understanding doripenem

1. Doripenem
A New Broad-
Spectrum Carbapenem
Antibiotic
Dr. B. K. Iyer

2. 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

3. 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

4. Mechanism
 Like all beta-lactam antimicrobial agents,
carbapenems act by inhibiting bacterial
cell wall synthesis by binding to and
inactivating penicillin-binding proteins
(PBPs).

5. 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.

6. Antimicrobial Features
 A particular feature, the side chain at
position 2 —sulfamoylaminomethyl group.

7. 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.

8. Comparison of
doripenem …
… With other carbapenems

9. Comparison of the MIC90 (μg/ml)
for doripenem against G+ve

10. Comparison of the MIC90 (μg/ml)
for doripenem against G-ve

11. Pharmacological comparison of
doripenem & 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.

12. 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.

13. 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

14. 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

15. 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.

16. 3. Antibacterial activity against P.
aeruginosa
 Doripenem could prevent growth of the
mutants of P. aeruginosa at a concentration
that would inhibit cell growth.

17. 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

18. 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.

19. Market prospects

20. 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.

21. 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.

22. 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.

23. Market development

24. 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.

25. 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.

26. References
4. 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

27. References
6. Ronald N. Jones,1,2* Holly K. Huynh,1 and Douglas J. Biedenbach1
Activities of Doripenem (S-4661) against Drug-Resistant Clinical
Pathogens
7. 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 _Lactamases
8. David Leif Anderson DORIPENEM Medical Information Department,
Prous Science, Barcelona, Spain
9. 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 evaluations
10. 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.