, Volume 62, Issue 7, pp 1041-1089
Date: 25 Sep 2012

Ceftriaxone

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Summary

Abstract

Ceftriaxone is a parenteral third-generation cephalosporin with a long elimination half-life which permits once-daily administration. It has good activity against Streptococcus pneumoniae, methicillin-susceptible staphylococci, Haemophilus influenzae, Moraxella catarrhalis and Neisseria spp. Although active against Enterobacteriaceae, the recent spread of derepressed mutants which hyperproduce chromosomal β-lactamases and extended-spectrum β-lactamases has diminished the activity of all third-generation cephalosporins against these pathogens necessitating careful attention to sensitivity studies.

Extensive data from randomised clinical trials confirm the efficacy of ceftriaxone in serious and difficult-to-treat community-acquired infections including meningitis, pneumonia and nonresponsive acute otitis media. Ceftriaxone also has efficacy in other community-acquired infections including uncomplicated gonorrhoea, acute pyelonephritis and various infections in children. In the nosocomial setting, extensive data also confirm the efficacy of ceftriaxone with or without an aminoglycoside in serious Gram-negative infections, pneumonia, spontaneous bacterial peritonitis and as surgical prophylaxis. Outpatient use of ceftriaxone, either as part of a step-down regimen or parenterally, is a distinguishing feature of the data gathered on the agent over the last decade. The review focuses on new applications of the drug and its use in infections in which the causative pathogens or their resistance patterns have changed over the past decade.

Ceftriaxone has a good tolerability profile, the most common events being diarrhoea, nausea, vomiting, candidiasis and rash. Ceftriaxone may cause reversible biliary pseudolithiasis, notably at higher dosages of the drug (≥2 g/day); however, the incidence of true lithiasis is <0.1%. Injection site discomfort or phlebitis can occur after intramuscular or intravenous administration.

Conclusions: As a result of its strong activity against S. pneumoniae, ceftriaxone holds an important place, either alone or as part of a combination regimen, in the treatment of invasive pneumococcal infections, including those with reduced β-lactam susceptibility. Its once-daily administration schedule allows simplification of otherwise complex regimens in a hospital setting and has also contributed to its popularity as a parenteral agent in an ambulatory setting. These properties, together with a well characterised tolerability profile, mean that ceftriaxone is likely to retain its place as an important third-generation cephalosporin in the treatment of serious community-acquired and nosocomial infections.

Antibacterial Activity

According to data from large in vitro studies published since 1998, ceftriaxone has good activity against Streptococcus pneumoniae, β-haemolytic group streptococci and methicillin-susceptible staphylococci. Its activity is more variable against viridans group streptococci and, as for other β-lactam agents, ceftriaxone is inactive against methicillin-resistant staphylococci and enterococci. Although penicillin-resistant S. pneumoniae are becoming increasingly common, the prevalence of resistance to ceftriaxone among S. pneumoniae remains <5% worldwide.

Ceftriaxone is highly active against Haemophilus influenzae, Moraxella catarrhalis, Neisseria spp. and has good activity against Salmonella and Shigella spp. However, data published since 1998 show that ceftriaxone, like other third-generation cephalosporins, now has variable activity against most Enterobacteriaceae. Ceftriaxone has little or no activity against Acinetobacter spp., Pseudomonas aeruginosa, Stenotrophomonas maltophilia or Achromobacter xylosoxidans.

Ceftriaxone is stable against TEM-1, TEM-2, SHV-1 and K1 chromosomal β-lactamases. Its activity is also unaffected by inducible AmpC β-lactamases. However, like other third-generation agents, its activity is reduced by derepressed mutants which hyperproduce chromosomal β-lactamases or extended-spectrum β-lactamases, both of which are now widespread. Other relevant mechanisms of resistance are modification or acquisition of supplementary penicillin-binding proteins, usually in Gram-positive bacteria. Resistance attributable to reduced porin expression or efflux is less common.

Studies in patients show that ceftriaxone reversibly alters the intestinal flora (suppresses enterobacteria, bifidobacteria, clostridia and Bacteroides and increases enterococci and Candida), but is associated with the emergence of fewer cephalosporin-resistant Gram-negative bacilli than cefotaxime or cefazolin in a randomised study. Additionally, in a study in 12 patients, the colonic microflora was found to normalise within 14 days of completion of treatment in all but one recipient.

