Carbapenems are a class of β-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most β-lactamases. 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 development to combat bacteria resistant to carbapenems, and worldwide spread of the resistance gene is considered a potential nightmare scenario.
Approved for clinical use 
The following drugs belong to the carbapenem class and are approved for use by health authorities:
- Imipenem, generally given as part of Imipenem/cilastatin (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
- Meropenem (FDA approval 1996)
- Ertapenem (FDA approval 2001, since approved for multiple indications)
- Doripenem (FDA Approval 2007)
- Panipenem/betamipron (Japanese approval 1993)
- Biapenem (Japanese approval 2001)
- 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.
Spectrum of Use 
These agents have the broadest antibacterial spectrum compared to other β-lactam classes such as penicillins and cephalosporins. 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. Carbapenems circumvent β-lactamase by binding it with high affinity and acylating the enzyme, render it inactive. 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 l,d-transpeptidases 
Emergence of bacterial resistance 
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.
A clinical isolate of E. coli from the sputum sample of a patient admitted to a Beijing hospital was found to show unusual resistance to carbapenem that it does not rely on the presence of carbapenemase. The isolate was determined to have four separate mutations to acquire the resistance to carbapenems. Two mutations removed the outer membrane proteins OmpF and OmpC to prevent the antibiotics from reaching the PBPs (penicillin binding proteins) in the inner membrane. A regulator gene marR was mutated and a normally non-translated membrane protein yedS was expressed, both were demonstrated to have effects on the ability of this strain of E.coli to resist carbapenems. The bacteria also increased the expression of a multidrug efflux pump. 
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.
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.
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.
See also 
- Livermore DM, Woodford N (October 2000). "Carbapenemases: a problem in waiting?". Current Opinion in Microbiology 3 (5): 489–95. doi:10.1016/S1369-5274(00)00128-4. ISSN 1369-5274. PMID 11050448.
- Birnbaum J, Kahan FM, Kropp H, MacDonald JS (June 1985). "Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin". American Journal of Medicine 78 (6A): 3–21. doi:10.1016/0002-9343(85)90097-X. ISSN 0002-9343. PMID 3859213.
- Smith, Stephen (2010-10-07). "Deadly bacteria's foothold spurs study: Mass. specialists try to halt spread". The Boston Globe.
- Pennington, Hugh (2010-08-11). "Can we stop the Indian superbug?". The Daily Telegraph (London).
- PRIMAXIN (Brand Name Drug) FDA Application No. (NDA) 050587 Drug Details, Drugs@FDA
- George, John (21 September 2010). "Novartis shutters Protez". BioValley.
- Drawz, Sarah; Bonomo, Robert (2010). "Three Decades of β-Lactamase Inhibitors". Clinical Microbiology Reviews 23 (1): 160–201. doi:10.1128/CMR.00037-09. Retrieved 25 April 2013.
- Mainardi JL, Villet R, Bugg TD, Mayer C, Arthur M (March 2008). "Evolution of peptidoglycan biosynthesis under the selective pressure of antibiotics in Gram-positive bacteria". FEMS Microbiology Reviews 32 (2): 386–408. doi:10.1111/j.1574-6976.2007.00097.x. PMID 18266857.
- Roberts, Michelle (2010-08-11). "New 'superbug' found in UK hospitals". BBC News. Retrieved 10 August 2010.
- Center for Disease Control and Prevention (June 2010). "Detection of Enterobacteriaceae isolates carrying metallo-beta-lactamase - United States, 2010". Morbidity and Mortality Weekly Report 59 (24): 750. PMID 20577157.
- Press Release (26 March 2013). "New Study Identifies Unique Mechanisms of Antibiotic Resistance". Tufts University. Retrieved 25 April 2013.
- Levy, Stuart; Warner, Douglas; Yang, Qiwen; Duval, Valerie; Chen, Minjun; Xu, Yingchun (2013). "Involvement of MarR and YedS in Carbapenem Resistance in a Clinical Isolate of Escherichia coli from China". Antimicrobial Agents and Chemotherapy 57 (4): 1935–1937. doi:10.1128/AAC.02445-12.
- Kumagai T, Tamai S, Abe T, Hikda M (January 2002). "Current status of oral carbapenem development". Current Medicinal Chemistry 1 (1): 1–14. doi:10.2174/1568012023355018. ISSN 1568-0126.
- Hamilton-Miller, JM (November 2003). "Chemical and Microbiologic Aspects of Penems, a Distinct Class of β-Lactams: Focus on Faropenem". Pharmacotherapy 23 (11): 1497–507. doi:10.1592/phco.23.14.1497.31937. PMID 14620395.
- 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