Carbapenem
Carbapenems are a class of very effective
Carbapenem antibiotics were originally developed at Merck & Co. from the carbapenem thienamycin, a naturally derived product of Streptomyces cattleya.[1][2] Concern has arisen in recent years over increasing rates of resistance to carbapenems, as there are few therapeutic options for treating infections caused by carbapenem-resistant bacteria (such as Klebsiella pneumoniae and other carbapenem-resistant Enterobacteriaceae[3]).[4][5][6]
Medical uses
Intra-abdominal infections
The carbapenem
Complicated urinary tract infections
A 2015 systematic review found little evidence that would support the identification of a best antimicrobial regimen for complicated
Pneumonia
The carbapenems imipenem and meropenem are recommended by the
Carbapenems are less commonly used in the treatment of community-acquired pneumonia, as community-acquired strains of the most common responsible pathogens (Streptococcus pneumoniae, Haemophilus influenazae, atypical bacteria, and Enterobactericeace) are typically susceptible to narrower spectrum and/or orally administered agents such as
Bloodstream Infections
A 2015 meta analysis concluded that the anti-pseudomonal penicillin-beta lactamase inhibitor combination
For bloodstream infections known to be due to extended spectrum beta-lactamase producing Enterobacteriaceace, carbapenems are superior to alternative treatments.[13]
Spectrum of activity
Carbapenems exhibit broad spectrum activity against
Gram-negative pathogens
The spectrum of activity of the carbapenems imipenem, doripenem, and meropenem includes most Enterobacteriaceace species, including Escherichia coli,
Gram-positive pathogens
The spectrum of activity of the carbapenems against gram-positive bacteria is fairly broad, but not as exceptionally so as in the case of gram-negative bacteria. Good activity is seen against methicillin-sensitive strains of Staphylococcus species, but many other antibiotics provide coverage for such infections. Good activity is also observed for most Streptococcus species, including penicillin-resistant strains. Carbapenems are not highly active against
Other
Carbapenems generally exhibit good activity against anaerobes such as Bacteroides fragilis. Like other beta lactam antibiotics, they lack activity against atypical bacteria, which do not have a cell wall and are thus not affected by cell wall synthesis inhibitors.[4]
Contraindications
Carbapenems are contraindicated in patients with prior allergic reactions to beta lactam antibiotics. In addition, as the
Adverse effects
Serious and occasionally fatal allergic reactions can occur in people treated with carbapenems.
Examples
Approved for clinical use
- Imipenem, the first clinically used carbapenem, was developed at Merck and Co. It was approved for use in the United States in 1985.[21] Imipenem is hydrolyzed in the mammalian kidney by a dehydropeptidase enzyme to a nephrotoxic intermediate, and thus is co-formulated with the dehydropeptidase inhibitor cilastatin.[5] Imipenem is available in both intravenous[22] and intramuscular[23] formulations.
- Meropenem is stable to mammalian dehydropeptidases and does not require co-administration of cilastatin. It was approved for use in the United States in 1996. In most indications it is somewhat more convenient to administer than imipenem, 3 times a day rather than 4. Doses of less than one gram may be administered as an IV bolus, whereas imipenem is usually administered as a 20-minute to one hour infusion. Meropenem is somewhat less potent than imipenem against gram-positive pathogens, and somewhat more potent against gram-negative infections. Unlike imipenem, which produced an unacceptable rate of seizures in a phase 2 trial, meropenem is effective for the treatment of bacterial meningitis.[24] A systematic review performed by an employee of the company that markets meropenem concluded that it provides a higher bacterial response and lower adverse event rates than imipenem in people with severe infections, but no difference in mortality rate.[25]
- Ertapenem is administered once daily as an intravenous infusion or intramuscular injection. It lacks useful activity against the P. aeruginosa and Acinetobacter species, both of which are important causes of hospital-acquired infections.[26]
- Doripenem has a spectrum of activity very similar to that of meropenem. Its greater stability in solution allows the use of prolonged infusions and it is somewhat less likely to produce seizures than other carbapenems.[27]
- Panipenem/betamipron (Japanese approval 1993)
- Biapenem (Japanese approval 2001) exhibits similar efficacy and adverse event rates as other carbapenems.[28]
- Tebipenem (Japanese approval 2015) is the first carbapenem whose prodrug form, the pivalyl ester, is orally available.[29]
Unapproved/experimental
- Razupenem (PZ-601)
- PZ-601 is a carbapenem antibiotic currently being tested as having a broad spectrum of activity including strains resistant to other carbapenems. Despite early Phase II promise, Novartis (who acquired PZ-601 in a merger deal with Protez Pharmaceuticals) recently dropped PZ-601, citing a high rate of adverse events in testing.[30]
- Lenapenem
- Sulopenem is in clinical trials for drug resistant urinary tract infections
- Tomopenem
- Thienamycin (thienpenem) the first discovered carbapenem
Bacterial resistance
Enterobacteriaceae
Enterobacteriaceae are common pathogens responsible for urinary tract infections,[31][32] abdominal infections,[33] and hospital-acquired pneumonia.[9] Beta lactam resistance in these pathogens is most commonly due to the expression of beta lactamase enzymes.[34]
