (i.e., strains resistant to ampicillin, chloramphenicol, and/or co-trimoxazole) have been reported with increasing frequency, and third generation cephalosporins (e.g., ceftriaxone, cefotaxime) and fluoroquinolones (e.g., ciprofloxacin, ofloxacin) are considered the agents of first choice for the treatment of typhoid fever or other severe infections known or suspected to be caused by these strains. Strains of S. typhi resistant to ceftriaxone have been reported only rarely in the US.

Salmonella Gastroenteritis

Anti-infective therapy generally is not indicated in otherwise healthy individuals with uncomplicated (noninvasive) gastroenteritis caused by Salmonella (e.g., S. enteritidis, S. typhimurium) since such therapy may prolong the duration of fecal excretion of the organism and there is no evidence that it shortens the duration of the disease; however, the CDC, AAP, IDSA, and others recommend anti-infective therapy in individuals with severe Salmonella gastroenteritis and in those who are at increased risk of invasive disease. These individuals include infants younger than 3-6 months of age; individuals older than 50 years of age; individuals with hemoglobinopathies, severe atherosclerosis or valvular heart disease, prostheses, uremia, chronic GI disease, or severe colitis; and individuals who are immunocompromised because of malignancy, immunosuppressive therapy, HIV infection, or other immunosuppressive illness.

When an anti-infective agent is considered necessary in an individual with Salmonella gastroenteritis, the CDC, AAP, IDSA, and others recommend use of ceftriaxone, cefotaxime, a fluoroquinolone (should be used in children only if the benefits outweigh the risks and no other alternative exists), ampicillin, amoxicillin, co-trimoxazole, or chloramphenicol, depending on the susceptibility of the causative organism. The fact that multidrug-resistant Salmonella serotype Newport have been reported with increasing frequency in the US should be considered.

During January-April 2002, 47 cases of gastroenteritis caused by Salmonella Newport were reported to the CDC; the vehicle of transmission appeared to be exposure to raw or undercooked ground beef. These strains usually are resistant to ampicillin, amoxicillin clavulanate, cefoxitin, cephalothin, chloramphenicol, streptomycin, sulfamethoxazole, or tetracycline and have either decreased susceptibility or resistance to ceftriaxone.

HIV-infected Individuals

While no controlled study has demonstrated a beneficial effect of such treatment and there is evidence from some studies in immunocompetent individuals that anti-infective agent therapy may prolong the duration of fecal excretion of the organism, some experts suggest that an anti-infective agent be administered to HIV-infected adults, HIV-exposed infants younger than 3 months of age, and severely immunosuppressed HIV-infected children with Salmonella gastroenteritis to prevent extraintestinal spread of the infection.

If anti-infective treatment is used in these HIV-infected patients, the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) recommends that adults receive ciprofloxacin and that children receive co-trimoxazole, ampicillin, cefotaxime, ceftriaxone, or chloramphenicol (fluoroquinolones should be used in children with caution and only if no alternatives exist).

However, pregnant HIV-infected women with Salmonella gastroenteritis should receive ampicillin, cefotaxime, ceftriaxone, or co-trimoxazole. In HIV-infected individuals who have been treated for bacteremia caused by Salmonella, the USPHS/IDSA and others recommended use of long-term suppressive or maintenance anti-infective therapy (secondary prophylaxis) to prevent recurrence or relapse.

The choice of anti-infective agent for such prophylaxis should be based on results of in vitro susceptibility testing of the causative organism. The USPHS/IDSA suggests use of a fluoroquinolone (usually ciprofloxacin) in HIV-infected adults and co-trimoxazole or, alternatively, ampicillin or chloramphenicol for HIV-infected children. In addition, the USPHS/IDSA recommends that household contacts of HIV-infected individuals treated for salmonellosis be evaluated for asymptomatic carriage of Salmonella so that strict hygienic measures and/or anti-infective prophylaxis can be instituted to prevent recurrent transmission to the HIV-infected individual.

Whipple’s Disease

Ceftriaxone has been effective when used in the treatment of Whipple’s disease, a progressive systemic infection caused by Tropheryma whippelii. The optimal anti-infective regimen for the treatment of Whipple’s disease has not been identified, in part because of difficulties in identifying and cultivating the causative agent and because relapses commonly occur, even after long-term therapy.

Some clinicians recommend that Whipple’s disease be treated with an initial 2-week parenteral regimen of penicillin G benzathine given in conjunction with streptomycin followed by oral co-trimoxazole given for 1-2 years.

Alternative regimens that have been recommended include oral co-trimoxazole given for at least 1 year; a 2-week parenteral regimen of ampicillin given in conjunction with ceftriaxone followed by a 1-year regimen of oral co-trimoxazole; or a 2-week parenteral regimen of ceftriaxone given in conjunction with streptomycin followed by a 1-year regimen of oral co-trimoxazole or oral cefixime.

Ceftriaxone has been effective for the treatment of Whipple’s disease when the CNS was involved, and some clinicians suggest that it may be a drug of choice for patients who experience cerebral relapse during or after treatment with penicillin G or co-trimoxazole.

Empiric Therapy in Febrile Neutropenic Patients

Ceftriaxone is used in conjunction with an aminoglycoside for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic adults or pediatric patients. While ceftriaxone has been used alone for empiric therapy in some febrile neutropenic patients considered to be at low risk, use of ceftriaxone monotherapy may not provide adequate coverage against some potential pathogens (e.g., Ps. aeruginosa) and generally is not recommended for empiric anti-infective therapy in febrile neutropenic patients. In studies in febrile neutropenic cancer patients 1 year of age or older, the overall response rate to a once-daily regimen of IV ceftriaxone (30 mg/kg in adults or 80 mg/kg in children) given in conjunction with IV amikacin (20 mg/kg daily) was similar to that of a regimen of IV ceftazidime (100-150 mg/kg daily given in 3 divided doses) given in conjunction with amikacin (20 mg/kg given once daily or in 3 divided doses).

Ceftriaxone has been administered in conjunction with amikacin on an outpatient basis for empiric anti-infective therapy in patients with advanced hematologic malignancies. For information on currently recommended regimens for the empiric treatment of febrile neutropenic patients, see Uses: Empiric Therapy in Febrile Neutropenic Patients, in the Cephalosporins General Statement 8:12.06.

Spirochetal Infections

Lyme Disease

Ceftriaxone is recommended by IDSA, AAP, and other clinicians for the treatment of severe forms or late complications of Lyme disease, a spirochetal disease caused by tick-borne Borrelia burgdorferi.

For information on the manifestations of Lyme disease and details about the efficacy of various anti-infective regimens in early or late Lyme disease, see Lyme Disease in Uses: Spirochetal Infections, in the Tetracyclines General Statement 8:12.. 497 Although oral anti-infectives (e.g., doxycycline, amoxicillin) generally are effective for the treatment of the early stages of the disease (e.g., erythema migrans, isolated facial nerve palsy, mild arthritis or carditis), more serious manifestations associated with early disseminated or late disease (e.g., severe carditis, meningitis, radiculoneuritis) generally require higher dosage, more prolonged therapy, and/or parenteral anti-infectives (e.g., IV ceftriaxone, cefotaxime, or penicillin G). (See Lyme Disease in Uses: Spirochetal Infections, in the Cephalosporins General Statement 8:12.06 and see Lyme Disease in Uses: Spirochetal Infections, in the Natural Penicillins General Statement 8:12..04.)

Although effective, IV ceftriaxone is not superior to recommended oral drugs for treatment of early Lyme disease and is not a recommended first-line agent in the absence of neurologic involvement or third-degree atrioventricular (AV) block. In a limited number of adults with late complications of Lyme disease (i.e., CNS dysfunction, peripheral neuropathy, and/or arthritis), most of whom failed to respond adequately to other anti-infectives (e.g., penicillin, tetracycline), ceftriaxone therapy (1 or 2 g IM or IV twice daily for 14 days) resulted in clinical improvement, including resolution of arthritis and chronic fatigue. A regimen of IV ceftriaxone (2 g once daily for 30 days) has been used with some success for the treatment of Lyme encephalopathy.

Although IV penicillin G therapy can be effective in treating neurologic abnormalities of Lyme disease, central or peripheral neurologic deficits associated with disease progression have been noted in a few patients after such therapy, and some clinicians suggest that therapy with IV ceftriaxone may be preferred for serious manifestations (i.e., involving major organs) of disseminated or late Lyme disease because of its greater in vitro and in vivo activity against B. burgdorferi compared with IV penicillin G and the prolonged serum concentrations and excellent CSF penetration achievable with once-daily administration of ceftriaxone.

The IDSA and other clinicians recommend IV ceftriaxone in patients with early Lyme disease who have acute neurologic disease manifested by meningitis or radiculopathy; alternatively, IV cefotaxime or IV penicillin G may be used.

Some clinicians suggest that oral or IV doxycycline for 14-28 days may be adequate therapy in adults with acute neurologic manifestations who are intolerant of cephalosporins and penicillin, although experience in the US with such a regimen for Lyme meningitis is limited. Most clinicians recommend that patients with severe cardiac involvement (e.g., third-degree AV block) be hospitalized for cardiac monitoring and receive IV ceftriaxone, penicillin G, or cefotaxime, although evidence supporting the superiority of IV versus oral therapy in these patients currently is lacking.

Some clinicians also recommend use of these IV regimens in patients with first-degree AV block and a PR-interval greater than 0.3 seconds. Patients with third-degree AV block may require a temporary pacemaker. While patients with uncomplicated Lyme arthritis generally can be treated with a prolonged course (e.g., 28 days) of oral anti-infectives (e.g., doxycycline or amoxicillin), the IDSA and other clinicians recommend that patients with Lyme arthritis and concomitant neurologic disease documented by CSF analysis should receive IV ceftriaxone or alternatively, IV cefotaxime or IV penicillin G.

Comparative studies evaluating different antibiotic regimens in patients with late Lyme disease generally are lacking. The IDSA and other clinicians recommend 14-28 days of therapy with IV ceftriaxone or a 28-day course of a recommended oral antibiotic in patients who have persistent or recurrent joint swelling after receiving an initial recommended antibiotic regimen. However, clinicians should consider allowing several months for joint inflammation to resolve after initial treatment before an additional course of antibiotic therapy is given. Patients with late neurologic disease affecting the CNS or peripheral nervous system (e.g., encephalopathy, neuropathy) should receive 14-28 days of IV ceftriaxone; alternative therapy is IV cefotaxime or IV penicillin G.

For additional details on antibiotic therapy in patients with late Lyme disease, see Treatment of Late or Persistent Manifestations of Lyme Disease under Spirochetal Infections: Lyme Disease, in Uses in the Tetracyclines General Statement 8:12.24. It has been suggested that, in order to facilitate rapid eradication and avoid possible congenital transmission of the infection, parenteral therapy with ceftriaxone or penicillin G may be preferred to oral antibiotic therapy in pregnant women with the early form of Lyme disease. However, available evidence to date suggests that transplacental transmission of B. burgdorferi occurs rarely, if at all, and epidemiologic studies in pregnant women have not documented an association between exposure to Lyme disease before conception or during pregnancy and subsequent fetal death, congenital malformations, or prematurity. The IDSA, AAP, and other clinicians state that pregnant or nursing women need not be treated differently than other patients with Lyme disease, except that they should not receive tetracyclines. (See Lyme Disease in Uses: Spirochetal Infections, in the Tetracyclines General Statement 8:12.24.)

Diagnosis of Lyme disease often is based on clinical manifestations, history of exposure in an endemic area, and positive results of an enzyme-linked immunoassay for serum antibodies to the organism. However, because of assay variability, lack of assay standardization, and the potential for false-positive results, this assay alone does not provide a definitive diagnosis of the disease.

After receiving recommended antibiotic therapy for Lyme disease, some patients manifest a post-infectious syndrome, which some clinicians have referred to as chronic Lyme disease or post-Lyme disease syndrome.