The inter-relationship between pharmacodynamic and pharmacokinetic parameters is also important in predicting antibacterial activity. A pharmacodynamic review of the Alexander Project surveillance data indicated that ceftriaxone was associated with plasma concentrations above the minimum inhibitory concentration required to inhibit the growth of 90% of isolates (MIC90) of S. pneumoniae, H. influenzae, M. catarrhalis and Staphylococcus aureus for >50% of the dosage interval. In healthy adult volunteers, serum concentrations of ceftriaxone (intravenous 30 minute infusion of 1g once daily) were bactericidal for 100% of the dosage interval against clinical isolates of S. pneumoniae, Klebsiella pneumoniae, Enterobacter aerogenes, Escherichia coli, Serratia marcescens and H. influenzae. In an in vitro study evaluating penicillin-susceptible, -intermediate and -resistant S. pneumoniae clinical isolates, ceftriaxone exerted post antibiotic effects (PAEs) ranging from 1 to 7.2 hours after isolates had been exposed to concentrations 10 times the MIC value. In another study, mean PAEs against S. aureus, S. pneumoniae, H. influenzae and E. coli strains were 0.9, 2.6, −0.8 and −2.1 hours, respectively, reflecting the fact that cephalosporins generally only demonstrate a PAE against Gram-positive bacteria.

Pharmacokinetic Profile

Intravenous ceftriaxone 0.5, 1 or 2g produces mean peak plasma concentrations (Cmax) of 82, 151 and 257 mg/L, respectively, whereas intramuscular ceftriaxone 0.5 or 1g achieves Cmax values of 38 and 76 mg/L, respectively, after 2 to 3 hours. 24 hours after intravenous ceftriaxone 2g, mean plasma concentrations range from 12 to 20 mg/L.

Repeated once-daily intravenous administration of ceftriaxone 2g results in an 8% increase in mean Cmax, and repeated intramuscular administration of ceftriaxone 1g results in 11% accumulation of the drug.

Ceftriaxone binds reversibly to albumin and the level of binding decreases with increasing ceftriaxone plasma concentrations (≈95% at >70 mg/L to ≈58% at 600 mg/L).

Ceftriaxone distributes widely in the body fluids and tissues. The volume of distribution of ceftriaxone in healthy volunteers ranges from 5.8 to 15.5L.

Ceftriaxone preferentially localises in bile and mean concentrations of ≈153 and ≈44 mg/L are obtained 1 and ≈3 hours, respectively, after intravenous administration of lg dose. The drug is primarily eliminated unchanged by the kidneys; 45 to 60% of a 0.5 to 3g dose is excreted in the urine of healthy subjects within 48 hours. The remainder is secreted in the bile and the faeces as microbiologically inactive compounds.

Total plasma clearance of ceftriaxone is dose related; it increases from mean values of 0.61 to 1.0 L/h after a 0.5g intravenous dose to 1.18 and 1.29 L/h after a 2g intravenous dose.

The mean elimination half-life (t½) of ceftriaxone in healthy adults is ≈6 to 9 hours, which is considerably longer than that of other cephalosporins (0.6 to 4.4 hours). The t½ of ceftriaxone does not vary according to dose size, frequency or route of administration.

Therapeutic Use in Community-Acquired Infections

Meningitis: In five randomised trials, intravenous ceftriaxone 60 to 100 mg/kg sterilised the CSF in 98 to 100% of infants and children with meningitis within 18 to 36 hours. Similar response rates were observed with alatrofloxacin, cefuroxime and cefotaxime (88 to 97% of patients), although cefuroxime was associated with delayed sterilisation more frequently than ceftriaxone (12 vs 2%). Neurological sequelae at discharge were reported in 9 to 23% of patients who received ceftriaxone. Two small comparative studies also showed that ceftriaxone was effective in the treatment of adults with meningitis.