Between 2007 and 2011, the percentage of Escherichia coli isolates from Canadian hospitals that produce
Prevalence of carbapenem-resistant Enterobacteriaceae in paediatric intensive care units (Cairo, Egypt) was 24% and various genes of carbapenemases were detected in 80% of carbapenem-resistant Enterobacteriaceae with dominance of blaOXA-48.[38]
Pseudomonas aeruginosa and Acinetobacter baumannii
Infections caused by the non-fermenting gram-negative bacteria Pseudomonas aeruginosa and Acinetobacter baumanni are most commonly encountered in hospitalized people. These bacteria exhibit an unusually high level of intrinsic resistance to antibiotics due to their expression of a wide range of resistance mechanisms. Antibiotics cross the outer membrane of Pseudomonas and Acinetobacter approximately 100 times more slowly than they cross the outer membrane of Enterobacteriaceae, due in part to their use of porins that can adopt a conformation having a very restricted entry channel. Further, the porin levels may be down-regulated in response to antibiotic exposure. Antibiotic molecules that successfully traverse the porin channels may be removed by efflux pumps. Downregulation of the porin OprD2 is an important contributor to imipenem resistance.[39]
Like the Enterobacteriaceae, Pseudomonas and Acinetobacter can express a wide range of antibiotic-deactivitating enzymes, including beta lactamases. Pseudomonas produces an inducible broad spectrum beta lactamase, AmpC, that is produced in response to beta lactam exposure. The combination of inducible AmpC expression, poor membrane permeability, and efflux pumps make Pseudomonas resistant to most beta lactams. The clinical efficacy of carbapenems in Pseudomonas infection arises in part because, while they are strong inducers of AmpC, they are poor substrates. The identification of Pseudomonas strains that produce beta lactamases capable of cleaving carbapenems, such as the New Delhi metallo beta lactamase has raised increasing concern regarding the potential for an era of untreatable Pseudomonas infections.[40]
Structure
In terms of structure, the carbapenems are very similar to the penicillins (penams), but the sulfur atom in position 1 of the structure has been replaced with a carbon atom, and an unsaturation has been introduced—hence the name of the group, the carbapenems.
Groups
Carbapenems are further broken down into groups with ertapenem being the lone member of group 1. Group 2 carbapenems (imipenem, meropenem, and doripenem) are identified by their efficacy with respect to multiresistant gram-negative (MDRGN) bacteria such as Pseudomonas and Acinetobacter species. [41]
Biosynthesis
The carbapenems are thought to share their early biosynthetic steps in which the core ring system is formed. Malonyl-CoA is condensed with glutamate-5-semialdehyde with concurrent formation of the five-membered ring. Next, a β-lactam synthetase uses ATP to form the β-lactam and the saturated carbapenam core. Further oxidation and ring inversion provides the basic carbapenem [citation needed].
Administration
Due to their expanded spectra, the desire to avoid generation of resistance and the fact that, in general, they have poor oral bioavailability, they are administered intravenously in hospital settings for more serious infections. However, research is underway to develop an effective oral carbapenem.[42]
See also
- Faropenem is closely related, but it is a penem, not a carbapenem.[43]
- Antimicrobial resistance
- NDM-1 is an enzyme that introduces bacterial resistance to carbapenem antibiotics via hydrolysis of the carbapenem backbone, thereby inactivating its ability to inhibit cell wall synthesis.
References
- ISBN 978-0-471-89980-8.
- PMID 3859213.
- ^ "Brazil: Klebsiella pneumoniae carbapenemase prompts closing of hospital ICU - Outbreak News Today". 2015-07-26.
- ^ S2CID 218660238.
- ^ PMID 21859938.
- ^
Livermore DM, Woodford N (October 2000). "Carbapenemases: a problem in waiting?". PMID 11050448.
- PMID 20034345.
- PMID 26243291.
- ^ PMID 15699079.
- PMID 21951385.
- PMID 25261419.
- PMID 26065059.
- PMID 22915465.
- ^ "www.accessdata.fda.gov" (PDF).
- ^ "www.accessdata.fda.gov" (PDF).M
- PMID 25578527.
- PMID 20609864.
- PMID 18983709.
- PMID 24324224.
- ^ "Pharmaceutical Sciences CSU Parenteral Antibiotic Allergy cross-sensitivity chart" (PDF). Vancouver Acute Pharmaceutical Sciences, Vancouver Hospital & Health Sciences Centre. 2016. Archived from the original (PDF) on April 17, 2016. Retrieved May 19, 2017.
- ^ PRIMAXIN (Brand Name Drug) FDA Application No. (NDA) 050587 Drug Details, Drugs@FDA
- ^ "www.accessdata.fda.gov" (PDF).
- ^ "www.accessdata.fda.gov" (PDF).
- PMID 22346545.
- S2CID 7654496.
- ^ "www.accessdata.fda.gov" (PDF).
- PMID 21098373.
- S2CID 36170846.
- PMID 24846409.
- ^ George, John (21 September 2010). "Novartis shutters Protez". BioValley.
- PMID 21292654.
- PMID 20175247.
- PMID 20163262.
- PMID 25165544.
- PMID 23587779.
- ^ "Antimicrobial Resistance in Europe 2013" (PDF). ecdc.europa.eu. European Centre for Disease Prevention and Control. 2013. p. 21. Retrieved 7 April 2022.
- PMID 26027916.
- S2CID 73444389.
- PMID 16894511.
- PMID 24409175.
- ^ {{Yoon YK, Yang KS, Lee SE, Kim HJ, Sohn JW, Kim MJ. Effects of Group 1 versus Group 2 carbapenems on the susceptibility of Acinetobacter baumannii to carbapenems: a before and after intervention study of carbapenem-use stewardship. PLoS One. 2014;9(6):e99101. Published 2014 Jun 9. doi:10.1371/journal.pone.0099101}}
- ISSN 1568-0126.
- S2CID 43705118.
External links
- Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD; beginning at pp131
- Page 2: Ertapenem vs. Meropenem: Equivalency of Clinical and Microbiological Outcomes. 2010