Carbapenems are a class of very effectiveantibiotic agents most commonly used for treatment of severe bacterialinfections. This class of antibiotics is usually reserved for known or suspectedmultidrug-resistant (MDR) bacterial infections. Similar topenicillins andcephalosporins, carbapenems are members of thebeta-lactam antibiotics drug class, which kill bacteria by binding topenicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins.
The carbapenemertapenem is one of several first-line agents recommended by theInfectious Disease Society of America for the empiric treatment of community-acquired intra-abdominal infections of mild-to-moderate severity. Agents with anti-pseudomonal activity, includingdoripenem,imipenem, andmeropenem, are not recommended in this population. Doripenem, imipenem, and meropenem are recommended for high-risk community-acquired abdominal infections and for abdominal infections that are hospital-acquired.[7]
A 2015 systematic review found little evidence that would support the identification of a best antimicrobial regimen for complicatedurinary tract infections, but identified three high-quality trials supporting high cure rates with doripenem, including in patients withlevofloxacin-resistantE. coli infections.[8]
The carbapenems imipenem and meropenem are recommended by theAmerican Thoracic Society and the Infectious Disease Society of America as one of several first-line therapy options for people with late-onsethospital-acquired orventilator-associated pneumonia, especially whenPseudomonas,Acinetobacter, orextended spectrum beta-lactamase producingEnterobacteriaceae are suspected pathogens. Combination therapy, typically with anaminoglycoside, is recommended forPseudomonas infections to avoid resistance development during treatment.[9]
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 asfluoroquinolones,amoxicillin, orazithromycin. Imipenem and meropenem are useful in cases in whichP. aeruginosa is a suspected pathogen.[10]
A 2015 meta analysis concluded that the anti-pseudomonal penicillin-beta lactamase inhibitor combinationpiperacillin-tazobactam gives results equivalent to treatment with a carbapenem in patients with sepsis.[11] In 2015, theNational Institute for Health and Care Excellence recommended piperacillin-tazobactam as first line therapy for the treatment of bloodstream infections in neutropenic cancer patients.[12]
For bloodstream infections known to be due to extended spectrum beta-lactamase producingEnterobacteriaceace, carbapenems are superior to alternative treatments.[13]
Carbapenems exhibit broad spectrum activity againstgram-negative bacteria and somewhat narrower activity againstgram-positive bacteria. Forempiric therapy (treatment of infections prior to identification of the responsible pathogen) they are often combined with a second drug having broader spectrum gram-positive activity.[citation needed]
The spectrum of activity of the carbapenems imipenem, doripenem, and meropenem includes mostEnterobacteriaceace species, includingEscherichia coli,Klebsiella pneumoniae,Enterobacter cloacae,Citrobacter freundii,Proteus mirabilis, andSerratia marcescens. Activity is maintained against most strains ofE. coli andK. pneumoniae that are resistant to cephalosporins due to the production ofextended spectrum beta-lactamases. Imipenem, doripenem, and meropenem also exhibit good activity against most strains ofPseudomonas aeruginosa andAcinetobacter species. The observed activity against these pathogens is especially valued as they are intrinsically resistant to many other antibiotic classes.[4]
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 ofStaphylococcus species, but many other antibiotics provide coverage for such infections. Good activity is also observed for mostStreptococcus species, including penicillin-resistant strains. Carbapenems are not highly active againstmethicillin-resistantStaphylococcus aureus or mostenterococcal infections because carbapenems do not bind to the penicillin-binding protein used by these pathogens.[4]
Carbapenems generally exhibit good activity against anaerobes such asBacteroides 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]
Carbapenems are contraindicated in patients with prior allergic reactions to beta lactam antibiotics. In addition, as theintramuscularformulations of ertapenem and imipenem are formulated withlidocaine, the intramuscular formulation of these two drugs are contraindicated in patients with prior adverse reactions to lidocaine.[14][15] Furthermore, carbapenems are also contraindicated in patients who are takingvalproic acid for seizures, as it has been shown to decrease valproic acid concentrations by as much as 90%.[16]
Serious and occasionally fatal allergic reactions can occur in people treated with carbapenems.[17]Seizures are a dose-limitingtoxicity for both imipenem and meropenem.[18]Clostridioides difficile-related diarrhea may occur in people treated with carbapenems or other broad-spectrum antibiotics.[19] Those with an allergy topenicillin may develop a cross sensitivity to carbapenems.[20]