Many patients with positive antibody test results but without classic Lyme disease manifestations (e.g., erythema migrans) reportedly have received empiric IV antibiotic therapy for suspected, late-stage Lyme disease. However, the IDSA and other clinicians state that currently available evidence is insufficient to consider chronic Lyme disease a separate diagnostic entity and that no controlled clinical studies currently support the efficacy of repeated or prolonged courses of oral and/or IV antibiotics in patients who remain symptomatic after receiving appropriate therapy for Lyme disease (i.e., 2-4 weeks of recommended antibiotic treatment). (See Chronic Lyme Disease or Post-Lyme Disease Syndrome under Spirochetal Infections: Lyme Disease, in Uses in the Tetracyclines General Statement 8:12..) In addition, serious complications (e.g., biliary disease resulting in cholecystectomy) have occurred in some patients receiving repeated and prolonged courses of anti-infectives; at least one death has been reported in a patient receiving prolonged empiric therapy with IV antibiotics. (See Cautions: GI Effects.)

The American College of Rheumatology and IDSA state that the risks and costs of treating suspected Lyme disease empirically with IV antibiotics (e.g., ceftriaxone) exceed the benefits in patients with a positive antibody titer for Borrelia burgdorferi and only nonspecific complaints of myalgia or fatigue.

Relapsing Fever

Ceftriaxone may be effective for the treatment of relapsing fever caused by Borrelia recurrentis; however, other drugs (e.g., tetracycline, penicillin G) are considered the drugs of choice for the treatment of the disease.

Syphilis

Ceftriaxone has some activity against Treponema pallidum and there is some limited evidence that the drug may be effective for the treatment of syphilis. Although penicillin G is the drug of choice for the treatment of all stages of syphilis and data to support the use of penicillin alternatives are limited, the CDC states that use of an oral tetracycline (doxycycline, tetracycline) can be considered for the treatment of primary or secondary syphilis, latent syphilis, and tertiary syphilis in nonpregnant adults and adolescents hypersensitive to penicillin.

Although some experts suggest that IM or IV ceftriaxone also can be considered an alternative for the treatment of early syphilis in patients hypersensitive to penicillin, the CDC cautions that the optimal dosage and duration of ceftriaxone therapy for this use have not been defined. The CDC does, however, state that ceftriaxone can be used as an alternative for the treatment of neurosyphilis in patients hypersensitive to penicillin, although the possibility of cross-allergenicity should be considered. Because other regimens have not been adequately studied, if safety of ceftriaxone is a concern for a neurosyphilis patient hypersensitive to penicillin, skin testing should be done to confirm penicillin allergy and, if necessary, the patient should be desensitized and managed in consultation with an expert.

The CDC states that data are insufficient to recommend use of ceftriaxone for the treatment of early syphilis in pregnant women or pediatric patients hypersensitive to penicillin or for the treatment of congenital syphilis and the only acceptable alternatives to penicillin G for patients with late latent syphilis, syphilis of unknown duration, or tertiary syphilis are doxycycline or tetracycline. Use of ceftriaxone in HIV-infected individuals with syphilis has not been adequately studied and such therapy should be undertaken with caution. Because of limited experience with penicillin alternatives, close follow-up is essential if ceftriaxone is used in the treatment of syphilis. If compliance with an alternative regimen cannot be ensured in patients hypersensitive to penicillin, the CDC recommends desensitization and treatment with penicillin G. For information on current recommendations for the treatment of syphilis, see Syphilis under Uses: Spirochetal Infections, in the Natural Penicillins General Statement 8:12.16.04.

Perioperative Prophylaxis

Ceftriaxone has been effective when used perioperatively to reduce the incidence of infection in patients undergoing contaminated or potentially contaminated surgical procedures, including cholecystectomy, intra-abdominal surgery, or vaginal or abdominal hysterectomy, and in those undergoing clean surgical procedures in which the development of infection at the surgical site would represent a serious risk, including coronary artery bypass, open heart surgery, thoracic surgery, or orthopedic surgery.

The drug also has been used perioperatively in patients undergoing transurethral resection of the prostate. Although results of several controlled studies indicate that a single dose of ceftriaxone is as effective as multiple doses of cefazolin in reducing the incidence of infection in intra-abdominal surgery, vaginal hysterectomy, biliary tract surgery, or open heart surgery, second or third generation cephalosporins generally appear to be no more effective than first generation cephalosporins (e.g., cefazolin) for perioperative prophylaxis in patients undergoing obstetric and gynecologic, biliary tract surgery, cardiovascular, or orthopedic surgery.

Because of cost considerations and concerns about potential emergence of resistance with widespread use of extended-spectrum anti-infectives, a first generation cephalosporin (e.g., cefazolin) generally is preferred when a cephalosporin is used for such perioperative prophylaxis. Some clinicians state that cefazolin, cefotetan, or cefoxitin are the preferred drugs for perioperative prophylaxis and that third generation cephalosporins (e.g., cefoperazone, cefotaxime, ceftriaxone, ceftazidime, ceftizoxime) and fourth generation cephalosporins (e.g., cefepime) should not be used for perioperative prophylaxis since they are expensive, some are less active than cefazolin against staphylococci, they have a spectrum of activity that is wider than necessary for organisms encountered in elective surgery, and their use for prophylaxis promotes emergence of resistant organisms. (See Uses: Perioperative Prophylaxis, in the Cephalosporins General Statement 8:12.06.)

Prophylaxis in Sexual Assault Victims

IM ceftriaxone is used in conjunction with oral metronidazole and either oral azithromycin or oral doxycycline for empiric anti-infective prophylaxis in adult or adolescent victims of sexual assault. Trichomoniasis, genital chlamydial infection, gonorrhea, and bacterial vaginosis are the sexually transmitted diseases most commonly diagnosed in women following sexual assault; however, the prevalence of these infections is substantial among sexually active women and their presence after assault does not necessarily indicate that the infections were acquired during the assault.

Chlamydial and gonococcal infections among females are of special concern because of the possibility of ascending infection. Many experts recommend routine empiric prophylactic therapy after a sexual assault, and use of such prophylaxis probably benefits most patients since follow-up of assault victims can be difficult and such prophylaxis allays the patient’s concerns about possible infections.

When empiric anti-infective prophylaxis is indicated in adult or adolescent sexual assault victims, the CDC recommends administration of a single 125-mg IM dose of ceftriaxone given in conjunction with a single 2-g oral dose of metronidazole and either a single 1-g oral dose of azithromycin or a 7-day regimen of oral doxycycline (100 mg twice daily). This 3-drug regimen provides coverage against gonorrhea, chlamydia, trichomoniasis, and bacterial vaginosis, but efficacy in preventing these infections after sexual assault has not been evaluated.

Because of possible adverse GI effects with the 3-drug regimen, use of anti-emetic drugs may be considered (particularly if emergency contraception also is provided). Alternative regimens may be required for some patients because of the likelihood of transmission of other sexually transmitted diseases from the assailant. Postexposure hepatitis B vaccination also is recommended for sexual assault victims who have not previously received the vaccine; hepatitis B vaccine (without hepatitis B immune globulin) should be given to susceptible victims at the time of the initial examination.

CDC states that although a definitive recommendation concerning the appropriateness of antiretroviral prophylaxis against HIV cannot be made based on currently available information, such prophylaxis should be considered in cases in which the risk for HIV exposure during the assault is considered high. The decision to offer such prophylaxis should be individualized taking into account the probability of HIV transmission from a single act of intercourse and the nature of the assault (e.g., extent and site of physical trauma and exposure to ejaculate), the potential benefits and risks of prophylaxis, and the time interval between the exposure and initiation of therapy. (See Guidelines for Use of Antiretroviral Agents: Postexposure Prophylaxis following Sexual Assault or Nonoccupational Exposures to HIV, in the Antiretroviral Agents General Statement 8:18.08.)

There are few data available to establish the risk of a child acquiring a sexually transmitted disease as a result of sexual assault or abuse. The risk is believed to be low in most circumstances, although documentation to support this position is inadequate. The CDC currently states that presumptive treatment for children who have been sexually assaulted or abused is not widely recommended because prepubertal girls appear to be at lower risk for ascending infection than adolescent or adult women and regular follow-up usually can be assured.

Even if the risk is perceived by the health-care provider to be low, some children or their parents or guardians may have concerns about the possibility of the child contracting a sexually transmitted disease as a result of the assault and these concerns may be an appropriate indication for presumptive treatment in some settings. If empiric anti-infective prophylaxis is indicated in a preadolescent child following sexual assault, the AAP recommends a single 125-mg IM dose of ceftriaxone (or a single oral dose of cefixime) given in conjunction with a single oral dose of azithromycin (20 mg/kg in those weighing less than 45 kg; 1 g in those weighing 45 kg or more) or a 7-day regimen of oral doxycycline (100 mg twice daily in those weighing 45 kg or more) or a 10- to 14-day regimen of oral erythromycin (50 mg/kg daily in those weighing less than 45 kg).

Prophylaxis following Bite Wounds

Ceftriaxone is one of several alternatives that can be used for anti-infective prophylaxis following a bite wound. It has been suggested that anti-infective prophylaxis (preferably initiated within 8 hours of injury and continued for 2-3 days) may decrease the rate of infection following human or animal bite wounds; however, only limited data are available regarding use of such prophylaxis for patients with wounds that are not overtly infected.

Prophylaxis generally is unnecessary in patients with mild injuries in which the skin is only abraded. The AAP recommends that anti-infective prophylaxis be initiated following moderate or severe bite wounds (especially if edema or crush injury is present); puncture wounds (especially if bone, tendon sheath, or joint penetration may have occurred); facial bites; and bites on the hand, foot, or genital area. Such prophylaxis is recommended following bite wounds in any individual at high risk for infection (e.g., immunocompromised or asplenic individuals). If anti-infective prophylaxis is indicated after a dog, cat, reptile, or human bite wound, the AAP recommends an empiric regimen of oral amoxicillin and clavulanate or, alternatively, an IV regimen of ampicillin and sulbactam (or ticarcillin and clavulanate) with gentamicin added for reptile bites. Ceftriaxone is a possible alternative to these penicillins, but should not be used in those with a history of immediate (anaphylactic) hypersensitivity reactions to penicillins.

Dosage and Administration

Reconstitution and Administration

Ceftriaxone sodium usually is administered by IV infusion or deep IM injection. Ceftriaxone has been administered IM or IV to adults or children in outpatient settings such as the physician’s office, outpatient clinics, infusion centers, skilled nursing facilities, rehabilitation centers, or the patient’s home for the treatment of certain infections suitable for community-based parenteral anti-infective agent therapy (e.g., community-acquired pneumonia, osteomyelitis, endocarditis) or for empiric anti-infective agent therapy in febrile neutropenic patients.

Outpatient parenteral anti-infective therapy often is used to complete a course of ceftriaxone therapy initiated during hospitalization, but ceftriaxone therapy also has been initiated on an outpatient basis.

Ceftriaxone usually is administered in the outpatient setting by a healthcare provider; however, the drug has been self-administered in the patients’ home by the patient, family member, or other responsible person.

Intermittent IV Infusion

For intermittent IV infusion, vials labeled as containing 250 mg, 500 mg, 1 g, or 2 g of ceftriaxone should be reconstituted with 2.4, 4.8, 9.6, or 19.2 mL, respectively, of a compatible IV solution to provide solutions containing approximately 100 mg/mL. ADD-Vantage® vials labeled as containing 1 or 2 g of ceftriaxone should be reconstituted according to the manufacturer’s directions.

The manufacturer states that diluted solutions prepared from ADD-Vantage® vials of the drug should be administered only by IV infusion. The 10-g pharmacy bulk package of ceftriaxone is reconstituted by adding 95 mL of a compatible IV solution to provide a solution containing approximately 100 mg/mL. The ceftriaxone pharmacy bulk package is not intended for direct IV infusion; doses of the drug from the reconstituted bulk package must be further diluted in a compatible IV infusion solution prior to administration.

Reconstituted solutions of the drug should then be further diluted in a compatible IV solution, generally to a concentration of 10-40 mg/mL, although lower concentrations may be used if desired. Alternatively, piggyback units containing 1 or 2 g of ceftriaxone should be reconstituted with 10 or 20 mL, respectively, of a compatible IV solution and then further diluted to 50-100 mL with a compatible IV solution.

Thawed solutions of the commercially available frozen ceftriaxone sodium injections should be administered only by intermittent IV infusion. Commercially available frozen ceftriaxone sodium in dextrose injections should not be thawed by warming them in a water bath or by exposure to microwave radiation. A precipitate may form while the commercially available injection in dextrose is frozen; however, this usually will dissolve with little or no agitation upon reaching room temperature, and the potency of ceftriaxone sodium frozen injection is not affected.

