Revision Year: 2012 Publisher: ANFARM HELLAS SA, 53-57 Perikleous str., 153 44, Gerakas, Athens, Greece Tel: (210) 6831632 Fax: (210) 6836540
Pharmacotherapeutic group: Beta-lactam antibiotics, cephalosporins
ATC Code: J01DA10
Cefotaxime is a third generation broad spectrum bactericidal cephalosporin antibiotic. The bactericidal properties are due to the inhibitory effect of cefotaxime on bacterial cell wall synthesis.
Resistance to Cefotaxime may be due to production of extended-spectrum beta- lactamases that can efficiently hydrolyse the drug, to the induction and/or constitutive expression of AmpC enzymes, to impermeability or to efflux pump mechanisms. More than one of these possible mechanisms may co-exist in a single bacterium.
Current MIC breakpoints used to interpret cefotaxime susceptibility data are shown below.
European Committee on Antimicrobial Susceptibility Testing (EUCAST) Clinical MIC Breakpoints (V1.1, 31/03/2006):
| Susceptible (≤ ) / Resistant (≥ ) | |
|---|---|
| Enterobacteriaceae2^^ | 1/2 |
| Pseudomonas | -- |
| Acinetobacter | -- |
| Staphylococcus3 | Note3 |
| Enterococcus | -- |
| Streptococcus A, B, C, G | 0.5/0.54 |
| Streptococcus pneumoniae | 0.5/24 |
| Haemophilus influenzae Moraxella Catarrhalis | 0.12/0.124 |
| Neisseria gonorrhoea | 0.12/0.124 |
| Neisseria Meningitidis | 0.12/0.124 |
| Gram-negative, anaerobes | -- |
| Non-species related breakpoints1 S≤ />R | 1/2 |
1 Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended (marked with - - or IE in the table).
2 The cephalosporin breakpoints for Enterobacteriaceae will detect resistance mediated by most ESBLs and other clinically important beta-lactamases in Enterobacteriaceae. However, some ESBL-producing strains may appear susceptible or intermediate with these breakpoints. Laboratories may want to use a test which specifically screens for the presence of ESBL.
3 Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility (except ceftazidime which should not be used for staphylococcal infections).
4 Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant.
-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.
IE = There is insufficient evidence that the species in question is a good target for therapy with the drug.
RD = rationale document listing data used by EUCAST for determining breakpoints.
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 an approximate guidance on the probabilities whether micro-organisms will be susceptible to cefotaxime or not.
Susceptible:
Gram-positive aerobes:
Staphylococcus aureus (Methicillin-susceptible)*
Group A Streptococci (including Streptococcus pyogenes)
Group B Streptococci
β-hemolytic Streptococci (Group C, F, G)
Streptococcus pneumoniae* / 12.7%
Viridans Group Streptococci
Gram-negative aerobes:
Citrobacter spp.*
Escherichia coli*
Haemophilus influenzae*
Haemophilus parainfluenzae*
Klebsiella spp.*
Moraxella catarrhalis*
Neisseria gonorrhoeae*
Neisseria meningitides *
Proteus spp.*
Providencia spp.*
Yersinia enterocolitica
Anaerobes:
Clostridium spp. (not Clostridium difficile)
Peptostreptococcus spp.
Propionibacterium spp.
Others:
Borrelia spp.
Resistant:
Gram-positive aerobes:
Enterococcus spp.
Enterococcus faecalis
Enterococcus faecium
Listeria spp.
Staphylococcus aureus (MRSA)
Staphylococcus epidermidis (MRSE)
Gram-negative aerobes:
Acinetobacter spp.
Citrobacter spp.
Enterobacter spp.
Morganella morganii
Pseudomonas spp.
Serratia spp.
Xanthomonas maltophilia
Anaerobes:
Bacteroides spp.
Clostridium difficile
Others:
Clamydiae
Mycoplasma spp.
Legionella pneumophilia
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.
Methicillin-(oxacillin) resistant staphylococci (MRSA) are resistant to all currently available β-lactam antibiotics including cefotaxime.
Penicillin-resistant Streptococcus pneumoniae show a variable degree of cross- resistance to cephalosporins such as cefotaxime.
After a 1000mg intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102 microgram/ml. Doses of 500mg and 2000mg produce plasma concentrations of 38 and 200 microgram/ml, respectively. There is no accumulation following administration of 1000mg intravenously or 500mg intramuscularly for 10 or 14 days.
The apparent volume of distribution at steady-state of cefotaxime is 21.6 litres/1.73m after 1g intravenous 30 minute infusion. Concentrations of cefotaxime (usually determined by non-selective assay) have been studied in a wide range of human body tissues and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed, but are between 3 and 30 microgram/ml in children with meningitis. Cefotaxime usually passes the blood-brain barrier in levels above the minimum inhibitory concentration of common sensitive pathogens when the meninges are inflamed. Concentrations (0.2-5.4 microgram/ml), inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 2g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gall bladder wall, after usual therapeutic doses. High concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile. Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in the urine – about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390ml/minute and renal clearance 145 to 217 ml/minute.
After intravenous administration of cefotaxime to healthy adults, the elimination half-life of the parent compound is 0.9 to 1.14 hours and that of the desacetyl metabolite, about 1.3 hours.
In neonates the pharmacokinetics are influenced by gestational and chronological age, the half-life being prolonged in premature and low birth weight neonates of the same age.
In severe renal dysfunction the elimination half-life of cefotaxime itself is increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about 10 hours. Total urinary recovery of cefotaxime and its principal metabolite decreases with reduction in renal function.
There are no pre-clinical data of relevance to the prescriber that are additional to those included in other sections.
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