Pharmacotherapeutic group: Carbapenems. ATC code: J01DH04.
Pharmacology: Pharmacodynamics: Mode of Action: Doripenem is a synthetic carbapenem 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.
Microbiology: Mechanism of Resistance: Bacterial resistance mechanism that effect doripenem include active substance inactivation by carbapenem-hydrolyzing enzymes, mutant or acquired PBPs, 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 co-resistance 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 on Antimicrobial Susceptibility Testing (EUCAST) are as follows: Non-species related Staphylococci: S ≤1 mg/L and R >4 mg/L inferred from the methicillin breakpoints.
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. pneumoniae: S ≤1 mg/L and R >1 mg/L.
S. Pneumoniae: S ≤1 mg/L and R >1 mg/L.
Enterococci: "Inappropriate target."
Haemophilus spp.: S ≤1 mg/L and R >1 mg/L.
N. gonorrheae: 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 infections due to carbapenem-resistant have been reported in the European Union. The information as follows 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; Staphylococcus aureus (methicillin susceptible strains only); Staphylococcus spp. (methicillin susceptible strains only); Streptococcus pneumoniae; Streptococcus spp.
Gram Negative Aerobes: Citrobacter diversus; Citrobacter freundii; Enterobacter aerogenes; Haemophilus influenzae; Escherichia coli; Klebsiella pneumoniae; Klebsiella oxytoca; Morganella morganii; Proteus mirabilis; Proteus vulgaris; Providencia rettgeri; Providencia stuartii; Salmonella species; Serratia marcescens; Shigella species.
Anaerobes: Bacteroides fragilis; Bacteroides caccae; Bacteroides ovatus; Bacteroides uniformis; Bacteroides thetaiotaomicron; Bacteroides vulgatus; Bilophila wadsworthia; Peptostreptococcus magnus; Peptostreptococcus micros; Porphyromonas spp.; Prevotella spp.; Sutterella wadsworthensis.
Species for which acquired resistance may be a problem: Acinetobacter baumannii; Acinetobacter spp.; Burkholderia cepacia; Pseudomonas aeruginosa.
Inherently resistant organisms: Gram Positive Aerobes; Enterococcus faecium; Gram Negative Aerobes; Stenotrophomonas maltophilia; Legionella spp.