After thawing at room temperature, the container should be checked for minute leaks by firmly squeezing the bag. The injection should be discarded if the container seal or outlet ports are not intact or leaks are found or if the solution is cloudy or contains a precipitate. Additives should not be introduced into the injection container. The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete. The manufacturer recommends that intermittent IV infusions of ceftriaxone sodium be infused over 30 minutes. In clinical studies, ceftriaxone has been infused over 15-30 minutes in adults or over 10-30 minutes in neonates or children.

IM Injection IM

injections of ceftriaxone sodium can be prepared by adding 0.9, 1.8, 3.6, or 7.2 mL of sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, bacteriostatic water for injection containing 0.9% benzyl alcohol, or 1% lidocaine hydrochloride (without epinephrine) to vials labeled as containing 250 mg, 500 mg, 1 g, or 2 g of ceftriaxone, respectively, to provide solutions containing approximately 250 mg/mL or by adding 1, 2.1, or 4.2 mL of one of these diluents to vials labeled as containing 500 mg, 1 g, or 2 g of ceftriaxone, respectively, to provide solutions containing approximately 350 mg/mL.

Alternatively, vials labeled as containing 500 mg or 1 g of ceftriaxone can be reconstituted according to the manufacturers’s instructions using the lidocaine hydrochloride diluent provided with the vials.

The manufacturer states that more dilute solutions of the drug may be used for IM injection if required. IM injections of ceftriaxone should be made deeply into a large muscle mass, using usual techniques and precautions. The plunger of the syringe should be drawn back before IM injection to ensure that the needle is not in a blood vessel. Solutions of the drug for IM injection that have been reconstituted with bacteriostatic water containing benzyl alcohol should not be used in neonates. (See Cautions: Pediatric Precautions.) The manufacturer states that solutions prepared from commercially available ADD-Vantage® vials should not be used for IM administration of the drug.

Dosage

Dosage of ceftriaxone sodium is expressed in terms of ceftriaxone and is identical for IM or IV administration. Adult Dosage The usual adult dosage of ceftriaxone for the treatment of most infections caused by susceptible organisms (except meningitis) is 1-2 g given once daily or in equally divided doses twice daily, depending on the type and severity of the infection.

The maximum adult dosage of ceftriaxone recommended by the manufacturer is 4 g daily. Endocarditis For the treatment of native valve endocarditis caused by penicillin-susceptible viridans streptococci or S. bovis (i.e., penicillin MIC 0.1 mcg/mL or less), the American Heart Association (AHA) recommends that adults receive 2 g of ceftriaxone IV or IM once daily for 4 weeks.

Alternatively, a 2-week regimen consisting of 2 g of ceftriaxone given IV once daily in conjunction with netilmicin (4 mg/kg IV once daily; no longer commercially available in the US) or gentamicin (3 mg/kg IV once daily) may be effective for the treatment of uncomplicated endocarditis caused by these organisms. However, 2-week regimens are not recommended for patients with complications such as extracardiac foci of infection or intracardiac abscesses. For the treatment of endocarditis caused by slow-growing fastidious gram-negative bacilli termed the HACEK group (i.e., Haemophilus parainfluenzae, H. aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae), the AHA recommends that adults receive 2 g of ceftriaxone IV or IM once daily given for 3-4 weeks for the treatment of native valve endocarditis or for 6 weeks for the treatment of prosthetic valve endocarditis.

Meningitis

For the treatment of meningitis caused by susceptible bacteria, the usual adult dosage of ceftriaxone is 2 g IV every 12 hours. IV ceftriaxone has been effective for the treatment of meningitis in some adults when administered in a dosage of 50-100 mg/kg (maximum dose 4 g) once daily. While 7 days of ceftriaxone therapy may be adequate for the treatment of uncomplicated meningitis caused by susceptible Haemophilus influenzae or Neisseria meningitidis, at least 10-14 days of therapy is suggested for complicated cases or meningitis caused by Streptococcus pneumoniae and at least 21 days of therapy is suggested for meningitis caused by susceptible Enterobacteriaceae (e.g., Escherichia coli, Klebsiella).

Respiratory Tract Infections

For empiric treatment of community-acquired pneumonia (CAP) in adults who are hospitalized for inpatient treatment, ceftriaxone usually is given in a dosage of 1 g every 12 or 24 hours (the twice daily dosage usually is recommended for critically ill patients) in conjunction with other anti-infectives. (See Community-acquired Pneumonia under Uses: Respiratory Tract Infections.)

Chancroid

For the treatment of chancroid caused by Haemophilus ducreyi, the US Centers for Disease Control and Prevention (CDC) and many clinicians recommend that adults and adolescents receive a single 250-mg IM dose of ceftriaxone.

Gonorrhea and Associated Infections

For the treatment of uncomplicated cervical, urethral, rectal, or pharyngeal gonorrhea caused by penicillinase-producing strains of Neisseria gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism, the CDC and many clinicians recommend that adults and adolescents receive a single 125-mg IM dose of ceftriaxone. The manufacturer recommends that adults receive a single 250-mg IM dose of ceftriaxone for the treatment of uncomplicated gonorrhea in adults; however, most experts prefer the lower dose for several reasons. (See Gonococcal Infections in Adults and Adolescents in Uses: Gonorrhea and Associated Infections.) For the treatment of disseminated gonococcal infections, adults and adolescents should receive 1 g of ceftriaxone IV or IM once daily.

The CDC recommends that ceftriaxone therapy be continued for 24-48 hours after improvement begins; therapy may then be switched to oral cefixime, oral ciprofloxacin, oral ofloxacin, or oral levofloxacin to complete at least 1 week of treatment.

For gonococcal meningitis or endocarditis, adults and adolescents should receive 1-2 g of ceftriaxone IV every 12 hours; therapy generally is continued for 10-14 days in patients with meningitis and for at least 4 weeks in patients with endocarditis.

For the treatment of gonococcal conjunctivitis, adults and adolescents should receive a single 1-g IM dose of ceftriaxone. For the treatment of epididymitis most likely to be caused by N. gonorrhoeae and/or chlamydia, adults and adolescents should receive a single 250-mg IM dose of ceftriaxone given in conjunction with a 10-day regimen of oral doxycycline. For the treatment of proctitis likely to be caused by N. gonorrhoeae and/or chlamydia, adults and adolescents should receive a single 125-mg IM dose of ceftriaxone given in conjunction with a 7-day regimen of oral doxycycline.

Pelvic Inflammatory Disease

For the treatment of acute pelvic inflammatory disease (PID) when the patient is not hospitalized, adolescents and adults may receive a single 250-mg IM dose of ceftriaxone followed by oral doxycycline (100 mg twice daily given for 14 days).

Neisseria meningitidis Infections

When ceftriaxone is used to eliminate nasopharyngeal carriage of Neisseria meningitidis or for chemoprophylaxis in close contacts following high-risk exposure to individuals with invasive meningococcal disease, adults and adolescents should receive a single 250-mg IM dose.

Typhoid Fever and Other Salmonella Infections

For the treatment of typhoid fever (enteric fever) or septicemia caused by Salmonella typhi or S. paratyphi, including infections caused by multidrug-resistant strains, adults have received ceftriaxone in a dosage of 2-4 g IM or IV once daily for 3-7 days. Alternatively, adults have received a dosage of 1 g once daily for 15 days.

While ceftriaxone has been effective for the treatment of typhoid fever when administered for 3-7 days,anti-infective therapy for the treatment of typhoid fever usually is continued for at least 14 days to prevent relapse and a duration of at least 4-6 weeks may be necessary for the treatment of immunocompromised individuals (including those with HIV infection) or for the treatment of Salmonella meningitis.

Empiric Anti-infective Agent Therapy in Febrile Neutropenic Patients

When used for empiric anti-infective agent therapy in febrile neutropenic patients, adults have received ceftriaxone in a dosage of 30 mg/kg (2 g) given IV once daily in conjunction with amikacin (20 mg/kg IV once daily).

Syphilis

If ceftriaxone is used as an alternative for the treatment of early syphilis in nonpregnant adults and adolescents hypersensitive to penicillins, some clinicians recommend a ceftriaxone dosage of 1 g IM or IV daily for 8-10 days. The CDC cautions that the optimal dosage and duration of the drug for the treatment of early syphilis have not been defined. If ceftriaxone is used as an alternative for the treatment of neurosyphilis in adults or adolescents hypersensitive to penicillin, some clinicians recommend a dosage of 2 g IM or IV daily for 10-14 days.

Lyme Disease

For the treatment of serious neurologic, cardiac, and/or arthritic manifestations of early disseminated or late Lyme disease in adults, many clinicians recommend a ceftriaxone dosage of 2 g IV once daily for 14-28 days.

Additional courses of antibiotic therapy generally are not recommended unless relapse of neurologic disease is documented with reliable objective measures. Perioperative Prophylaxis If ceftriaxone is used for perioperative prophylaxis in adults, 1 g should be given IV 0.5-2 hours prior to surgery.

For perioperative prophylaxis in patients undergoing cholecystectomy, adults have received 1 g of ceftriaxone IV 0.5-2 hours prior to surgery; however, higher doses (e.g., 2 g) also have been used. If ceftriaxone is used for perioperative prophylaxis, the drug usually is administered 0.5-2 hours prior to surgery to ensure adequate anti-infective tissue concentrations at the time of surgery. If signs of infection occur following surgery, specimens should be obtained for identification of the causative organism and appropriate therapy instituted.

Prophylaxis in Sexual Assault Victims

The CDC and AAP currently state that if empiric anti-infective prophylaxis is indicated in adult or adolescent sexual assault victims, a single 125-mg IM dose of ceftriaxone is given in conjunction with a single 2-g dose of oral metronidazole and either a single 1-g dose of oral azithromycin or a 7-day regimen of oral doxycycline (100 mg twice daily).

Pediatric Dosage

Children older than 12 years of age may receive usual adult dosages of ceftriaxone.

The usual dosage of ceftriaxone for neonates and children 12 years of age or younger for the treatment of skin and skin structure infections caused by susceptible organisms is 50-75 mg/kg daily given in a single daily dose or in equally divided doses every 12 hours.

For the treatment of serious infections (other than meningitis), the usual dosage of ceftriaxone is 50-75 mg/kg given in divided doses every 12 hours. The maximum dosage recommended by the manufacturer for pediatric patients is 2 g daily.

The American Academy of Pediatrics (AAP) recommends that neonates younger than 1 week of age receive 50 mg/kg of ceftriaxone once daily, and that neonates 1-4 weeks of age receive 50 mg/kg once daily (for those weighing 2 kg or less) or 50-75 mg/kg once daily (for those weighing more than 2 kg).

The AAP and other clinicians recommend that children older than 1 month of age receive ceftriaxone in a dosage of 50-75 mg/kg daily for the treatment of mild to moderate infections or a dosage of 80-100 mg/kg daily for the treatment of severe infections; daily dosage may be given in 1 or 2 doses.

Meningitis

For the treatment of meningitis caused by susceptible bacteria, the usual dosage of ceftriaxone for neonates and children 12 years of age or younger is 100 mg/kg daily (maximum 4 g daily) given once daily or in equally divided doses every 12 hours for 7-21 days. Some clinicians recommend that neonates and children with meningitis receive an initial dose of 80-100 mg/kg (maximum dose 4 g) of the drug at the time of diagnosis, followed by 80-100-mg/kg doses given 12 and 24 hours after the initial dose, then 80- to 100-mg/kg doses given once daily thereafter.

A twice-daily dosing regimen may be preferred for the treatment of meningitis caused by S. pneumoniae; if the once-daily dosing schedule is used, the daily dose must be given at the same time each day to ensure adequate CSF concentrations of the drug.

While 7 days of therapy may be adequate for the treatment of uncomplicated meningitis caused by susceptible H. influenzae or N. meningitidis, at least 10-14 days of therapy is suggested for complicated cases or meningitis caused by S. pneumoniae and at least 21 days is suggested for meningitis caused by susceptible Enterobacteriaceae (e.g., E. coli, Klebsiella).

