Pharmacology: Mechanism of Action: Doripenem is synthetic carbapenems antibacterial agent.
Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs), resulting in inhibition of cell wall synthesis with subsequent cell death.
In vitro doripenem showed little potential to antagonize or be antagonized by other antibacterial agents.
Additive activity or weak synergy with Amikacin and Levofloxacin has been seen for Pseudomonas aeruginosa and for gram-positive bacteria with Daptomycin, Linezolid, Levofloxacin and Vancomycin.
Mechanism of Resistance: Bacterial resistance mechanisms that effect Doripenem include active substance inactivation by carbapenem-hydrolyzing enzymes, mutants or acquired PBP's, decreased outer membrane permeability and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram positive and gram negative bacteria, with the exception of relatively rare carbapenem hydrolyzing beta-lactamases. Species resistant to other carbapenems do generally express coresistance to Doripenem. Methicillin-resistant staphylococci should always be considered as resistant to Doripenem. As with other antimicrobial agents, including carbapenems, Doripenem has been shown to select for resistant bacterial strains.
Breakpoints: Minimum Inhibitory Concentration (MIC) breakpoints established by the European Committee of Antimicrobial Susceptibility Testing (EUCAST) are as follows: Non species related: Staphylococci: S ≤ 1 mg/L and R > 4 mg/L inferred from the Methicillin breakpoint
Enterobactericeae: S ≤ 1 mg/L and R > 4 mg/L
Acinetobacter spp.: S ≤ 1 mg/L and R > 4 mg/L
Pseudomonas spp.: S ≤ 1 mg/L and R > 4 mg/L
Streptococcus spp. other than S. Pneumonia: S ≤ 1 mg/L and R > 1 mg/L
S. Pneumonia: S ≤ 1 mg/L and R > 1 mg/L
Enterococci: "inappropriate target"
Haemophilus spp.: S ≤ 1 mg/L and R > 1 mg/L
N. Gonorrhoeae: IE (Insufficient Evidence)
Anaerobes: S ≤ 1 mg/L and R > 1 mg/L
Susceptibility: The prevalence of acquired resistance 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.
Localised clusters of infection due to carbapenem-resistant have been reported in the European Union. The information below gives only approximate guidance on the probability as to whether the micro organism will be susceptible to Doripenem or not.
Commonly Susceptible Species: Gram-positive aerobes: Enterococcus faecalis*s
Staphylococcus aureus (methicillin susceptible strains only)*^
Staphylococcus spp. (methicillin susceptible strains only)*
Gram-negative aerobes: Citrobacter diversus
Anaerobes: Bacteroides fragilis*
Species for which acquired resistance may be a problem: Acinetobacter baumanii*
Inherently resistant organisms: Gram-positive aerobes: Enterococcus faecium
Gram-negative aerobes: Stenotrophomonas malthopilia
* species against which activity has been demonstrated in clinical studies
S species that show natural intermediate susceptibility
+ species with > 50% acquired resistance in one or more Member State
^ all Methicillin-resistant Staphylococci should be regarded as resistant to Doripenem.