Doripenem a new broad-spectrum carbapenem antibiotic
Doripenem A New Broad- Spectrum Carbapenem AntibioticDr. B. K. Iyer
Carbepenems Carbapenems are beta-lactam antibiotics useful in treating life-threatening infections caused by G+ve & G-ve bacteria. The drawback of carbapenems is that they are very expensive, acid-labile and therefore used only intravenously. Doripenem is an ultra-broad spectrum injectable carbepenem
Structure of Doripenem (1R,5S,6S)-2-[(3S,5S)-5-substituted pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]- 1- methylcarbapen-2-em-3-carboxylic acids
Mechanism Like all beta-lactam antimicrobial agents, carbapenems act by inhibiting bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins (PBPs).
b-lactamase stability Doripenem has a trans-configured 6- hydroxyethyl group, which protects it against beta-lactamases. Resistance to carbapenems develops when bacteria acquire or develop structural changes within their PBPs, when they acquire metallo- beta-lactamases that are capable of rapidly degrading carbapenems, or when changes in membrane permeability arise as a result of loss of specific outer membrane porins.
Antimicrobial Features A particular feature, the side chain at position 2 —sulfamoylaminomethyl group.
Toxic Effects Doripenem displays favorable pharmacokinetic, pharmacodynamic and toxicological features, similar to those of meropenem. Doripenem has no convulsive activity. Doripenem did not cause any inhibition muscimol binding to the GABA receptor. So,its neurotoxicity may be negligible in clinical use.
Comparison of doripenem …… With other carbapenems
Comparison of the MIC90 (μg/ml)for doripenem against G+ve
Comparison of the MIC90 (μg/ml)for doripenem against G-ve
Pharmacological comparison ofdoripenem & other carbapenems Antibacterial mechanisms are the same with other beta-lactam antibiotics : combining with bacterial penicillin-binding protein (PBPs) inhibits bacterial cell wall synthesis. Doripenem has strong antibacterial activity and stability against the vast majority of beta-lactamase and kidney dehydrogenation endopeptidase (DHP) -1.
1. Antibacterial activity against G+ Methicillin- susceptible staphylococcus aureus, Staphylococcus epidermidis : slightly lower than imipenem, stronger than merop Methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis : 2 ~ 4 times stronger than other control drugs Strongest antibacterial activity to Streptococcus pyogenes.
1. Antibacterial activity against G+ Penicillin-susceptible Streptococcus pneumoniae: similar to imipenem ,stronger than meropenem & biapenem Penicillin-resistant Streptococcus pneumoniae: identical with others Enterococcus faecalis: slightly lower than imipenem, strong in contrast to others
2. Antibacterial activity against G- Doripenem is sensitive to many G-ve bacteria, such as: E. coli Klebsiella pneumoniae Enterobacteriaceae Proteus mirabilis Proteus vulgaris Haemophilus influenza P. aeruginosa
3. Antibacterial activity against P.aeruginosa Pseudomonas, a Gram-negative bacterium, is one of the leading causes of resistant hospital-acquired infections and, because of increasing multi-drug resistance, treatment options are limited. Doripenem appears to have more potent in vitro activity against P. aeruginosa than meropenem.
3. Antibacterial activity against P.aeruginosa Doripenem could prevent growth of the mutants of P. aeruginosa at a concentration that would inhibit cell growth.
4. Pharmacokinetics Parenteral injection antibiotics The main metabolites: the beta-lactam ring hydrolysis untied product Product is cleared mainly by glomerulus filtration - 90% of urine excretion
Conclusion Doripenem is a promising new carbapenem with - similaranti-G+ve activity to those of imipenem, & Anti-G-ve activity to those of meropenem Doripenem had slightly greater activity against Pseudomonas aeruginosa.
Market prospects Ideal antibiotic: Safe, efficient, broad-spectrum The situation for antibiotics is: as their usage in clinical applications increase, resistance of the bacteria increase - leading to serious problems. Overcome resistance with 3 aspects: Prevent the abuse of antibiotics, Develop new antibiotics, Search for inhibitors of bacterial enzyme responsible for hydrolysis of antibiotics.
Market prospects In clinical trials, doripenem was well- tolerated. The most adverse events seen were diarrhea, nausea, constipation, urinary tract infection and decubitus ulcer, commonly known as a bedsore. Globally, antibiotics make the largest share, about 8 billion dollars. The carbapenem antibiotics is 1 billion annually.
Market development Doripenem was first launched in Japan in Sep.2005. Its commercial name is Finibax. The injection had been licensed for the treatment of complicated intra-abdominal and complicated urinary tract infections. The nosocomial pneumonia indication for doripenem had been granted "fast-track" status by the FDA in Dec 2006.
Market development Now carbapenem in the drug market share is rising, The demand for carbapenem in market had increased by 50% last year. Thus carbapenem drug has been the hot favorite in antibiotics. However, the potential exists; for some metallo-beta lactamases that can destroy carbapenem compounds, to be more disseminated.
Market development Prudent prescribing practice should screen multidrug-resistant isolates for this mechanism. Only with this effort will doripenem be able to maintain its wide spectrum of activity and potential clinical utility.
References4. Shihomi Sakyo, Haruyoshi Tomita, Koichi Tanimoto, Shuhei Fujimoto, Yasuyoshi Ike. Potency of Carbapenems for the Prevention of Carbapenem-Resistant Mutants of Pseudomonas aeruginosa. J. Antibiot. 59(4): 220–228, 2006.5. Masahito Horiuchi, Megumi Kimura, Miwa Tokumura, Nobuyoshi Hasebe, Tohko Arai, Kohji Abe Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with _-lactam antibiotics
References6. Ronald N. Jones,1,2* Holly K. Huynh,1 and Douglas J. Biedenbach1 Activities of Doripenem (S-4661) against Drug-Resistant Clinical Pathogens7. Shazad Mushtaq,1 Yigong Ge,2 and David M. Livermore1 Comparative Activities of Doripenem versus Isolates, Mutants, and Transconjugants of Enterobacteriaceae and Acinetobacter spp. with Characterized _Lactamases8. David Leif Anderson DORIPENEM Medical Information Department, Prous Science, Barcelona, Spain9. Ronald N. Jones1,2*, Holly K. Huynh1, Douglas J. Biedenbach1, Thomas R. Fritsche1 and Helio S. Sader1 Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations10. THYE DA, KILFOIL T, LEIGHTON A, WIKLER M. Doripenem: a Phase 1 Study to Evaluate Safety, Tolerability and Pharmacokinetics in a Western Healthy Volunteer Population.