Otitis Media

For the treatment of acute bacterial otitis media, pediatric patients should receive a single 50-mg/kg IM dose of ceftriaxone (maximum dose 1 g). Chancroid When ceftriaxone is used for the treatment of chancroid caused by H. ducreyi in infants or children, the AAP recommends a single 50-mg/kg IM dose. Gonorrhea and Associated Infections For the treatment of uncomplicated gonorrhea, the CDC states that children who weigh 45 kg or more can receive the ceftriaxone regimens recommended for the treatment of the treatment of uncomplicated gonorrhea in adults and adolescents.

Children who weigh less that 45 kg and who have uncomplicated gonococcal vulvovaginitis, cervicitis, urethritis, epididymitis, pharyngitis, or proctitis should receive a single 125-mg IM dose of ceftriaxone. For the treatment of disseminated gonococcal infections (e.g., bacteremia, arthritis) in prepubertal children who weigh less than 45 kg, 50 mg/kg (maximum 1 g) of ceftriaxone IM or IV once daily for 7 days.

For the treatment of gonococcal meningitis or endocarditis, these children should receive 50 mg/kg (maximum 2 g) of ceftriaxone IM or IV daily in equally divided doses every 12 hours; treatment generally is continued for 10-14 days in children with meningitis or for at least 4 weeks in children with endocarditis.

For the treatment of disseminated gonococcal infections (e.g., sepsis, arthritis, meningitis) or gonococcal scalp abscess in neonates, the usual dosage of ceftriaxone is 25-50 mg/kg once daily given IM or IV for 7 days or for 10-14 days if meningitis is documented. When ceftriaxone is used for parenteral prophylaxis of gonococcal infections in neonates born to mothers with documented peripartum gonococcal infections, the CDC recommends that 25-50 mg/kg (not to exceed 125 mg) of the drug be given IM or IV at birth; the AAP recommends use of a single 125-mg IM or IV dose.

For the treatment of gonococcal ophthalmia neonatorum, the CDC and AAP recommend that neonates receive a single 25- to 50-mg/kg (not to exceed 125 mg) dose of ceftriaxone given IM or IV. Neisseria meningitidis Infections When ceftriaxone is used to eliminate nasopharyngeal carriage of N. meningitidis or for chemoprophylaxis in household or other close contacts of individuals with invasive meningococcal disease, the AAP recommends a single 125-mg IM dose for children 12 years of age or younger and a single 250-mg IM dose for older children. The CDC recommends that children younger than 15 years of age receive a single 125-mg IM dose of ceftriaxone for such chemoprophylaxis.

Shigella Infections

For the treatment of shigellosis caused by Shigella sonnei or S. flexneri in pediatric patients, ceftriaxone has been given in a dosage of 50 mg/kg once daily for 2-5 days.

Typhoid Fever and Other Salmonella Infections

For the treatment of typhoid fever (enteric fever) or septicemia caused by Salmonella typhi, including multidrug-resistant strains, pediatric patients have received ceftriaxone in a dosage of 50-75 mg/kg given IM or IV once daily.

While ceftriaxone has been effective for the treatment of typhoid fever when administered for 3-7 days, anti-infective therapy for the treatment of typhoid fever usually is continued for at least 14 days to prevent relapse and a duration of at least 4-6 weeks may be necessary for the treatment of immunocompromised individuals (including those with HIV infection) or for the treatment of Salmonella meningitis.

Lyme Disease

For the treatment of serious neurologic, cardiac, and/or arthritic manifestations of early disseminated or late Lyme disease in children, the AAP and many clinicians recommend a ceftriaxone dosage of 75-100 mg/kg IM or IV once daily for 14-28 days. Additional courses of antibiotic therapy generally are not recommended unless relapse of neurologic disease is documented with reliable objective measures.

Prophylaxis in Sexual Assault Victims

The AAP currently states that if empiric anti-infective prophylaxis is indicated in a preadolescent sexual assault victim, a single 125-mg IM dose of ceftriaxone should be given in conjunction with a single oral dose of azithromycin (20 mg/kg in those weighing less than 45 kg; 1 g in those weighing 45 kg or more) or a 7-day regimen of oral doxycycline (100 mg twice daily in those weighing 45 kg or more) or a 10- to 14-day regimen of oral erythromycin (50 mg/kg daily in those weighing less than 45 kg).

Dosage in Renal and Hepatic Impairment

Modification of the usual dosage of ceftriaxone generally is unnecessary in patients with impaired renal or hepatic function alone; however, serum concentrations of the drug should be monitored when ceftriaxone is used in patients with severe renal impairment (e.g., dialysis patients) and in patients with both hepatic and substantial renal impairment. If evidence of accumulation of the drug occurs, dosage should be decreased accordingly. Dosage in adults with both hepatic and substantial renal impairment should not exceed 2 g daily unless serum concentrations of the drug are monitored closely. Because ceftriaxone is not removed by hemodialysis, supplemental doses of the drug are unnecessary during or after dialysis.

Cautions

Adverse effects reported with ceftriaxone are similar to those reported with other cephalosporins. For information on adverse effects reported with cephalosporins, see Cautions in the Cephalosporins General Statement 8:12.06. Ceftriaxone generally is well tolerated; adverse effects have been reported in about 10% of patients receiving ceftriaxone and have required discontinuance of the drug in less than 2% of these patients.

Hematologic Effects

Hematologic effects are among the most frequent adverse effects reported with ceftriaxone. Eosinophilia has been reported in about 6%, thrombocytosis in about 5%, and leukopenia in about 2% of patients receiving ceftriaxone. Anemia, neutropenia, lymphopenia, and thrombocytopenia have been reported in less than 1%1 and leukocytosis, lymphocytosis, monocytosis, agranulocytosis, and basophilia have been reported in less than 0.1% of patients receiving ceftriaxone.

Hypoprothrombinemia or prolongation of prothrombin time (PT), with or without bleeding, has been reported only rarely in patients receiving ceftriaxone (i.e., in less than 0.1% of patients). Although in one in vitro study very high concentrations of ceftriaxone (3-4 g/L) inhibited platelet aggregation, in vivo studies indicate that the drug does not interfere with platelet function.

Fatal hemolytic reactions have been reported in at least one adult and 2 children who received ceftriaxone. These reactions occurred shortly after administration of a ceftriaxone dose and consisted of severe intravascular hemolysis and anemia, decreased hemoglobin concentrations, reticulocytosis, hemoglobinuria, and cardiac arrest. In at least one case, the direct antiglobulin (Coombs’) test was strongly positive and the patient’s serum agglutinated washed erythrocytes in the presence of complement and ceftriaxone.

GI Effects

Diarrhea has generally been reported in 2-4% of patients receiving ceftriaxone. However, transient diarrhea reportedly occurred in 42-44% of children receiving ceftriaxone in 2 studies and in 28% (10/36) of adults receiving the drug in another study. Nausea, vomiting, and dysgeusia have been reported in less than 1%1 and abdominal pain, flatulence, dyspepsia, colitis, gallbladder sludge, and biliary lithiasis have been reported in less than 0.1% of patients receiving the drug. Clostridium difficile-associated diarrhea and colitis (also called antibiotic-associated pseudomembranous colitis) has been reported rarely in patients receiving ceftriaxone.

Mild cases of colitis may respond to discontinuance of ceftriaxone alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic and toxin studies and treatment with fluid, electrolyte, and protein supplementation as indicated. C. difficile-associated diarrhea and colitis may occur during or following discontinuance of cephalosporins. If colitis is severe or is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered.

Other causes of colitis should be considered. In studies in dogs and baboons receiving high dosages of ceftriaxone sodium, concretions consisting of the precipitated calcium salt of ceftriaxone have been found in gallbladder bile. These appeared as gritty sediment in dogs who received ceftriaxone in a dosage of 100 mg/kg daily for 4 weeks but were evident in the baboon only after a daily dosage of 335 mg/kg or more for 6 months.

The likelihood of this occurrence in humans has been considered to be low since ceftriaxone has a longer plasma half-life in humans, the calcium salt of ceftriaxone is more soluble in human gallbladder bile, and the calcium content of human gallbladder bile is relatively low. Sonographic abnormalities of the gallbladder have been reported in patients who received ceftriaxone; 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 material detected has been determined to be predominantly a ceftriaxone-calcium salt. In one study in children with various infections who received IV ceftriaxone in a dosage of 60-100 mg/kg daily, gallbladder precipitates developed in 43% of patients. The typical abnormality observed sonographically in these children was a strikingly hyperechogenic material with postacoustic shadowing; the precipitates differed from typical biliary sludge or cholelithiasis, usually were mobile, and tended to clump in the most dependent part of the gallbladder.

Although most patients have been asymptomatic, biliary symptoms (e.g., colic, nausea, vomiting, anorexia) can occur and may be severe enough to require discontinuance of ceftriaxone therapy. In a retrospective study of more than 1300 patients admitted to the hospital during a 2-year period with a diagnosis of Lyme disease, biliary symptoms (e.g., cholecystitis, cholelithiasis) or cholecystectomy occurred in approximately 2% of patients (84% were female with a median age of 12 years [range: 3-40 years]); 56% of these patients underwent laparoscopic cholecystectomy, mainly for cholelithiasis. Among cases and controls who received anti-infective therapy for treatment of suspected Lyme disease, each patient had received a median of 3 courses of oral and/or IV anti-infectives.

All patients with biliary symptoms had received IV ceftriaxone therapy within 90 days prior to the occurrence of biliary disease; daily ceftriaxone dosage at the time of onset of biliary symptoms in these patients averaged 57 mg/kg (range: 27-96 mg/kg), and the median duration of therapy was 28 days (range: 4-170 days). These data suggest an association between biliary complications and the repeated and often prolonged courses of IV ceftriaxone therapy used in these patients, most of whom lacked documented objective clinical or laboratory evidence of Lyme disease. (See Lyme Disease in Uses: Spirochetal Infections.)

The manufacturer states that ceftriaxone therapy should be discontinued in patients who develop manifestations suggestive of gallbladder disease and/or in those in whom characteristic sonographic abnormalities have been observed. Because the condition appears to be transient and generally resolves following discontinuance of the drug, surgery generally does not appear to be necessary.

The time to resolution, however, is variable and may range from a few days to several months. Upper abdominal ultrasonography should be considered for patients who develop biliary colic while receiving ceftriaxone therapy; biliary precipitates of ceftriaxone may be detected by ultrasonography after only 4 days of ceftriaxone therapy.

The risk of precipitation may depend on the dose and rate of IV administration of ceftriaxone, occurring more frequently with relatively high dosages and rapid (e.g., over several minutes) rates of administration. In some patients with renal impairment or those receiving higher than usual dosages of the drug, precipitates containing traces of ceftriaxone, possibly combined with calcium, have been recovered in surgical specimens.

Dermatologic and Sensitivity Reactions

Rash (e.g., erythematous, urticarial) has been reported in about 2% of patients receiving ceftriaxone and pruritus, fever, and chills have been reported in less than 1% of patients receiving the drug. Bronchospasm, anaphylaxis, and serum sickness have been reported in less than 0.1% of patients receiving the drug.

Hepatic Effects

Increased serum concentrations of AST (SGOT) and ALT (SGPT) have been reported in about 3% of patients and increased serum concentrations of alkaline phosphatase and bilirubin have been reported in less than 1% of patients receiving ceftriaxone. Jaundice has been reported in less than 0.1% of patients receiving the drug.

Renal Effects

Increased concentrations of BUN have been reported in about 1% of patients receiving ceftriaxone and increased concentrations of serum creatinine and the presence of casts in urine have been reported in less than 1% of patients receiving the drug. Glycosuria, hematuria, renal precipitations, and nephrolithiasis have been reported in less than 0.1% of patients receiving the drug. Urolithiasis (with renal colic) and transient impairment of renal function (e.g., increased serum creatinine concentration, decreased GFR), combined with cholelithiasis (see Cautions: GI Effects), has occurred in at least one patient during ceftriaxone therapy; these effects resolved following discontinuance of the drug.

Local Effects

Local reactions, including pain, induration, ecchymosis, and tenderness at the injection site, have been reported in 1-2% of patients receiving IM ceftriaxone. Local reactions occur less frequently and are less intense when IM injections of ceftriaxone are reconstituted with 1% lidocaine hydrochloride (without epinephrine) rather than sterile water for injection.