Acute otitis media: According to data from six randomised trials, a single intramuscular dose of ceftriaxone 50 mg/kg had similar clinical efficacy to 10-day oral regimens of amoxicillin plus or minus clavulanic acid, cefaclor or cotrimoxazole (trimethoprim/sulfamethoxazole) in infants and children with uncomplicated acute otitis media (AOM). In children with AOM unresponsive to previous antibacterial therapy, three trials showed that a three-dose regimen of intramuscular ceftriaxone 50 mg/kg/day eradicated 93 to 98% of middle ear pathogens. Significantly lower eradication rates were observed with one versus three doses of ceftriaxone in this patient group in one comparative trial (73 vs 98%; p < 0.001).

A flexible approach advocated by McCracken recommends that in uncomplicated AOM a single dose of ceftriaxone be given, with additional doses if necessary (after 48 to 72 hours) if there is a clinical failure with the first dose. It is suggested that the second dose may be given at 48 to 72 hours rather than 24 hours, since the concentration of ceftriaxone exceeds the MIC90 for approximately 120 hours or longer for most organisms including penicillin-intermediate and -resistant strains of S. pneumoniae. This approach allows for the possibility that some children failing the one-dose ceftriaxone regimen may be cured by the second dose and hence not require the third dose.

Community-acquired pneumonia: According to data from ten randomised trials in hospitalised adults with community-acquired pneumonia (CAP), ceftriaxone 1 to 4 g/day, alone or as part of a step-down regimen, had similar efficacy to that of other β-lactam agents (amoxicillin/clavulanic acid, cefepime, cefpodoxime proxetil, cefodizime), fluoroquinolones (ciprofloxacin, levofloxacin, gatifloxacin, trovafloxacin) and linezolid. Clinical success rates with ceftriaxone-based therapy ranged from 81 to 98% versus 85 to 98% with comparator regimens. A step-down regimen of ceftriaxone 50 mg/kg/day followed by oral cefixime or amoxicillin/clavulanic acid achieved similar clinical success rates in children with CAP in a randomised trial.

Additionally, in a nonblind study in 31 patients with CAP, the average length of stay in hospital was reduced by 1.2 days (4.8 vs 6 days) in patients receiving step-down therapy with intravenous ceftriaxone (dosage not reported) followed by oral cefpodoxime proxetil 200mg twice daily compared with those receiving ceftriaxone followed by other oral treatment regimens (choice of oral agent was at the physician’s discretion). There were no recurrences of primary infection or readmissions to hospital at 1-month follow-up in either treatment group.

Invasive infections caused by ceftriaxone-nonsusceptible Streptococcus pneumoniae: In patients with pneumococcal meningitis, treatment failures or unpredictable responses have been observed with strains with MICs ≥1 mg/L. Combination therapy with vancomycin or rifampicin is therefore recommended for patients with ceftriaxone-nonsusceptible strains, although published data concerning the efficacy of these regimens remain very limited. In contrast, recent data in other pneumococcal infections (predominantly pneumonia and bacteraemia) suggest that ceftriaxone can be used effectively to treat infections caused by S. pneumoniae with ceftriaxone MICs ≤2 mg/L.

Sexually transmitted infections: Single dose intramuscular ceftriaxone 0.25g consistently produces bacteriological eradication rates of ≥95% in adults with uncomplicated gonorrhoea according to 15 large randomised trials. Eradication rates achieved with ceftriaxone were similar to those reported with single doses of comparator agents (90 to 100%; cefixime, ceftizoxime, cefotaxime, ampicillin/sulbactam plus probenecid, trospectomycin, ciprofloxacin, fleroxacin and enoxacin).

A single intramuscular dose of ceftriaxone 0.25g combined with oral doxycycline achieved clinical success in 95% of women with mild to moderate pelvic inflammatory disease compared with 97% treated with oral clindamycin plus ciprofloxacin in a randomised trial.

Acute pyelonephritis: In pregnant women with acute pyelonephritis, four randomised trials showed that parenteral ceftriaxone 1 g/day followed by oral cefalexin or cefradine achieved bacteriological cure in 92 and 98% of patients. Treatment was effective whether administered completely or partially on an outpatient basis, although medical or infectious complications precluded outpatient management in over 50% of women at >24 weeks gestation. Similar results were achieved with comparator regimens (intravenous cefazolin or ampicillin plus gentamicin followed by similar step-down therapy). No differences in birth outcomes were noted between regimens.

