Carbapenem

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Backbone structure of a carbapenem. Carbapenems structure.svg
Backbone structure of a carbapenem.

Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.[ medical citation needed ]

Contents

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 ertapenem is one of several first-line agents recommended by the Infectious Disease Society of America for the empiric treatment of community-acquired intra-abdominal infections of mild-to-moderate severity. Agents with anti-pseudomonal activity, including doripenem, imipenem, and meropenem, 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]

Complicated urinary tract infections

A 2015 systematic review found little evidence that would support the identification of a best antimicrobial regimen for complicated urinary tract infections, but identified three high-quality trials supporting high cure rates with doripenem, including in patients with levofloxacin-resistant E. coli infections. [8]

Pneumonia

The carbapenems imipenem and meropenem are recommended by the American Thoracic Society and the Infectious Disease Society of America as one of several first-line therapy options for people with late-onset hospital-acquired or ventilator-associated pneumonia, especially when Pseudomonas, Acinetobacter, or extended spectrum beta-lactamase producing Enterobacteriaceae are suspected pathogens. Combination therapy, typically with an aminoglycoside, is recommended for Pseudomonas 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 as fluoroquinolones, amoxicillin, or azithromycin. Imipenem and meropenem are useful in cases in which P. aeruginosa is a suspected pathogen. [10]

Bloodstream infections

A 2015 meta analysis concluded that the anti-pseudomonal penicillin-beta lactamase inhibitor combination piperacillin-tazobactam gives results equivalent to treatment with a carbapenem in patients with sepsis. [11] In 2015, the National 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 producing Enterobacteriaceace, carbapenems are superior to alternative treatments. [13]

Spectrum of activity

Carbapenems exhibit broad spectrum activity against gram-negative bacteria and somewhat narrower activity against gram-positive bacteria. For empiric 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 ]

Gram-negative pathogens

The spectrum of activity of the carbapenems imipenem, doripenem, and meropenem includes most Enterobacteriaceace species, including Escherichia coli, Klebsiella pneumoniae , Enterobacter cloacae , Citrobacter freundii , Proteus mirabilis , and Serratia marcescens . Activity is maintained against most strains of E. coli and K. pneumoniae that are resistant to cephalosporins due to the production of extended spectrum beta-lactamases. Imipenem, doripenem, and meropenem also exhibit good activity against most strains of Pseudomonas aeruginosa and Acinetobacter species. The observed activity against these pathogens is especially valued as they are intrinsically resistant to many other antibiotic classes. [4]

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 methicillin-resistant Staphylococcus aureus or most enterococcal infections because carbapenems do not bind to the penicillin-binding protein used by these pathogens. [4]

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 intramuscular formulations of ertapenem and imipenem are formulated with lidocaine, 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 taking valproic acid for seizures, as it has been shown to decrease valproic acid concentrations by as much as 90%. [16]

Adverse effects

Serious and occasionally fatal allergic reactions can occur in people treated with carbapenems. [17] Seizures are a dose-limiting toxicity 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 to penicillin may develop a cross sensitivity to carbapenems. [20]

Examples

Approved for clinical use

Unapproved/experimental

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 extended spectrum beta lactamases (ESBL) increased from 3.4% to 4.1%; among Klebsiella pneumoniae isolates ESBL producers increased from 1.5% to 4.0%. These strains are resistant to third generation cephalosporins that were developed for the treatment of beta lactamase-producing Enterobacteriaceae and carbapenems are generally regarded as the treatment of choice. [35] More recently, many countries have experienced a dramatic upswing in the prevalence of Enterobacteriaceae that produce both ESBLs and carbapenemases such as the Klebsiella pneumoniae carbapenemase (KPC). As of 2013, 70% of Greek Klebsiella 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 resistant Enterobacteriaceae has led to a renaissance of the use of antibiotics such as colistin, which was discovered in the 1950s but rarely used until recently due to unattractive levels of toxicity. [37]

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

Related Research Articles

<span class="mw-page-title-main">Beta-lactamase</span> Class of enzymes

Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

<span class="mw-page-title-main">Ertapenem</span> Antibiotic medication

Ertapenem, sold under the brand name Invanz, is a carbapenem antibiotic medication used for the treatment of infections of the abdomen, the lungs, the upper part of the female reproductive system, and the diabetic foot.

<i>Klebsiella pneumoniae</i> Species of bacterium

Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose-fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.

<span class="mw-page-title-main">Aztreonam</span> Chemical compound

Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa. This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis. It is given by intravenous or intramuscular injection or by inhalation.

<span class="mw-page-title-main">Amoxicillin/clavulanic acid</span> Combination antibiotic medication

Amoxicillin/clavulanic acid, also known as co-amoxiclav or amox-clav, sold under the brand name Augmentin, among others, is an antibiotic medication used for the treatment of a number of bacterial infections. It is a combination consisting of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor. It is specifically used for otitis media, streptococcal pharyngitis, pneumonia, cellulitis, urinary tract infections, and animal bites. It is taken by mouth or by injection into a vein.

<span class="mw-page-title-main">Meropenem</span> Broad-spectrum antibiotic

Meropenem, sold under the brand name Merrem among others, is an intravenous carbapenem antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax.