Results of a cross-over study involving IM injection into the buttock of 1-g doses of ceftriaxone diluted in 2 mL of sterile water for injection, 1% lidocaine, or 1% lidocaine buffered with sodium carbonate indicate that the pharmacokinetics of ceftriaxone are not affected by the diluent; however, use of a lidocaine diluent was associated with a 50-78% eduction in injection pain scores compared with use of sterile water for injection.

Buffered lidocaine did not appear to offer any advantages over unbuffered lidocaine. Phlebitis reportedly occurs in less than 1% of patients receiving IV ceftriaxone.

Other Adverse Effects

Other adverse effects that have been reported in less than 1% of patients receiving ceftriaxone include diaphoresis and flushing, headache, dizziness, oral candidiasis, and candidal vaginitis. Palpitation and epistaxis have been reported in less than 0.1% of patients receiving the drug. In at least one patient, inadvertent IV injection over 5 minutes of a 2-g dose of ceftriaxone resulted in a reaction that consisted of restlessness, shivering, diaphoresis with dilated pupils, and palpitations; this reaction did not occur when the drug was administered by IV infusion over 30 minutes as recommended by the manufacturer.

Precautions and Contraindications

Ceftriaxone shares the toxic potentials of the cephalosporins, and the usual precautions of cephalosporin therapy should be observed. Prior to initiation of therapy with ceftriaxone, careful inquiry should be made concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among cephalosporins and other b-lactam antibiotics including penicillins and cephamycins.

Ceftriaxone is contraindicated in patients who are hypersensitive to any cephalosporin and should be used with caution in patients with a history of hypersensitivity to penicillins. Use of cephalosporins should be avoided in patients who have had an immediate (anaphylactic) hypersensitivity reaction to penicillins.

Although it has not been proven that allergic reactions to antibiotics are more frequent in atopic individuals, the manufacturer states that ceftriaxone should be used with caution in patients with a history of allergy, particularly to drugs. Use of ceftriaxone may result in overgrowth of nonsusceptible organisms, especially Candida, enterococci, Bacteroides fragilis, or Pseudomonas aeruginosa. Resistant strains of Ps. aeruginosa and Enterobacter have developed during therapy with ceftriaxone. (See Resistance.) Careful observation of the patient during ceftriaxone therapy is essential. If superinfection or suprainfection occurs, appropriate therapy should be instituted. Ceftriaxone should be used with caution in patients with a history of GI disease, particularly colitis.

Because Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) has been reported with the use of cephalosporins, it should be considered in the differential diagnosis of patients who develop diarrhea during ceftriaxone therapy. Since ceftriaxone can precipitate in the gallbladder (see Cautions: GI Effects), some clinicians recommend that ceftriaxone be used with caution in patients with preexisting disease of the gallbladder, biliary tract, liver, or pancreas, and, if the drug is used in such patients, that serial abdominal ultrasonography be performed during therapy. The drug should be discontinued and conservative management considered in any patient who develops signs and symptoms suggestive of gallbladder disease, including sonographic abnormalities.

Although prolongation of prothrombin time (PT) has been reported only rarely in patients receiving ceftriaxone, the manufacturer states that PT should be monitored when the drug is used in patients with impaired vitamin K synthesis or low vitamin K stores (e.g., patients with chronic hepatic disease, malnutrition). The manufacturer states that administration of vitamin K (10 mg weekly) may be necessary if the PT is prolonged before or during ceftriaxone therapy. Although dosage adjustments are not usually necessary when ceftriaxone is used in patients with renal impairment or hepatic impairment alone, serum concentrations of the drug should be monitored when ceftriaxone is used in patients with severe renal impairment (e.g., dialysis patients) and in patients with both renal and hepatic impairment. In this latter group of patients, ceftriaxone dosage should not exceed 2 g daily unless serum concentrations of the drug are monitored closely. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Pediatric Precautions

Ceftriaxone, at therapeutic concentrations, has been shown to displace bilirubin from albumin binding sites in vitro. Addition of the drug to blood samples obtained from hyperbilirubinemic neonates resulted in increased free and erythrocyte-bound bilirubin concentrations and decreased unconjugated (albumin-bound) bilirubin concentrations.

Because the drug can displace bilirubin from serum albumin, ceftriaxone should not be administered to hyperbilirubinemic neonates, particularly those who are premature. Ceftriaxone that has been reconstituted for IM use with bacteriostatic water for injection containing benzyl alcohol should not be used in neonates. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates.

Mutagenicity and Carcinogenicity

In vitro studies using microbial (i.e., Ames test) or mammalian cell (i.e., human lymphoblasts) systems have not shown ceftriaxone to be mutagenic. Specific studies to determine the carcinogenic potential of ceftriaxone have not been performed to date, and animal toxicity studies have been performed to a maximum duration of only 6 months.

Pregnancy, Fertitlity and Lactation

Safe use of ceftriaxone during pregnancy has not been definitely established. Reproduction studies in mice and rats using dosages up to 20 times the usual human dosage have not revealed evidence of embryotoxicity, fetotoxicity, or teratogenicity. In primates, dosages up to approximately 3 times the usual human dosage have not revealed evidence of embryotoxicity or teratogenicity. There are no adequate or controlled studies using ceftriaxone in pregnant women, and the drug should be used during pregnancy only when clearly needed. Studies in rats using IV dosages of ceftriaxone up to 20 times the usual human dosage have not revealed evidence of impaired fertility. Because ceftriaxone is distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Probenecid

Concomitant administration of oral probenecid (500 mg daily) does not appear to affect the pharmacokinetics of ceftriaxone, presumably because ceftriaxone is excreted principally by glomerular filtration and nonrenal mechanisms. However, higher dosages of oral probenecid (1 or 2 g daily) administered concomitantly reportedly may partially block biliary secretion of ceftriaxone as well as displace the drug from plasma proteins. As a result, serum clearance of ceftriaxone may be increased by about 30% and elimination half-life of ceftriaxone may be decreased by about 20%.

Aminoglycosides

In vitro studies indicate that the antibacterial activity of ceftriaxone and aminoglycosides (amikacin, gentamicin, tobramycin) may be additive or synergistic against some strains of Enterobacteriaceae and some strains of Pseudomonas aeruginosa. Although the clinical importance has not been determined to date, antagonism has also occurred rarely in vitro when ceftriaxone was used in combination with an aminoglycoside. Organisms with high-level resistance to both the aminoglycoside and the b-lactam antibiotic alone are unlikely to be synergistically inhibited by concomitant use of the drugs.

Quinolones

Although the clinical importance is unclear, results of an in vitro study indicate that the combination of ceftriaxone and trovafloxacin is synergistic against both penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae, including some strains that also were resistant to ceftriaxone alone. There was no evidence of antagonism with the combination of ceftriaxone and trovafloxacin.

Alcohol

A disulfiram-like reaction reportedly occurred in one patient who ingested alcohol while receiving ceftriaxone; however, this effect generally has been reported only with b-lactam antibiotics that contain an N-methylthiotetrazole (NMTT) side chain (e.g., cefamandole, cefoperazone, cefotetan).

Laboratory Test Interferences

Tests for Urinary Glucose

Like most cephalosporins, ceftriaxone interferes with urinary glucose determinations using cupric sulfate (e.g., Benedict’s solution, Clinitest®); however, glucose oxidase methods (e.g., Clinistix®, Tes-Tape®) are unaffected by the drug.

Tests for Creatinine

In one in vitro study, high concentrations of ceftriaxone (50 mcg/mL or greater) caused falsely elevated serum creatinine values when a manual method was used; however, other studies indicate that the drug does not interfere with automated methods for determining serum or urinary creatinine concentrations.

Acute Toxcicity

Limited information is available on the acute toxicity of ceftriaxone; there is no specific antidote. If acute overdosage of ceftriaxone occurs, supportive and symptomatic treatment should be initiated. Ceftriaxone is not removed by hemodialysis or peritoneal dialysis, and these procedures would be ineffective in reducing ceftriaxone concentrations following overdosage.

Mechanism of Action

Ceftriaxone usually is bactericidal in action.

Like other cephalosporins, the antibacterial activity of the drug results from inhibition of mucopeptide synthesis in the bacterial cell wall. For information on the mechanism of action of cephalosporins, see Mechanism of Action in the Cephalosporins General Statement 8:12.06. Spectrum Based on its spectrum of activity, ceftriaxone is classified as a third generation cephalosporin.

For information on the classification of cephalosporins and closely related b-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06.

Like other currently available parenteral third generation cephalosporins (e.g., cefoperazone, cefotaxime, ceftazidime, ceftizoxime), ceftriaxone generally is less active in vitro against susceptible staphylococci than first generation cephalosporins but has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins.

The spectrum of activity of ceftriaxone closely resembles that of cefotaxime, ceftazidime, and ceftizoxime. In vitro on a weight basis, the activity of ceftriaxone against most susceptible organisms, including most Enterobacteriaceae, is approximately equal to that of cefotaxime or ceftizoxime.

In Vitro Susceptibility Testing

Results of in vitro susceptibility tests with ceftriaxone for some bacteria (e.g., Enterobacter cloacae, Klebsiella pneumoniae, Proteus, Pseudomonas, Serratia, staphylococci) may be affected by the size of the inoculum.

Although results of ceftriaxone susceptibility tests do not appear to be affected by culture media, results may be affected by pH101, 104 or the presence of serum. MICs of ceftriaxone for Staphylococcus aureus, Pseudomonas aeruginosa, or Enterobacteriaceae may be 4-8 times higher when tested in the presence of serum. The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to ceftriaxone, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to ceftriaxone, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated (e.g., urine) or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.

If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to ceftriaxone, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical studies. Strains of staphylococci resistant to penicillinase-resistant penicillins should be considered resistant to ceftriaxone, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to ceftriaxone, a disk containing 30 mcg of ceftriaxone should be used. The cephalosporin class disk containing 30 mcg of cephalothin or disks containing other cephalosporins should not be used to test susceptibility to ceftriaxone. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus, Enterobacteriaceae, Pseudomonas aeruginosa, or Acinetobacter with growth inhibition zones of 21 mm or greater are susceptible to ceftriaxone, those with zones of 14-20 mm have intermediate susceptibility, and those with zones of 13 mm or less are resistant to the drug.

Strains of Escherichia coli and Klebsiella that produce extended-spectrum b-lactamases (ESBLs) may not respond to ceftriaxone therapy despite apparent evidence of susceptibility in standard in vitro susceptibility procedures. Specialized screening and confirmatory tests should be performed on clinical isolates ofE. coli and K pneumoniae, and K. oxytoca to evaluate presence of ESBLs, and all ESBL-producing strains should be considered resistant to ceftriaxone. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 26 mm or greater should be considered susceptible to ceftriaxone. Because of limited data on resistant strains, NCCLS recommends that any Haemophilus isolate that appears to be nonsusceptible to ceftriaxone be submitted to a reference laboratory for further testing. When disk-diffusion is performed according to NCCLS standardized procedures using GC agar base (with 1% defined growth supplement), N. gonorrhoeae with growth inhibition zones of 35 mm or greater should be considered susceptible to ceftriaxone.

Because of limited data on resistant strains, NCCLS recommends that any N. gonorrhoeae isolate that appears to be nonsusceptible to ceftriaxone be submitted to a reference laboratory for further testing. Interpretive criteria are not available to determine susceptibility of Streptococcus pneumoniae to ceftriaxone using the disk-diffusion procedure, and NCCLS states that dilution susceptibility tests should be used for this organism. NCCLS states that S. pneumoniae found to be susceptible to penicillin using a 1-mcg oxacillin disk and the NCCLS standardized procedure can be considered susceptible to ceftriaxone.

When the NCCLS standardized procedure for disk susceptibility testing of streptococci is performed using Mueller-Hinton agar (supplemented with 5% sheep blood), viridans streptococci with growth inhibition zones of 27 mm or greater are susceptible to ceftriaxone, those with zones of 25-26 mm have intermediate susceptibility, and those with zones of 24 mm or less are resistant to the drug. When the standardized procedure is used to test susceptibility of b-hemolytic streptococci, those with growth inhibition zones of 24 mm or greater should be considered susceptible to ceftriaxone. Because strains of b-hemolytic streptococci with zone diameters less than 24 mm have not been reported to date, any such strains should be submitted to a reference laboratory.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus, Enterobacteriaceae, and Ps. aeruginosa and other non-Enterobacteriaceae gram-negative bacilli (e.g., other Pseudomonas spp., Acinetobacter, Stenotrophomonas maltophilia) with MICs of 8 mcg/mL or less are susceptible to ceftriaxone, those with MICs of 16-32 mcg/mL have intermediate susceptibility, and those with MICs of 64 mcg/mL or greater are resistant to the drug. Strains of E. coli and Klebsiella that produce extended-spectrum b-lactamases (ESBLs) may not respond to ceftriaxone therapy despite apparent evidence of susceptibility in standard in vitro susceptibility procedures.