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 themammalian kidney by a dehydropeptidase enzyme to a nephrotoxic intermediate, and thus is co-formulated with the dehydropeptidase inhibitorcilastatin.[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 theP. aeruginosa andAcinetobacter 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]
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]
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 ofEscherichia coli isolates from Canadian hospitals that produceextended spectrum beta lactamases (ESBL) increased from 3.4% to 4.1%; amongKlebsiella pneumoniae isolates ESBL producers increased from 1.5% to 4.0%. These strains are resistant tothird generation cephalosporins that were developed for the treatment of beta lactamase-producingEnterobacteriaceae and carbapenems are generally regarded as the treatment of choice.[35] More recently, many countries have experienced a dramatic upswing in the prevalence ofEnterobacteriaceae that produce both ESBLs andcarbapenemases such as the Klebsiella pneumoniae carbapenemase (KPC). As of 2013, 70% of GreekKlebsiella pneumoniae isolates are resistant to third generation cephalosporins and 60% are resistant to carbapenems.[36] The growing prevalence and difficulty of treating such multi-drug resistantEnterobacteriaceae has led to a renaissance of the use of antibiotics such ascolistin, which was discovered in the 1950s but rarely used until recently due to unattractive levels of toxicity.[37]
Prevalence of carbapenem-resistantEnterobacteriaceae in paediatric intensive care units (Cairo, Egypt) was 24% and various genes of carbapenemases were detected in 80% of carbapenem-resistantEnterobacteriaceae with dominance ofblaOXA-48.[38]
Infections caused by the non-fermenting gram-negative bacteriaPseudomonas aeruginosa andAcinetobacter 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 ofPseudomonas andAcinetobacter approximately 100 times more slowly than they cross the outer membrane ofEnterobacteriaceae, due in part to their use ofporins 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 theEnterobacteriaceae,Pseudomonas andAcinetobacter 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 makePseudomonas resistant to most beta lactams. The clinical efficacy of carbapenems inPseudomonas infection arises in part because, while they are strong inducers of AmpC, they are poor substrates. The identification ofPseudomonas strains that produce beta lactamases capable of cleaving carbapenems, such as theNew Delhi metallo beta lactamase has raised increasing concern regarding the potential for an era of untreatablePseudomonas infections.[40]
Carbapenem (formulaC6H7NO,registry number 63838-48-2) is the parent of this class of compounds. The parent is only of theoretical interest. The carbapenems are very similar to thepenicillins (penams): the sulfur in penams is replaced withmethylene and anunsaturation has been introduced—hence the name of the group, the carbapenems.
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]
The carbapenems are thought to share their early biosynthetic steps in which the core ring system is formed.Malonyl-CoA is condensed withglutamate-5-semialdehyde with concurrent formation of the five-membered ring. Next, a β-lactam synthetase usesATP to form the β-lactam and the saturatedcarbapenam core. Further oxidation and ring inversion provides the basic carbapenem[citation needed].
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]
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.
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^Herrero, Miranda (2015). "Pharmacological interaction between valproic acid and carbapenem: what about levels in pediatrics?".European Journal of Paediatric Neurology.19 (2):155–61.doi:10.1016/j.ejpn.2014.12.010.PMID25578527.
^Torres MJ, Blanca M (2010). "The complex clinical picture of beta-lactam hypersensitivity: penicillins, cephalosporins, monobactams, carbapenems, and clavams".Med. Clin. North Am.94 (4):805–20, xii.doi:10.1016/j.mcna.2010.04.006.PMID20609864.
^Edwards SJ, Emmas CE, Campbell HE (2005). "Systematic review comparing meropenem with imipenem plus cilastatin in the treatment of severe infections".Curr Med Res Opin.21 (5):785–94.doi:10.1185/030079905X46223.PMID15969878.S2CID7654496.
^Chahine EB, Ferrill MJ, Poulakos MN (2010). "Doripenem: a new carbapenem antibiotic".Am J Health Syst Pharm.67 (23):2015–24.doi:10.2146/ajhp090672.PMID21098373.
^Pei G, Yin W, Zhang Y, Wang T, Mao Y, Sun Y (2014). "Efficacy and safety of biapenem in treatment of infectious disease: a meta-analysis of randomized controlled trials".J Chemother.28 (1):28–36.doi:10.1179/1973947814Y.0000000226.PMID25407221.S2CID36170846.
^Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, O'Neill PJ, Chow AW, Dellinger EP, Eachempati SR, Gorbach S, Hilfiker M, May AK, Nathens AB, Sawyer RG, Bartlett JG (2010). "Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America".Surg Infect (Larchmt).11 (1):79–109.doi:10.1089/sur.2009.9930.PMID20163262.
^{{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}}