Other paediatric infections: Data from randomised trials also show that ceftriaxone is effective in the treatment of acute pyelonephritis, multidrug-resistant Salmonella typhi septicaemia, typhoid fever, skin and soft-tissue infections, bone infections, infectious diarrhoea, febrile episodes in children with sickle haemoglobinopathies and in the prevention of invasive infections in febrile children (aged 3 to 36 months). Furthermore, regimens including ceftriaxone have proven effective and were generally well tolerated in neonates (including newborn) with proven or suspected infection.

Therapeutic Use in Nosocomial Infections

Gram-negative infections: One large multinational randomised trial showed that ceftriaxone plus tobramycin achieved similar clinical response rates to ceftazidime monotherapy in adult hospitalised patients with serious nosocomial Gram-negative infections (59 to 76% vs 73 to 80% depending on the infection site).

Pneumonia: In patients with nosocomial pneumonia, intravenous ceftriaxone 2 g/day achieved clinical success in 70% of patients compared with 80% of patients treated with intravenous cefoperazone in a randomised trial.

Surgical or procedural prophylaxis: Ceftriaxone was associated with wound infection rates of 3 to 6% after abdominal or biliary surgery, 3% after breast or gynaecological surgery, 0.5% after orthopaedic surgery and 15% after percutaneous endoscopic gastrotomy. In all studies, ceftriaxone was administered intravenously as a single 1 or 2g dose prior to or during surgery. The rate of postoperative wound infections observed with ceftriaxone was generally similar to that achieved with comparator regimens, except for two studies in which ceftriaxone was associated with a significantly lower infection rate: 0.5 vs 4% with placebo in orthopaedic surgery (p < 0.001) and 6 vs 17% with metronidazole in combination with gentamicin in bowel surgery (p < 0.05).

Spontaneous bacterial peritonitis: In two small prospective trials, empirical treatment with intravenous ceftriaxone 2 g/day achieved a bacteriological cure in 95 and 100% of patients with spontaneous bacterial peritonitis. This compared with a bacteriological cure rate of 94% with intravenous cefonicid in a randomised trial.

Tolerability

In general, adverse events associated with ceftriaxone were mild to moderate in severity and resolved spontaneously. With rare exceptions, severe or serious events were not observed after single dose treatment with ceftriaxone in adults, children or infants. In addition, studies in neonates also indicated that ceftriaxone monotherapy or combination therapy was generally well tolerated.

According to data from clinical trials, gastrointestinal events are the most common adverse events associated with ceftriaxone. In general, diarrhoea was reported in 1 to 15% of patients, nausea and vomiting in ≤4%, and abdominal pain or discomfort in ≤2% of patients. All third-generation cephalosporins, including ceftriaxone, have been associated with rare reports of pseudomembranous colitis; therefore, overgrowth of Clostridium difficile should be considered in patients with diarrhoea. Other systemic events associated with ceftriaxone included rash in ≤6% of patients, candidiasis (oral or vaginal) in about 4 to 5% of patients and pruritus, headache and dizziness in ≤3% of patients each.

Ceftriaxone can cause reversible biliary pseudolithiasis, usually at higher dosages (≥2 g/day); however, the incidence of true lithiasis is <0.1%. Data from six small incidence studies (n = 8 to 118 patients in each study) show that sonographic abnormalities indicative of pseudolithiasis were observed in 12 to 43% (n = 37 patients in the latter study) of adolescents and children and 21 and 25% of adults treated with intravenous ceftriaxone. Up to one-third (0 to 33%) of patients developed symptoms, but pseudolithiasis resolved spontaneously in all cases.

Haematological reactions with ceftriaxone include anaemia, haemolytic anaemia, leucopenia, neutropenia, thrombocytopenia, eosinophilia, agranulocytosis and a positive Coomb’s test. Prolongation of prothrombin time has been observed rarely with ceftriaxone. As with other third-generation agents, mild reversible abnormalities in liver function tests have been documented with ceftriaxone. Ceftriaxone appears to have a low nephrotoxic potential and can be coad-ministered with aminoglycosides.