Specialized screening and confirmatory tests should be performed on clinical isolates of E. coli, K. pneumoniae, and K. oxytoca to evaluate presence of ESBLs, and all ESBL-producing strains should be considered resistant to ceftriaxone. When NCCLS standardized procedures for broth dilution are performed using HTM, Haemophilus with MICs of 2 mcg/mL or less should be considered susceptible to ceftriaxone. Because of limited data on resistant strains, NCCLS recommends that any Haemophilus isolate that appears to be nonsusceptible to ceftriaxone be submitted to a reference laboratory for further testing. When agar dilution susceptibility testing for N. gonorrhoeae is performed according to the NCCLS standardized procedure using GC agar base (with 1% defined growth supplement), N. gonorrhoeae with MICs of 0.25 mcg/mL or less should be considered susceptible to ceftriaxone.

Because of limited data on resistant strains, NCCLS recommends that any N. gonorrhoeae isolate that appears to be nonsusceptible to ceftriaxone be submitted to a reference laboratory for further testing. When broth dilution susceptibility testing for S. pneumoniae is performed according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (supplemented with 2-5% lysed horse blood), S. pneumoniae isolates from patients with meningitis with MICs of 0.5 mcg/mL or less are susceptible to ceftriaxone, those with MICs of 1 mcg/mL have intermediate susceptibility, and those with MICs of 2 mcg/mL or greater are resistant to the drug. NCCLS states that S. pneumoniae isolates from patients with infections other than meningitis with MICs of 1 mcg/mL or less are susceptible to ceftriaxone, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug. In addition, NCCLS states that S. pneumoniae isolates found to be susceptible to penicillin using NCCLS standardized broth dilution procedure can be considered susceptible to ceftriaxone.

When broth dilution susceptibility testing of viridans streptococci is performed according to NCCLS standardized procedures, those with MICs of 1 mcg/mL or less are susceptible to ceftriaxone, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug. When this procedure is used to test susceptibility of b-hemolytic streptococci, those with MICs of 0.5 mcg/mL or less are considered susceptible to ceftriaxone. Because of limited data on resistant strains, any b-hemolytic streptococcal isolate that appears to be nonsusceptible to ceftriaxone should be submitted to a reference laboratory for further testing.

Gram-positive Aerobic Bacteria

Ceftriaxone is active in vitro against most gram-positive aerobic cocci including penicillinase-producing and nonpenicillinase-producing strains of Staphylococcus aureus and S. epidermidis; Streptococcus pneumoniae; S. pyogenes (group A b-hemolytic streptococci); S. agalactiae (group B streptococci); and viridans streptococci (including the S. milleri group [S. anginosus, S. constellatus, S. intermedius]). Staphylococci resistant to penicillinase-resistant penicillins also generally are resistant to ceftriaxone. Group D streptococci and enterococci, including E. faecalis (formerly S. faecalis), generally are resistant to ceftriaxone. The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of ceftriaxone for penicillinase-producing and nonpenicillinase-producing S. aureus is 3-8 mcg/mL. The MIC90 of the drug reported for S. epidermidis is 16-50 mcg/mL and the MIC50 of the drug reported for this organism is 3.1-7.3 mcg/mL. The MIC90 of ceftriaxone for S. pyogenes is 0.15-0.25 mcg/mL, and the MIC90 of the drug reported for S. agalactiae is 0.06-0. mcg/mL.

The MIC90 reported for viridans streptococci is 0.5-4 mcg/mL. In one study, the MIC50 and MIC90 of ceftriaxone for the S. milleri group of viridans streptococci were 0.25 and 0.5 mcg/mL, respectively. Although the MIC90 reported for S. pneumoniae generally is 0.15-0.25 mcg/mL, some strains have reduced susceptibility and require ceftriaxone concentrations of 0.5-2 mcg/mL or greater for in vitro inhibition.

Strains of S. pneumoniae with MICs of 2 mcg/mL or greater generally are considered resistant to ceftriaxone; however, strains with MICs of 0.5-1 mcg/mL that are isolated from patients with meningitis generally also are considered resistant to the drug. Although a few strains of Listeria monocytogenes may be inhibited in vitro by ceftriaxone concentrations of 0.8-32 mcg/mL, most strains of the organism are resistant to the drug.

Gram-negative Aerobic Bacteria

Neisseria

Ceftriaxone is active in vitro against Neisseria meningitidis and against most strains of penicillinase-producing (PPNG) and nonpenicillinase-producing Neisseria gonorrhoeae and those with chromosomally mediated resistance (e.g., to penicillin) (CMRNG) or plasmid-mediated tetracycline resistance (TRNG). Ceftriaxone concentrations of 0.001-0.025 mcg/mL generally inhibit N. meningitidis. The MIC90 of ceftriaxone is 0.002-0.02 mcg/mL for nonpenicillinase-producing N. gonorrhoeae and 0.001-0.15 mcg/mL for penicillinase-producing strains of the organism. In a large Centers for Disease Control and Prevention (CDC) surveillance program of N. gonorrhoeae isolates, of which 1% were PPNG and 5% were TRNG, the mean MIC of ceftriaxone was 0.003 mcg/mL; no isolate was resistant to the drug, but 2% of isolates had MICs of 0.06-0.25 mcg/mL.

Haemophilus

Ceftriaxone is active in vitro against most b-lactamase-producing and non-b-lactamase-producing strains of Haemophilus influenzae, H. parainfluenzae, and H. ducreyi.The MIC90 of the drug reported for H. influenzae is 0.003-0.03 mcg/mL. H. ducreyi generally is inhibited in vitro by ceftriaxone concentrations of 0.002-0.06 mcg/mL.

Enterobacteriaceae

Generally, ceftriaxone is active in vitro against the following Enterobacteriaceae: Citrobacter diversus, C. freundii, Enterobacter cloacae, E. aerogenes, Escherichia coli, Klebsiella pneumoniae, Morganella morganii (formerly Proteus morganii), Proteus mirabilis, P. vulgaris, Providencia rettgeri (formerly Proteus rettgeri), P. stuartii, Serratia marcescens, Salmonella, Shigella, and Yersinia enterocolitica. The MIC90 of ceftriaxone for most of these Enterobacteriaceae, including Citrobacter, E. coli, Klebsiella, M. morganii, P. vulgaris, Providencia, and Yersinia enterocolitica, is 0.05-4 mcg/mL. The MIC90 of the drug for P. mirabilis is 0.006-0. mcg/mL. Although the MIC90 of ceftriaxone reported for E. aerogenes generally is 0.12-8 mcg/mL, the MIC90 of the drug reported for E. cloacae is 0.5-25 mcg/mL. The MIC90 of ceftriaxone for S. marcescens is 0.25-32 mcg/mL. The MIC90 of ceftriaxone reported for Salmonella enteritidis, S. paratyphi, S. sendai, S. typhi, and S. typhimurium is 0.04-0. mcg/mL. Strains of Salmonella resistant to ceftriaxone have been reported rarely. Multidrug-resistant Salmonella serotype Newport has been reported with increasing frequency in the US. These strains usually are resistant to ampicillin, amoxicillin clavulanate, cefoxitin, cephalothin, chloramphenicol, streptomycin, sulfamethoxazole, or tetracycline and have either decreased susceptibility or resistance to ceftriaxone. The MIC90 of ceftriaxone reported for Shigella, including Sh. sonnei, is 0.02-0.5 mcg/mL.

Pseudomonas

Although ceftriaxone is active in vitro against some strains of Pseudomonas aeruginosa, many strains of the organism require ceftriaxone concentrations of 64 mcg/mL or greater for in vitro inhibition and are therefore considered resistant to the drug.

Ceftriaxone generally is less active in vitro against susceptible Ps. aeruginosa than cefoperazone, ceftazidime, or extended-spectrum penicillins (e.g., piperacillin). In some in vitro studies, the MIC50 of ceftriaxone for Ps. aeruginosa was 4-16 mcg/mL and the MIC90 of the drug was 16-32 mcg/mL. However, in other studies, the MIC50 was 16-64 mcg/mL and the MIC90 was 64 mcg/mL or greater. Ceftriaxone has some activity against Pseudomonas other than Ps. aeruginosa. The MIC90 of ceftriaxone reported for Ps. acidovorans and Ps. stutzeri is 2-16 mcg/mL, but Ps. fluorescens and Ps. putida generally are resistant to the drug.

Other Gram-Negative Aerobic Bacteria

Ceftriaxone is active in vitro against Moraxella and Eikenella corrodens, and the MIC90 of the drug reported for these organisms is 1-2 mcg/mL. While ceftriaxone has some activity in vitro against Acinetobacter and the MIC90 of ceftriaxone reported for A. calcoaceticus and A. lwoffi is 8-32 mcg/mL, the MIC90 reported for A. baumanii is 64 mcg/mL and this organism is considered resistant to the drug. Alcaligenes faecalis may be inhibited in vitro by ceftriaxone concentrations of 0.5 mcg/mL or less; however, A. denitrificans and A. xylosoxidans generally are resistant to the drug. In vitro, some strains of Bartonella bacilliformis are inhibited by ceftriaxone concentrations of 0.003-0.006 mcg/mL. In one study, all strains of Burkholderia cepacia (formerly Pseudomonas cepacia) tested were resistant to ceftriaxone. Ceftriaxone is active in vitro against Capnocytophaga, including C. canimorsus (formerly CDC group DF-2). The MIC90 of ceftriaxone reported for Capnocytophaga is 4 mcg/mL.

Stenotrophomonas maltophilia (formerly Ps. maltophilia or Xanthomonas maltophilia) generally is resistant to ceftriaxone. Some strains of Weeksella virosa are inhibited in vitro by ceftriaxone concentrations of 0.5 mcg/mL or lower.

Anaerobic Bacteria

Ceftriaxone is active in vitro against some anaerobic bacteria including Actinomyces, Fusobacterium, Lactobacillus, Peptococcus, Peptostreptococcus, Propionibacterium, andVeillonella. The MIC90 of ceftriaxone reported for most of these anaerobic bacteria is 0.5-16 mcg/mL. Some strains of Clostridium, including C. perfringens, are inhibited in vitro by ceftriaxone concentrations of 0.5-16 mcg/mL; however, C. difficile generally is resistant to the drug. Most strains of Bacteroides fragilis are resistant to ceftriaxone. Although the MIC50 of ceftriaxone reported for B. fragilis, B. distasonis, B. ovatus, B. thetaiotaiomicron, and B. vulgatus is 2-64 mcg/mL, the MIC90 is 32 mcg/mL or greater. The MIC90 of ceftriaxone reported for Prevotella melaninogenica (formerly Bacteroides melaninogenicus) is 4-16 mcg/mL.

Spirochetes

Studies in rabbits with experimentally induced syphilis indicate that ceftriaxone has some activity against Treponema pallidum. Borrelia burgdorferi, the causative organism of Lyme disease, reportedly may be inhibited in vitro by ceftriaxone concentrations of 0.1-1 mcg/mL; minimum bactericidal concentrations (MBCs) of ceftriaxone for B. burgdorferi generally have ranged from 0.02-0.16 mcg/mL.

