Carbapenem
Encyclopedia
Carbapenems are a class of β-lactam antibiotic
s with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most β-lactamase
s. Carbapenem antibiotics were originally developed from thienamycin
, a naturally derived product of Streptomyces
cattleya.
Carbapenems are one of the antibiotics of last resort for many bacterial infections, such as Escherichia coli (E. coli) and Klebsiella pneumoniae. Recently, alarm has been raised over the spread of drug resistance to carbapenem antibiotics among these coliforms, due to production of the New Delhi metallo-β-lactamase, NDM-1
. There are currently no new antibiotics in the pipeline to combat bacteria resistant to carbapenems, and worldwide spread of the resistance gene is considered a potential nightmare scenario.
s and cephalosporin
s. In addition, they are generally resistant to the typical bacterial enzyme, β-lactamase
, which is one of the principal β-lactam resistance mechanisms of bacteria. However, in the United States and United Kingdom, strains of carbapenem-resistant enteric bacteria have been isolated from patients having received recent medical care in Pakistan, Bangladesh, and India. These strains carry a gene called New Delhi metallo-β-lactamase
(shortened NDM-1) that is responsible for the production of a metallo-β-lactamase enzyme
that hydrolyses
carbapenem.
Carbapenems are active against both Gram-positive
and Gram-negative
bacteria, and anaerobes, with the exception of intracellular bacteria (atypicals), such as the Chlamydiae
. Carbapenems also are thus far the only β-lactams capable of inhibiting ,-transpeptidases
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.
Beta-lactam antibiotic
β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...
s with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most β-lactamase
Beta-lactamase
Beta-lactamases are enzymes produced by some bacteria and are responsible for their resistance to beta-lactam antibiotics like penicillins, cephamycins, and carbapenems . These antibiotics have a common element in their molecular structure: a four-atom ring known as a beta-lactam...
s. Carbapenem antibiotics were originally developed from thienamycin
Thienamycin
Thienamycin, one of the most potent naturally produced antibiotics known thus far, was discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes.Thienamycin is a zwitterion...
, a naturally derived product of Streptomyces
Streptomyces
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...
cattleya.
Carbapenems are one of the antibiotics of last resort for many bacterial infections, such as Escherichia coli (E. coli) and Klebsiella pneumoniae. Recently, alarm has been raised over the spread of drug resistance to carbapenem antibiotics among these coliforms, due to production of the New Delhi metallo-β-lactamase, NDM-1
New Delhi metallo-beta-lactamase
New Delhi metallo-beta-lactamase-1 is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections...
. There are currently no new antibiotics in the pipeline to combat bacteria resistant to carbapenems, and worldwide spread of the resistance gene is considered a potential nightmare scenario.
Examples
The following drugs belong to the carbapenem class:- ImipenemImipenemImipenem is an intravenous β-lactam antibiotic developed in 1980. It has an extremely broad spectrum of activity.Imipenem belongs to the subgroup of carbapenems. It is derived from a compound called thienamycin, which is produced by the bacterium Streptomyces cattleya...
, generally given as part of Imipenem/cilastatinImipenem/cilastatinImipenem/cilastatin is a broad spectrum beta-lactam antibiotic containing equal quantities of imipenem and cilastatin. It is related to the penicillin/cephalosporin family of antibiotics but is classified as belonging to the carbapenem class.-Mechanism:It has the ability to kill a wide variety of...
(FDA approval 1985)- Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme to a nephrotoxic metabolite, and so is given with a dehydropeptidase inhibitor, cilastatin
- MeropenemMeropenemMeropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals...
(FDA approval 1996) - ErtapenemErtapenemErtapenem is a carbapenem antibiotic marketed by Merck as Invanz. It is structurally very similar to meropenem in that it possess a 1-β-methyl group.-Indications:...
(FDA approval 2001, since approved for multiple indications) - DoripenemDoripenemDoripenem is an ultra-broad spectrum injectable antibiotic. It is a beta-lactam and belongs to the subgroup of carbapenems. It was launched by Shionogi Co. of Japan under the brand name Finibax in 2005 and is being marketed outside Japan by Johnson & Johnson...
(FDA Approval 2007) - Panipenem/betamipronPanipenem/betamipronPanipenem/betamipron is a carbapenem antibiotic marketed by Daiichi Sankyo Co. of Japan. It was launched in 1993, under the brand name Carbenin....
(Japanese approval 1993) - BiapenemBiapenemBiapenem is a carbapenem antibiotic. It has in vitro activity against anaerobes.Approved in Japan in 2001.-External links:...
(Japanese approval 2001)
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 PII 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.
- Tebipenem
Uses
These agents have the broadest antibacterial spectrum compared to other β-lactam classes such as penicillinPenicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
s and cephalosporin
Cephalosporin
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...
s. In addition, they are generally resistant to the typical bacterial enzyme, β-lactamase
Beta-lactamase
Beta-lactamases are enzymes produced by some bacteria and are responsible for their resistance to beta-lactam antibiotics like penicillins, cephamycins, and carbapenems . These antibiotics have a common element in their molecular structure: a four-atom ring known as a beta-lactam...
, which is one of the principal β-lactam resistance mechanisms of bacteria. However, in the United States and United Kingdom, strains of carbapenem-resistant enteric bacteria have been isolated from patients having received recent medical care in Pakistan, Bangladesh, and India. These strains carry a gene called New Delhi metallo-β-lactamase
New Delhi metallo-beta-lactamase
New Delhi metallo-beta-lactamase-1 is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections...
(shortened NDM-1) that is responsible for the production of a metallo-β-lactamase enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that hydrolyses
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
carbapenem.
Carbapenems are active against both Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
and Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria, and anaerobes, with the exception of intracellular bacteria (atypicals), such as the Chlamydiae
Chlamydiae
Chlamydiae is a bacterial phylum and class whose members are obligate intracellular pathogens. Many Chlamydiae coexist in an asymptomatic state within specific hosts, and it is widely believed that these hosts provide a natural reservoir for these species....
. Carbapenems also are thus far the only β-lactams capable of inhibiting ,-transpeptidases
Structure
In terms of structure, the carbapenems are very similar to the penicillins, but the sulfur atom in position 1 of the structure has been replaced with a carbon atom, and hence the name of the group, the carbapenems.Biosynthesis
The carbapenems are thought to share their early biosynthetic steps in which the core ring system is formed. Malonyl-CoAMalonyl-CoA
Malonyl-CoA is a coenzyme A derivative.-Functions:It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis....
is condensed with glutamate-5-semialdehyde with concurrent formation of the five-membered ring. Next, a β-lactam synthetase uses ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
to form the β-lactam and the saturated carbapenam
Carbapenam
A carbapenam is a β-lactam compound that is a saturated carbapenem. They exist primarily as biosynthetic intermediates on the way to the carbapenem antibiotics....
core. Further oxidation and ring inversion provides the basic carbapenem.
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.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