Ceftriaxone can cause discomfort or pain at the injection site following intramuscular administration, and phlebitis following intravenous injection. In clinical trials, the incidence of these events ranged from 0 to 45% and up to 11%, respectively. Of note, in comparison with water, 1% lidocaine has been shown to reduce the severity and duration of pain associated with ceftriaxone injection (250 to 1g) in healthy volunteers (aged 14 to 55 years) in randomised, single- or double-blind trials.

Comparative data with ceftriaxone monotherapy are limited because the drug is often administered as part of a step-down regimen or in combination with other agents. Available data show that the incidence of adverse events with ceftriaxone is generally similar to that of other β-lactams and fluoroquinolones in adults and children. Significant differences noted between regimens include fewer adverse reactions, notably gastrointestinal events, than amoxicillin/clavulanic acid and fewer gastrointestinal events than cefixime but higher incidences of diarrhoea than cotrimoxazole and cefpodoxime proxetil and rash compared with oral amoxicillin.

Dosage and Administration

Ceftriaxone can be administered by intravenous or intramuscular injection. The recommended dose in adults and children (aged ≥12 years) is 1 to 2g once daily (or in two equally divided doses) in the US or 1g once daily in the UK. The total daily dose should not exceed 4g. A single intramuscular dose of 250mg is recommended for the treatment of uncomplicated gonorrhoea. For surgical prophylaxis, a single intravenous 1g dose given 0.5 to 2 hours before surgery is advised.

In children aged <12 years, ceftriaxone 50 to 75 mg/kg/day is recommended for serious infections and a dose of 100 mg/kg/day is recommended for meningitis in the US; the dose may be administered once daily or split into two equally divided doses. In the UK, ceftriaxone 20 to 50 mg/kg once daily is recommended as the standard dose, with doses of up to 80 mg/kg for severe infections. AOM should be treated with a single intramuscular dose of 50 mg/kg.

Dosage adjustment is not required in patients with impaired hepatic or renal function, although plasma concentrations of ceftriaxone should be monitored regularly in patients with concomitant renal and hepatic dysfunction.

Various sections of the manuscript reviewed by: S.L. Block, Physicians To Children & Adolescents, Bardstown, Kentucky, USA; J. Lipman, Intensive Care Facility and Department of Anaesthesiology and Critical Care, University of Queensland, Royal Brisbane Hospital, Brisbane, Queensland, Australia; K.G. Naber, Urologische Klinik, Klinikum St. Elisabeth Straubing, Straubing, Germany; R. Nau, Georg-August-Universitat Göttingen, Göttingen, Germany; F. Scaglione, Department of Pharmacology, Chemotherapy and Toxicology, Faculty of Medicine, University of Milan, Milan, Italy; K. Weiss, Hopital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec, Canada.
Data Selection
Sources: Medical literature published in any language since 1988 on ceftriaxone, identified using Medline, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘ceftriaxone’ or ‘ceftriaxone sodium’ and (lower respiratory tract infections or pneumonia or bronchitis or AECB or acute otitis media or bacterial otitis media or skin structure infections or urinary tract infections or uncomplicated gonorrhoea or bacterial septicaemia or bone and joint infections or intra-abdominal infections or meningitis-bacterial or surgical prophylaxis or febrile neutropenia or pharmacoeconomics). AdisBase search terms were ‘ceftriaxone’ and (lower respiratory tract infections or pneumonia or bronchitis or AECB or acute otitis media or skin structure infections or urinary tract infections or uncomplicated gonorrhoea or pelvic inflammatory disease or bacterial septicaemia or bone-and-joint-infections or osteomyelitis or infectious arthritis or meningitis or surgical prophylaxis or febrile neutropenia). Searches were last updated 13 Mar 2002.
Selection: Studies in patients with community-acquired or nosocomial infections who received ceftriaxone. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well-controlled, randomised trials with appropriate statistical methodology were preferred. Relevant in vitro and pharmacokinetic data are also included.
Index terms: Community-acquired pneumonia, otitis media, meningitis, sexually transmitted infections, acute pyelonephritis, paediatric infections, nosocomial infections, surgical prophylaxis, antibacterial activity, pharmacokinetics, therapeutic use, peritonitis.