<span class="mw-page-title-main">Piperacillin</span> Antibiotic medication

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<span class="mw-page-title-main">Imipenem</span> Carbapenem antibiotic

Imipenem is a synthetic β-lactam antibiotic belonging to the carbapenems chemical class. developed by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s. Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria, thus playing a key role in the treatment of infections not readily treated with other antibiotics. It is usually administered through intravenous injection.

Ampicillin/sulbactam is a fixed-dose combination medication of the common penicillin-derived antibiotic ampicillin and sulbactam, an inhibitor of bacterial beta-lactamase. Two different forms of the drug exist. The first, developed in 1987 and marketed in the United States under the brand name Unasyn, generic only outside the United States, is an intravenous antibiotic. The second, an oral form called sultamicillin, is marketed under the brand name Ampictam outside the United States, and generic only in the United States. Ampicillin/sulbactam is used to treat infections caused by bacteria resistant to beta-lactam antibiotics. Sulbactam blocks the enzyme which breaks down ampicillin and thereby allows ampicillin to attack and kill the bacteria.

<span class="mw-page-title-main">Temocillin</span> Chemical compound

Temocillin is a β-lactamase-resistant penicillin introduced by Beecham, marketed by Eumedica Pharmaceuticals as Negaban. It is used primarily for the treatment of multiple drug-resistant, Gram-negative bacteria.
It is a 6-methoxy penicillin; it is also a carboxypenicillin.

<span class="mw-page-title-main">Doripenem</span> Antibiotic

Doripenem is an antibiotic drug in the carbapenem class. It is a beta-lactam antibiotic drug able to kill Pseudomonas aeruginosa.

<span class="mw-page-title-main">Thienamycin</span> Chemical compound

Thienamycin is one of the most potent naturally produced antibiotics known thus far, 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 at pH 7.

β-Lactamase inhibitor Drugs that inhibit β-Lactamase enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">New Delhi metallo-beta-lactamase 1</span> Enzyme

NDM-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. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to in the news media as "superbugs" because infections caused by them are difficult to treat. Such bacteria are usually sensitive only to polymyxins and tigecycline.

Multidrug resistant Gram-negative bacteria are a type of Gram-negative bacteria with resistance to multiple antibiotics. They can cause bacteria infections that pose a serious and rapidly emerging threat for hospitalized patients and especially patients in intensive care units. Infections caused by MDR strains are correlated with increased morbidity, mortality, and prolonged hospitalization. Thus, not only do these bacteria pose a threat to global public health, but also create a significant burden to healthcare systems.

Carbapenem-resistant Enterobacteriaceae (CRE) or carbapenemase-producing Enterobacteriaceae (CPE) are gram-negative bacteria that are resistant to the carbapenem class of antibiotics, considered the drugs of last resort for such infections. They are resistant because they produce an enzyme called a carbapenemase that disables the drug molecule. The resistance can vary from moderate to severe. Enterobacteriaceae are common commensals and infectious agents. Experts fear CRE as the new "superbug". The bacteria can kill up to half of patients who get bloodstream infections. Tom Frieden, former head of the Centers for Disease Control and Prevention has referred to CRE as "nightmare bacteria". Examples of enzymes found in certain types of CRE are KPC and NDM. KPC and NDM are enzymes that break down carbapenems and make them ineffective. Both of these enzymes, as well as the enzyme VIM have also been reported in Pseudomonas.

<span class="mw-page-title-main">Ceftolozane/tazobactam</span> Antibiotic

Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a fixed-dose combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

ESKAPE is an acronym comprising the scientific names of six highly virulent and antibiotic resistant bacterial pathogens including: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. The acronym is sometimes extended to ESKAPEE to include Escherichia coli. This group of Gram-positive and Gram-negative bacteria can evade or 'escape' commonly used antibiotics due to their increasing multi-drug resistance (MDR). As a result, throughout the world, they are the major cause of life-threatening nosocomial or hospital-acquired infections in immunocompromised and critically ill patients who are most at risk. P. aeruginosa and S. aureus are some of the most ubiquitous pathogens in biofilms found in healthcare. P. aeruginosa is a Gram-negative, rod-shaped bacterium, commonly found in the gut flora, soil, and water that can be spread directly or indirectly to patients in healthcare settings. The pathogen can also be spread in other locations through contamination, including surfaces, equipment, and hands. The opportunistic pathogen can cause hospitalized patients to have infections in the lungs, blood, urinary tract, and in other body regions after surgery. S. aureus is a Gram-positive, cocci-shaped bacterium, residing in the environment and on the skin and nose of many healthy individuals. The bacterium can cause skin and bone infections, pneumonia, and other types of potentially serious infections if it enters the body. S. aureus has also gained resistance to many antibiotic treatments, making healing difficult. Because of natural and unnatural selective pressures and factors, antibiotic resistance in bacteria usually emerges through genetic mutation or acquires antibiotic-resistant genes (ARGs) through horizontal gene transfer - a genetic exchange process by which antibiotic resistance can spread.

<span class="mw-page-title-main">Cefiderocol</span> Antibiotic

Cefiderocol, sold under the brand name Fetroja among others, is an antibiotic used to treat complicated urinary tract infections when no other options are available. It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa. It is given by injection into a vein.

References

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