Chlamydia

Studies using a limited number of isolates indicate that some strains of Chlamydia trachomatis are inhibited in vitro by ceftriaxone concentrations of 8-32 mcg/mL; however, the clinical importance of this in vitro activity is unclear. Ceftriaxone generally is considered to be inactive against C. trachomatis. Resistance For information on possible mechanisms of bacterial resistance to cephalosporins, see Resistance in the Cephalosporins General Statement 8:12.06. C

eftriaxone generally is stable against hydrolysis by b-lactamases classified as Richmond-Sykes types II, III (TEM types), and V; some PSE types; and most b-lactamases produced by Neisseria gonorrhoeae, Haemophilus influenzae, and staphylococci. Ceftriaxone may be inactivated by Richmond type IV b-lactamases, and in vitro studies indicate that some b-lactamases produced by Bacteroides, Citrobacter, Enterobacter, Morganella, Proteus, and Pseudomonas can inactivate the drug. Ceftriaxone generally is as stable as cefotaxime against inactivation by b-lactamases but less stable than cefoxitin. Resistant strains of some organisms, including Enterobacter and Ps. aeruginosa, have developed during therapy with ceftriaxone.

Although further study is needed, it has been suggested that resistance may develop in many of these organisms because they possess inducible b-lactamases. These inducible enzymes generally are chromosomally mediated cephalosporinases classified as Richmond-Sykes type I. In vitro studies indicate that following exposure to certain b-lactam antibiotics (e.g., cefoxitin), inducible b-lactamases are derepressed. Inducible b-lactamases appear to inactivate b-lactam antibiotics by binding to the drugs, which prevents them from binding to penicillin-binding proteins of the organism. Most b-lactam antibiotics, including second and third generation cephalosporins and extended-spectrum penicillins, are inactivated by inducible b-lactamases.

Strains of S. pneumoniae considered resistant to ceftriaxone have been reported with increasing frequency. These strains generally have intermediate- or high-level resistance to penicillin G as well as decreased susceptibility to third generation cephalosporins. Resistance to ceftriaxone in S. pneumoniae appears to be related to alterations in the target enzymes, penicillin-binding proteins (PBPs), of the organism.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, ceftriaxone was administered as ceftriaxone sodium; dosages and concentrations of the drug are expressed in terms of ceftriaxone. Ceftriaxone exhibits nonlinear dose-dependent pharmacokinetics. Serum concentrations, the area under the serum concentration-time curve (AUC), and most pharmacokinetic parameters (except elimination half-life and the fraction excreted unchanged in urine) of total ceftriaxone (both protein-bound and unbound drug) are dose dependent and increase nonlinearly with increases in dosage.

However, pharmacokinetic parameters of free (unbound) ceftriaxone are not dose dependent and increase linearly with dosage. Dose-dependent changes in the pharmacokinetic parameters of ceftriaxone apparently occur because the drug exhibits concentration-dependent protein binding. (See Pharmacokinetics: Distribution.) Some clinicians suggest that because of this concentration-dependent protein binding, distribution and clearance parameters calculated with data obtained using concentrations of total ceftriaxone may be invalid and misleading. Other clinicians suggest that concentration-dependent protein binding and dose-related changes in the pharmacokinetic parameters of ceftriaxone over the usual dosage range of the drug are small and not clinically important.

Absorption

Ceftriaxone is not appreciably absorbed from the GI tract and must be given parenterally. Following IM administration of a single ceftriaxone dose of 0.5-1 g in healthy adults, the drug appears to be completely absorbed, and peak serum concentrations are attained 1.5-4 hours after the dose. In one study in healthy adults who received a single 1-g IM dose of ceftriaxone, serum concentrations of the drug averaged 28.9,43.7,62.3,83.2,40.6,35.5 and 7.8 mcg/mL at 0.25, 0.5, 1, 2, 6, 12, and 24 hours, respectively, after the dose.

Following IV infusion over 30 minutes of a single 1-g dose of ceftriaxone in healthy adults, peak serum concentrations of the drug at completion of the infusion average 123.-150. mcg/mL and serum concentrations at 1, 2, 6, 12, and 24 hours after start of the infusion average 109.5-111, 60.8-88.2,33-52.5,20.2-28.1, and 4.6-9.3 mcg/mL, respectively. IV infusion over 30 minutes of a single 2-g dose of ceftriaxone in healthy adults results in peak serum concentrations of the drug at completion of the infusion that range from 223-276 mcg/mL and serum concentrations at 1, 2, 6, 12, and 24 hours after start of the infusion that range from 166-209, 135-173, 75-104, 32-58, and 7-22 mcg/mL, respectively. In one study in healthy adults, a ceftriaxone dosage of 2 g daily was given either as 1 g every 12 hours or 2 g every 24 hours; each dose was administered by IV infusion over 30 minutes. At steady state, peak serum concentrations of the drug ranged from 132-213 mcg/mL in those who received 1 g every 12 hours and from 216-281 mcg/mL in those who received 2 g every 24 hours; trough serum concentrations ranged from 23-58 and 7-27 mcg/mL, respectively.

Average steady-state serum concentrations of ceftriaxone were similar for both regimens and were 72 mcg/mL when 1 g was given every 12 hours and 63 mcg/mL when 2 g was given every 24 hours. In multiple-dose studies in healthy adults who received a ceftriaxone dosage of 0.5-2 g given every 12 or 24 hours by IM injection or IV infusion over 30 minutes, serum concentrations of the drug at steady state on the fourth day of therapy were 15-36% higher than serum concentrations attained with single doses of the drug. In one study in adults with neoplastic disease, IM administration of a single 500-mg dose of ceftriaxone resulted in serum concentrations of the drug averaging 28, 31.9, 32.9, 28.3 and 25.5 mcg/mL at 0.5, 1, 2, 4, and 6 hours, respectively, after the dose.

IV infusion over 5 minutes of a single ceftriaxone dose of 500 mg or 1 g in these patients resulted in serum concentrations of the drug at 0.5, 1, 2, 4, and 8 hours that averaged 54.4,44.7, 33.5, 25.4,and 16. mcg/mL, respectively, after the 500-mg dose and 79.3, 65.7, 52.2, 28.7 and 22. mcg/mL, respectively, after the 1-g dose. In one study in neonates and children 1-45 days of age with meningitis who received a single ceftriaxone dose of 50 mg/kg by IV infusion over 15 minutes, serum concentrations of the drug immediately following the infusion and 1, 2, 4, and 6 hours later averaged 136-173, 91-116, 80-112, 70-86, and 66-74 mcg/mL, respectively. In another study in neonates 1-4 days of age with meningitis who received a single 50-mg/kg dose of ceftriaxone by IV infusion over 5 minutes, serum concentrations of the drug 1, 12, and 24 hours after the dose ranged from 108-141, 43-76, and 20-52 mcg/mL, respectively.

Serum concentrations of ceftriaxone in neonates 9-30 days of age with meningitis who received a single 100-mg/kg dose of the drug by IV infusion over 5 minutes ranged from 100-262, 43-140, and 8-33 mcg/mL at 1, 12, and 24 hours, respectively, after the dose. In one study in children 7-15 months of age who received a single ceftriaxone dose of 50 mg/kg by IV infusion over 5 minutes, serum concentrations of the drug ranged from 139-197, 66.6-99.2, 31.3-58.9,2.4-14.8, and 0.85-8.4 mcg/mL at 0.5, 4, 8, 24, and 32 hours, respectively, after the dose.

When the same dose was administered by IV infusion over 5 minutes to children 2-6 years of age, serum concentrations of the drug at the same time intervals ranged from 180-209, 74.4-108, 32.5-70.2, 5.1-16.1, and 2.4-7. mcg/mL, respectively. In another study in children 2 months to 16 years of age with CNS infections who received a single ceftriaxone dose of 50 or 75 mg/kg by IV infusion over 15 minutes, peak serum concentrations of the drug occurred immediately following the infusion and ranged from 162-370 mcg/mL after the 50-mg/kg dose and 218-348 mcg/mL after the 75-mg/kg dose; serum concentrations of the drug 12 hours after the dose ranged from 8-56.7 and 13.4-51.2 mcg/mL, respectively.

Distribution

The volume of distribution of ceftriaxone is dose dependent and ranges from 5.8-13. L in healthy adults. The volume of distribution of the drug averages 8.5-9.4 L in healthy adults following a single 500-mg dose of the drug and 10-11.4 L following a single 2-g dose. The volume of distribution of ceftriaxone is 0.497-0.608 L/kg in neonates 1-45 days of age and 0.26-0.54 L/kg in children 1.5 months to 16 years of age following a single ceftriaxone dose of 50-100 mg/kg. Following IM or IV administration, ceftriaxone is widely distributed into body tissues and fluids including the gallbladder, lungs, bone, heart, bile, prostate adenoma tissue, uterine tissue, atrial appendage,sputum, tears, middle ear fluid, and pleural, peritoneal, synovial, ascitic, and blister fluids.

In pediatric patients with otitis media who received a single 50-mg/kg IM dose of ceftriaxone, peak concentrations of ceftriaxone (both protein-bound and unbound drug) in middle ear fluid were attained 24-30 hours after the dose and averaged 35 mcg/mL; middle ear fluid concentrations 48-52 hours after the dose averaged 19 mcg/mL. In one study in adults with normal hepatobiliary and renal function who received a single 500-mg IV dose of ceftriaxone, peak concentrations of the drug in bile occurred 1-2 hours after the dose and concentrations in bile were generally 2-5 times higher than concurrent serum concentrations. In another study in patients who received a single 1-g IV dose of ceftriaxone, concentrations of the drug in specimens obtained 1-3 hours after the dose averaged 62.1 mcg/mL in plasma, 78.2 mcg/g in the gallbladder wall, and 581, 788, and 898 mcg/mL in gallbladder, common duct, and cystic duct biles, respectively. In one study in patients undergoing open heart surgery who received a single 1-g IV dose of ceftriaxone approximately 1 hour prior to surgery, concentrations of the drug in the right atrial appendage ranged from 3.6-10.2 mcg/g in samples obtained 1.5-3 hours after the dose. In a study in patients undergoing abdominal or vaginal hysterectomy who received a single 2-g IV dose of ceftriaxone, peak concentrations of the drug in gynecologic tissue occurred during the first 2 hours after the dose and concentrations of the drug were higher in the salpinges than in myometrium or endometrium. Ceftriaxone concentrations in the salpinges averaged 53.1 and 31.3 mcg/mL at 1-2 and 4-5 hours, respectively, after the dose, and concentrations in myometrium or endometrium averaged 29.8-36.6 and 21.4-24.9 mcg/mL at 1-2 and 4-5 hours, respectively, after the dose.

Only low concentrations of ceftriaxone are distributed into aqueous humor following IV or IM administration of the drug. In one study in patients undergoing cataract surgery who received a single 1- or 2-g dose of ceftriaxone by IV infusion over 10 minutes, peak concentrations of the drug in aqueous humor were attained approximately 2 hours after the dose and averaged 0.93 and 2.47 mcg/mL, respectively. Aqueous humor concentrations averaged 0.88 mcg/mL 12 hours after the 1-g dose and were 2.1 and 2.5 mcg/mL in two patients 12 hours after the 2-g dose.

Ceftriaxone generally diffuses into CSF following IM or IV administration of the drug; however, CSF concentrations of the drug are higher in patients with inflamed meninges than in those with uninflamed meninges.

Studies in neonates and children with meningitis indicate that peak CSF concentrations of ceftriaxone generally are attained 3-6 hours after an IV dose of the drug, and CSF concentrations of ceftriaxone may be 1-32% of concurrent serum concentrations. CSF concentrations of ceftriaxone do not generally correlate with CSF leukocyte cell counts or CSF protein or glucose concentrations.

In one study in neonates and children with meningitis who received a single 50- or 100-mg/kg dose of ceftriaxone, CSF concentrations of the drug were 5-31. and 1.4-4. mcg/mL at 4 and 24 hours, respectively, after the dose. In another study in children 2-42 months of age with meningitis who received a single ceftriaxone dose of 50 mg/kg given by IV infusion over 10-15 minutes, CSF concentrations of the drug averaged 1.2-3, 1.4-4.3, and 2.8-7.2 mcg/mL at 1, 4, and 6 hours, respectively, after the dose. In one adult with meningitis who received 2 g of the drug once daily, the concentration in CSF was 8.5 mcg/mL in a specimen obtained 5 hours after the third dose of the drug.

The degree of protein binding of ceftriaxone is concentration dependent and decreases nonlinearly with increasing concentrations of the drug. It has been suggested that ceftriaxone may have more than one concentration-dependent protein binding site.

The drug is 93-96% bound to plasma proteins at a concentration less than 70 mcg/mL, 84-87% bound at a concentration of 300 mcg/mL, and 58% or less bound at a concentration of 600 mcg/mL. Ceftriaxone binds mainly to albumin.

