Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Roche Products Limited 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW United Kingdom
Pharmacotherapeutic group: cephalosporins and related substances
ATC code: J01DA13
Ceftriaxone has bactericidal activity resulting from the inhibition of bacterial cell wall synthesis ultimately leading to cell death. Ceftriaxone is stable to a broad range of bacterial β-lactamases and is active against a broad spectrum of bacterial pathogens including both Gram-positive and Gram-negative species.
Ceftriaxone is stable to a wide range of both Gram-positive and Gram-negative beta-lactamases, including those which are able to hydrolyse advanced generation penicillin derivatives and other cephalosporins. Resistance to ceftriaxone is encoded mainly by the production of some beta-lactam hydrolysing enzymes (including carbapenemases and some ESBLs) especially in Gram-negative organisms. For Gram-positive organisms such as S. aureus and S. pneumoniae, acquired resistance is mainly encoded by cell wall target site alterations. Outside of the advanced generation parenteral cephalosporins, cross-resistance to other drug classes is generally not encountered.
Current MIC breakpoints used to interpret ceftriaxone susceptibility data are shown below. The use of NCCLS breakpoints predominate and are the breakpoints used in data presented in the Table. Values quoted comprise mg/L (MIC testing) or mm (disk diffusion testing) using a 30mg/L drug concentration.
National Committee for Clinical Laboratory Standards (NCCLS) (M100-S12) - 2002:
| Susceptible | Intermediate | Resistant | |
|---|---|---|---|
| Enterobacteriaceae, P. aeruginosa and other non-Enterobacteriaceae, Staphylococcus spp. | ≤ 8 Disk: < 13 | 16-32 Disk: 14 – 20 | ≥ 64 Disk: ≥ 21 |
| Haemophilus spp. | ≤ 2 Disk: ≥ 26 | - | - |
| Neisseria spp. | ≤ 0.25 Disk: ≥ 35 | - | - |
| Streptococcus pneumoniae* | ≤ 0.5 | 1 | ≥ 2 |
| Other Streptococcus spp.** | Beta strep ≤ 0.5 Disk: ≥ 24 | - | - |
| Viridans group: ≤ 0.5 Disk: ≥ 27 | Viridans group: 1 Disk: 25-26 | Viridans group: ≥ 2 Disk: ≤ 24 |
* Recent 2002 S. pneumoniae breakpoints (NCCLS M100-S12) defined as ≤ 1 (Sensitive), 2 (Intermediate) and ≥ 4 (Resistant) for non-meningitis specimens and ≤ 0.5 (Sensitive), 1 (Intermediate), and > 2 (Resistant) for meningitis specimens.
** Recent 2002 Streptococcus viridans group breakpoints (NCCLS M100-S12) defined ≤ 1 (Sensitive), 2 (Intermediate), and ≥ 4 (Resistant)
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Ceftriaxone susceptibility among Gram-positive and Gram-negative bacterial species in Europe from January 1999-December 2001:
Commonly susceptible species (i.e. resistance < 10% in all EU Member States)
Gram-Positive aerobes:
MSa coagulase negative Staphylococcus spp. (including S. epidermis)*
MSb Staphylococcus aureus*
Group B (Streptococcus agalactiae)
Streptococcus bovis
Streptococcus pneumoniae*
Group A Streptococcus (Streptococcus pyogenes)*
Streptococcus viridans*
Gram-Negative aerobes:
Citrobacter spp. (including C.freundii)
Escherichia coli*
Haemophilus influenzae (including beta-lactamase positive isolates)c*
Haemophilus para-influenzae*
Klebsiella spp. (including K. pneumoniae and K. oxytoca)*
Moraxella catarrhalis*
Morganella morganii*
Neisseria gonorrhoea (including penicillin-resistant isolates)*
Neisseria meningitidis*
Proteus spp. (including P. mirabilis and P. vulgaris)*
Salmonella spp. (including S. typhimurium)
Serratia spp. (including Serratia marsescens)*
Shigella spp.
Anaerobes:
Clostridium spp.*
Species for which acquired resistance may be a problem (i.e. resistance ≥ 10% in at least one EU Member State)
Gram-Negative aerobes:
Pseudomonas aeruginosa+
Enterobacter spp. (including E. aerogenes and E. cloacae)*+
Acinetobacter spp. (including A. baumanii and A. calcoaceticus)*+
Anaerobes:
Bacteroides spp.*
Peptostreptococcus spp.*
Inherently resistant organisms
Gram-Positive aerobes:
MRd coagulase negative Staphylococcus spp. (including S. epidermidis)
MRe Staphylococcus aureus
Enterococcus spp.
Gram-Negative aerobes:
Listeria monocytogenes
Mycoplasma spp.
Stenotrophomonas maltophilia
Ureaplasma urealyticum
Others:
Chlamydia spp.
a Methicillin-susceptible Coagulase-Negative Staphylococcus
b Methicillin-susceptible Staphylococcus aureus
c Non-susceptible range (no resistant breakpoints defined)
d Methicillin-resistant Coagulase-Negative Staphylococcus
e Methicillin-resistant Staphylococcus aureus
* Species for which the efficacy of ceftriaxone has been demonstrated both in vitro and in vivo
+ Species for which high rates of resistance have been observed in one or more regions within the EU approximate guidance on probabilities whether micro-organisms will be susceptible. The table above comprises current levels of susceptibility according to routinely produced susceptibility test results in France, Germany, Greece, Italy, the Netherlands, Spain, and the United Kingdom. All data is presented using contemporary NCCLS derived susceptibility breakpoints except France (CA-SFM). Data is derived from The Surveillance Network™ (TSN) Databases in each respective region. The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only approximate guidance on probabilities whether microorganisms will be susceptible to ceftriaxone or not.
The pharmacokinetics of Rocephin are largely determined by its concentration-dependent binding to serum albumin. The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300mg/l. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.
Plasma concentrations: Mean peak concentrations after bolus intravenous injection are about 120mg/l following a 500mg dose and about 200mg/l following a 1g dose; mean levels of 250mg/l are achieved after infusion of 2g over 30 minutes. Intramuscular injection of 500mg Rocephin in 1.06% Lidocaine produces mean peak plasma concentrations of 40 – 70mg/l within 1 hour. Bioavailability after intramuscular injection is 100%.
Excretion: Rocephin is eliminated mainly as unchanged ceftriaxone, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The total plasma clearance is 10 – 22ml/min. The renal clearance is 5 – 12ml/min. The elimination half-life in adults is about 8 hours. The half-life is not significantly affected by the dose, the route of administration or by repeated administration.
In the first week of life, 80% of the dose is excreted in the urine; over the first month, this falls to levels similar to those in the adult. In infants aged less than 8 days the average elimination half-life is usually two to three times longer than that of young adults.
In elderly persons aged over 75 years, the average elimination half-life is usually 2 to 3 times longer than in the young adult group. As with all cephalosporins, a decrease in renal function in the elderly may lead to an increase in half-life. Evidence gathered to date with ceftriaxone however, suggests that no modification of the dosage regimen is needed.
In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.
Cerebrospinal fluid: Rocephin crosses non-inflamed and inflamed meninges, attaining concentrations 4 – 17% of the simultaneous plasma concentration.
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
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