Dr. Anant Patil answers ten questions on the broad spectrum antibiotics agent- Carbapenems used for severe, multi-drug resistant bacterial infections.

What are carbapenems?

Carbapenems are bactericidal agents belonging to the class of beta-lactam antibiotic group. [1,2] They are structurally related to penicillins. [2] Carbapenems are an important armamentarium for clinicians in the management of severe infections caused by susceptible bacteria.

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How do carbapenems act?

Carbapenems are closely related to penicillins. Similar to other beta-lactam antibiotics, carbapenems bind to penicillin-binding proteins and cause inhibition of bacterial wall synthesis. The resultant action is killing of the bacteria. [2]

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What are some examples of carbapenems?

Examples of carbapenems include imipenem, meropenem, ertapenem and doripenem. The other examples are faropenem, panipenem and biapenem. [2,3,4]

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What is the spectrum of antibacterial action for carbapenems?

Carbapenems have broader antibacterial spectrum than other commonly used drugs (i.e. penicillins and cephalosporins) from the beta-lactam antibiotics class. Carbapenems are unique because they are relatively resistant to hydrolysis by most beta-lactamases i.e. enzymes which can degrade beta-lactam antimicrobials. [3] Carbapenems are very useful in treatment of infections caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales. [5] The structure of carbapenems also provide protection against metallo-beta lactamase (MBL) as well as extended spectrum beta-lactamases.

Among carbapenems, doripenem is least susceptible to hydrolysis by carbapenemases. [3] Doripenem also has lower minimum inhibitory concentrations than meropenem and imipenem for bacteria Acinetobacter baumannii and Pseudomonas aeruginosa. Among carbapenems, ertapenem has lowest activity against Pseudomonas species.[2]

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Pharmacokinetics of carbapenems

As oral bioavailability of carbapenems is low, they are given intravenously. Imipenem-cilastatin and ertapenem can also be given intramuscularly. [3] Faropenem is an orally-active carbapenem. [4] Carbapenems are widely distributed in the body. Plasma protein binding is low for panipenem (4%), biapenem (4%), meropenem (10%) and imipenem (13-20%) but high for ertapenem (95%). [6]

Elimination of carbapenems is predominately through the kidneys. [3] Imipenem may be degraded by the enzyme dehydropeptidase-1 in renal tubules and hence, it needs to be co-administration with cilastatin, inhibitor of this enzyme. [2] Panipenem is also degraded by dehydropeptidase-I, hence administered with betamipron, another dehydropeptidase-1 inhibitor. [6] Other carbapenems i.e. meropenem, biapenem and ertapenem do not required addition of dehydropeptidase-1 inhibitor. The rates of urinary excretion are different for different carbapenems; lowest for panipenem (30%) and highest for imipenem and meropenem (70% for both). [6] Carbapenems demonstrate time dependent killing. [6]

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What are the uses of carbapenem antibacterial agents?

Carbapenems have broad spectrum of activity and high potency against gram-positive bacteria, gram-negative bacteria as well anaerobes. [2,3,4] They are often used as choice of treatment in patients with severe infection or suspected with multi-drug resistant [1] and complicated bacterial infections.

Carbapenems can be combined with other antimicrobial agents for the treatment of serious infections. An antibiotic active against gram-positive bacteria is often used along with carbapenem for empirical treatment of serious nosocomial infections with unidentified cause. [3] They are useful agents for treatment of invasive or life-threatening bacterial infections. [2] Meropenem can be given in children with three months of age and older with bacterial meningitis. [7]

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Warnings and precautions for the use of carbapenems

• Imipenem and cilastatin combination is not recommended for children with infections of central nervous system due to risk of seizures [8]
• Imipenem is also not recommended for children with less than 30 kg body weight with impairment of renal functions [8]
• It is not given in patients with meningitis due to lack of established efficacy and safety [8]
• Concomitant use of carbapenems with valproic acid or diavalproex sodium can increase the risk of breakthrough seizures due to reduced levels of valproic acid [7-10]
• Concomitant use of probenecid inhibits the renal excretion of carbapenems [7-10]
• Adjustment in dosage of carbapenems is required in patients with renal impairment [7-10]
• They should not be mixed with solutions containing other drugs [7-10]

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Resistance

Development of resistance to antimicrobial agents is a concern for all agents and carbapenems are not an exception to it. In general, gram-negative bacteria are more resistant to antimicrobial agents than gram-positive bacteria because of several reasons including differences in the cell wall and other contributing factors such as efflux pumps and drug destroying enzymes. [2] Understanding resistance is important because it can limit the use of particular agent and/or complicate the process of drug selection.

The development of resistance may be intrinsic or acquired or can be both.

1. Natural resistance: Many bacteria may be naturally resistant to some antimicrobial agents. This is known as intrinsic resistance. Some of the reasons for development of resistance are gram-negative pathogen decrease uptake of beta lactams due to selective alteration of cell membrane porin channels. This prevents the beta-lactam agents from reaching their target of action. [2]
2. Acquired resistance: The reasons for acquired resistance by bacteria include production of enzymes which inactivate the drug, mutation of the target site or development of efflux pumps. The examples of beta lactam-hydrolysing enzymes include penicillinases, cephalosporinases, extended spectrum beta lactamases (ESBLs) and metallo-beta lactamases (MBLs) and other carbapenemases. [2]

There has been emergence of multidrug-resistant pathogens even against carbapenems and the resistance is increasing worldwide.[3,11] Development of metallo-beta lactamases by bacteria has significantly affected the use of carbapenems. Spread of carbapenem-destroying enzymes will result in limited therapeutic options for clinicians. Carbapenem resistance in gram-negative bacteria especially Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia may be a challenge. [12] Isolates from intensive care units have significantly higher resistance to carbapenems than non-intensive care unit patients. [13]

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What are the important adverse effects associated with use of carbapenems?

Carbapenems are generally well-tolerated by patients. They may be associated with adverse events of allergic reactions (e.g. rash, urticaria), [1] gastrointestinal disturbances, nephrotoxicity, hepatotoxicity, [1] and neurotoxicity. [3] It is important to consider other factors which may predispose similar type of adverse effects when using carbapenems. Effect on intestinal microflora and its role in carbapenem-resistance should also be considered. [3]

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Strategies for prevention of resistance

Infection in carbapenem-resistant Enterobacteriaceae (CRE) is an important challenge in healthcare settings. [2] All efforts should be done to reduce the development of drug-resistant bacteria and maintain the effectiveness of antibacterial agents. Following practices may be useful for prevention of resistance against carbapenems:

1. Antimicrobial stewardship programme: Hospitals should have an antibiotic stewardship team. Hospitals should prepare antibiograms periodically, and antibiotics should be used accordingly.
2. Carbapenems should be used only in patients with infections proven or strongly suspected to be caused by bacteria susceptible to them.
3. If culture and sensitivity results are available, they should be used for selection or modification of antibacterial agents.
4. If culture and sensitivity report is not available, local data of prevalent causative agents and their susceptibility patterns can be considered for selection of appropriate antibacterial therapy.
5. Proper hospital wastewater disposal: A study from West Bengal reported presence of high numbers of carbapenem-hydrolysing Proteobacteriain in hospital wastewater. [14] Considering this, proper hospital wastewater disposal is important.

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Disclaimer: The content is for educational purpose only. For agent specific information, healthcare providers are requested to refer the updated prescribing information.

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Anant Patil is Assistant Professor of Pharmacology.