Protein binding of ceftriaxone is lower in neonates and children than in adults because of decreased plasma albumin concentrations in this age group. In one study in children 7 months to 6 years of age with ceftriaxone plasma concentrations of 118-202 mcg/mL, ceftriaxone was 80-87% bound to plasma proteins. Ceftriaxone also is less protein bound in patients with renal or hepatic impairment as the result of decreased plasma albumin concentrations or displacement from protein binding sites by bilirubin and other endogenous compounds that may accumulate.

Ceftriaxone crosses the placenta and is distributed into amniotic fluid. In one study in women who received a single 2-g dose of ceftriaxone given by IV injection over 2-5 minutes during labor, peak concentrations of the drug in cord blood, amniotic fluid, and the placenta occurred 4-8 hours after the dose; ceftriaxone concentrations in the first voided urine of infants born to these women ranged from 6-92 mcg/mL. Ceftriaxone also is distributed into milk in low concentrations. In one study in lactating women who received a single 1-g IM or IV dose of ceftriaxone, peak concentrations of the drug in milk occurred 4-6 hours after the dose and the AUC for milk was 3-4% of the AUC for serum.

Elimination

Plasma concentrations of ceftriaxone decline in a biphasic manner. In adults with normal renal and hepatic function, the distribution half-life (t1/2a) of ceftriaxone is 0.12-07. hours and the elimination half-life (t1/2b) is 5.4-10. hours.

Ceftriaxone is excreted both by renal and nonrenal mechanisms. The drug is excreted principally in urine by glomerular filtration and also is excreted in feces via bile. Following IM or IV administration of a single dose of ceftriaxone in adults with normal renal and hepatic function, 33-67% of the dose is excreted in urine as unchanged drug and the remainder of the dose is excreted in feces as unchanged drug and microbiologically inactive metabolites.

Ceftriaxone is metabolized to a small extent in the intestines after biliary excretion. Following IM or IV administration of a single 1-g dose of ceftriaxone in healthy adults, urinary concentrations of the drug average 504-995 mcg/mL in urine collected over the first 2 hours after the dose, 293-418 mcg/mL in urine collected 4-8 hours after the dose, and 132 mcg/mL in urine collected 12-24 hours after the dose.

Serum clearance of ceftriaxone is dose dependent and ranges from 9.7-25 mL/minute in healthy adults. The serum clearance of the drug averages 10.2-16.7 mL/minute in healthy adults following a single 500-mg IV dose and 19.8-21.6 mL/minute following a single 2-g IV dose. In children 2 months to 16 years of age who receive a single ceftriaxone dose of 50-100 mg/kg, the serum clearance of ceftriaxone averages 32-40.8 mL/minute per 1.73 m. Preliminary studies in patients with cystic fibrosis suggest that serum clearance of ceftriaxone is higher in these patients than in healthy individuals.

The serum half-life of ceftriaxone is longer in neonates than in older children and adults. In one study, the serum half-life of ceftriaxone was longer in neonates weighing less than 1.5 kg than in heavier neonates. Results of another study in neonates 1-8 days of age weighing 1.8-3.9 kg suggested that there was no correlation between weight and serum half-life of the drug at this weight range. In one study, the serum half-life of the drug averaged 16. hours in neonates 1-4 days of age and 9.2 hours in those 9-30 days of age. The serum half-life of ceftriaxone in children is similar to that reported in adults, and the elimination half-life of the drug averages 4-7. hours in children 1.5 months to 16 years of age. In one study in children 2-42 months of age, the t1/2a of ceftriaxone averaged 0.25 hours and the t1/2b of the drug averaged 4 hours.

The elimination half-life of ceftriaxone is only slightly prolonged in patients with moderately impaired renal function and has been reported to range from 10-16 hours in adults with creatinine clearances of 5-73 mL/minute. In patients with creatinine clearances less than 5 mL/minute, the elimination half-life of ceftriaxone has generally been reported to average 12.2-18.2 hours. However, the elimination half-life of ceftriaxone was 15-57 hours in several uremic patients with creatinine clearances less than 5 mL/minute who had no apparent liver impairment.

Studies in patients with hepatic impairment (e.g., patients with fatty liver, liver fibrosis, compensated liver cirrhosis) indicate that the pharmacokinetics of ceftriaxone are not generally altered in these patients. Although the elimination half-life of ceftriaxone was not prolonged in patients with ascites, the volume of distribution and plasma clearance of the drug were increased slightly compared with healthy individuals and averaged 22 L and 28 mL/minute, respectively. Ceftriaxone is not removed by hemodialysis or peritoneal dialysis.

Chemistry and Stability

Chemistry

Ceftriaxone is a semisynthetic cephalosporin antibiotic. Like cefepime, cefotaxime, ceftazidime, and ceftizoxime, ceftriaxone is a parenteral aminothiazolyl cephalosporin. Ceftriaxone contains an aminothiazolyl-acetyl side chain, with a methoxyimino group, at position 7 of the cephalosporin nucleus. The aminothiazolyl side chain enhances antibacterial activity, particularly against Enterobacteriaceae, and generally results in enhanced stability against b-lactamases; the methoxyimino group contributes to stability against hydrolysis by many b-lactamases.

Ceftriaxone also has an acidic enol in the triazine moiety at position 3 of the cephalosporin nucleus, which presumably is responsible for the long serum half-life of the drug. Ceftriaxone is commercially available as the disodium salt; however, the drug is referred to as ceftriaxone sodium.

Potency of ceftriaxone sodium is expressed in terms of ceftriaxone. Each mg of ceftriaxone sodium contains not less than 776 mcg of ceftriaxone, calculated on the anhydrous free acid basis. Commercially available sterile ceftriaxone sodium occurs as a white to yellowish-orange crystalline powder. Ceftriaxone sodium is readily soluble in water, having an aqueous solubility of 400 mg/mL at 25°C.

The drug has a solubility of 1 mg/mL in alcohol at 25°C. Ceftriaxone sodium has pKas of 3, 3.2, and 4.1. Ceftriaxone sodium contains approximately 3.6 mEq of sodium per gram of ceftriaxone. When reconstituted as directed, solutions of the drug are light yellow to amber in color depending on the diluent used, concentration of the drug, and length of storage. The pH of an aqueous solution containing 10 mg of ceftriaxone per mL is approximately 6.7. Commercially available frozen ceftriaxone sodium injections containing 1 or 2 g of ceftriaxone in 3.8 or 2.4% dextrose injection, respectively, are light yellow to amber and have osmolalities of 276-324 mOsm/kg and a pH of 6.6 (range: 6-8).

Stability

Commercially available ceftriaxone sodium sterile powder for injection should be stored at 25°C or lower and protected from light. However, it is unnecessary to protect reconstituted solutions of the drug from normal light. The commercially available frozen ceftriaxone sodium injection should be stored at a temperature not greater than -20°C. Following reconstitution with sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection, ceftriaxone sodium solutions containing approximately 100 mg of ceftriaxone per mL are stable for 3 days at room temperature or 10 days when refrigerated at 4°C, and solutions containing approximately 250 or 350 mg/mL are stable for 24 hours at room temperature or 3 days at 4°C.

Following reconstitution with 1% lidocaine hydrochloride injection (without epinephrine) or bacteriostatic water for injection (containing 0.9% benzyl alcohol), solutions of the drug containing 100 mg/mL are stable for 24 hours at room temperature or 10 days when refrigerated at 4°C, and solutions containing 250 or 350 mg/mL are stable for 24 hours at room temperature or 3 days at 4°C. Following reconstitution with sterile water for injection, 0.9% sodium chloride injection, or 5 or 10% dextrose injection, ceftriaxone sodium solutions containing 10-40 mg of ceftriaxone per mL are stable in glass or PVC containers for 3 days at room temperature or 10 days when refrigerated at 4°C.

Following reconstitution with 5% dextrose and 0.45 or 0.9% sodium chloride, solutions of the drug containing 10-40 mg/mL are stable for 3 days at room temperature when stored in glass or PVC containers; however, these solutions are reportedly unstable at 4°C. Solutions of the drug containing 10-40 mg/mL are stable for 24 hours at room temperature in 10% invert sugar, 5% sodium bicarbonate, 5 or 10% mannitol, FreAmine® III, Normosol®-M and 5% dextrose, or Ionosol® B and 5% dextrose when stored in glass containers. The same concentrations of the drug are stable for 24 hours at room temperature in sodium lactate or Normosol®-M with 5% dextrose when stored in PVC containers.

Piggyback units containing 1 or 2 g of ceftriaxone that have been reconstituted to a concentration of 100 mg/mL and commercially available 10-g pharmacy bulk packages of ceftriaxone that have been reconstituted to a concentration of 100 mg/mL with one of the above IV solutions are stable under the storage conditions described above. The manufacturer states that when reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection solutions of ceftriaxone sodium prepared from ADD-Vantage® vials of the drug are stable for 3 days at room temperature (25°C) and 10 days when refrigerated at 4°C; these solutions should not be frozen. The manufacturer states that following reconstitution with 0.9% sodium chloride injection or 5% dextrose injection, extemporaneously prepared ceftriaxone sodium solutions containing 10-40 mg of ceftriaxone per mL are stable for 26 weeks when frozen at -20°C in PVC or polyolefin containers.

Frozen solutions of ceftriaxone sodium should be thawed at room temperature. Once thawed, unused portions should be discarded and should not be refrozen. The manufacturer states that the stability of the commercially available frozen ceftriaxone sodium injections may vary. These injections are stable for at least 90 days from the date of shipment when stored at -20°C.

The frozen injection should be thawed at room temperature and, once thawed, should not be refrozen. Thawed solutions of the commercially available frozen injection are stable for 72 hours at room temperature (25°C) or 21 days when refrigerated at 5°C. The commercially available frozen injection of the drug in dextrose is provided in a plastic container fabricated from specially formulated multilayered plastic PL 2040 (Galaxy®). Solutions in contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Ceftriaxone is physically incompatible with fluconazole and vancomycin, and the manufacturer states that ceftriaxone should not be admixed with these drugs. If fluconazole or vancomycin is to be administered in a patient receiving ceftriaxone by intermittent IV infusion, the drugs should be given sequentially and IV infusion lines should be thoroughly flushed with a compatible infusion fluid before administering the other drug. Admixtures containing ceftriaxone 10 mg/mL and metronidazole hydrochloride 5-7. mg/mL in 0.9% sodium chloride injection or 5% dextrose injection are stable for 24 hours at room temperature; however, precipitation will occur if these admixtures are refrigerated or if metronidazole concentrations greater than 8 mg/mL are used. Specialized references should be consulted for specific compatibility information.

Preparations

Ceftriaxone Sodium Parenteral For injection 250 mg (of ceftriaxone) Rocephin®, Roche 500 mg (of ceftriaxone) Rocephin®, Roche 1 g (of ceftriaxone) Rocephin®, Roche 2 g (of ceftriaxone) Rocephin®, Roche 10 g (of ceftriaxone) Rocephin®, pharmacy bulk package Roche For injection, for 500 mg (of ceftriaxone) Rocephin® Intramuscular IM use Convenience Kit, (with 2.1 mL lidocaine hydrochloride [Xylocaine®-MPF 1%], diluent, a disposable syringe, 2 needles, and alcohol swabs) Roche 1 g (of ceftriaxone) Rocephin® Intramuscular Convenience Kit, (with 2.1 mL lidocaine hydrochloride [Xylocaine®-MPF 1%], diluent, a disposable syringe, 2 needles, and alcohol swabs) Roche For injection, for 1 g (of ceftriaxone) Rocephin ADD-Vantage®, IV infusion Roche Rocephin® Piggyback, Roche 2 g (of ceftriaxone) Rocephin® ADD-Vantage®, Roche Rocephin® Piggyback, Roche Ceftriaxone Sodium in Dextrose Parenteral Injection (frozen) 20 mg (of ceftriaxone) per Rocephin® in Iso-osmotic , for IV infusion mL (1 g) in 3.8% Dextrose Dextrose Injection, (Galaxy® [Baxter]) Roche 40 mg (of ceftriaxone) per Rocephin® in Iso-osmotic mL (2 g) in 2.4% Dextrose Dextrose Injection, (Galaxy® [Baxter]) Roche

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