71. Carbapenems, monobactams, beta lactamase inhibitors

Carbapenems

Carbapenems have the broadest antibacterial spectrum of all beta lactam antibiotics. They are effective against many Gram-positive, Gram-negative and anaerobes, but not MRSA or enterococci. The most important ones are imipenem, meropenem and ertapenem. Imipenem is combined with cilastatin, a drug which delays its metabolism.

Due to the potentially significant side effects and driving of resistance these drugs are considered a “last resort”.

Mechanisms of resistance

Carbapenems are not inactivated by beta-lactamases, but carbapenemases exists.

Pharmacokinetics and dosing

Carbapenems have low oral bioavailability, so only parenteral formulations are available.

Imipenem is metabolized by an enzyme in the kidney called dipeptidase. Cilastatin is a dipeptidase inhibitor and therefore increases the half-life of imipenem. Other carbapenems are excreted unchanged by the kidneys.

Adverse effects

These drugs, especially imipenem, lower the seizure threshold and can cause convulsions. Due to this they should be used with care in people with decreased renal function.

Other common side effects include hypersensitivity, GI symptoms and irritation at the site of infusion.

Monobactams

The only important monobactam is aztreonam. It’s composed of a monocyclic beta-lactam ring, which makes it different from other beta-lactams, which have dicyclic beta-lactam rings.

Monobactams are interesting as they are effective only against Gram-negatives aerobes like pseudomonas, N. meningitidis and H. influenzae. It has no action against Gram-positives or anaerobes.

Aztreonam only exists in IV formulation. It distributes well, enters the CNS and is eliminated by the kidneys.

Side effects are similar to those of other beta-lactam antibiotics. Cross-allergy with penicillins is very rare, but hypersensitivity reactions can occur.

Beta-lactamase inhibitors

Because beta-lactamase production is the predominant cause of clinically important resistance to beta-lactam antibiotics, sensitive antibiotics can be given together with beta-lactamase inhibitors. This prevents the antibiotics from being inactivated.

We divide them into two types: those that have a beta-lactam structure and those who don’t.

• Beta-lactam structure
  • Clavulanate
  • Sulbactam
  • Tazobactam
• Non-beta-lactam structure
  • Avibactam
  • Vaborbactam

Type	Beta-lactamase inhibitors	Antibiotic combined with
Beta-lactam structure	Clavulanate	Amoxicillin
	Sulbactam	Ampicillin
	Tazobactam	Piperacillin
Non-beta-lactam structure	Avibactam	Ceftazidime
	Vaborbactam	Meropenem

Not all beta-lactamases are the same. Some bacteria have the beta-lactamase encoded on a plasmid (a piece of DNA in the cytoplasm, separate from the chromosomes) while some bacteria have it encoded in the chromosome, as an inducible gene. Different beta-lactamases produced by different bacteria have affinity against different antibiotics.

For example, the extended-spectrum beta-lactamases (ESBL) have a very broad spectrum and can inactivate penicillins, cephalosporins and aztreonam, but not carbapenems. For bacteria who produce ESBL, carbapenems are usually the only effective option.

Beta-lactamases that can inactivate carbapenems, so-called carbapenemases, exist. There are two major types, KPC and metallo-beta-lactamases.

Beta-lactamase inhibitors with beta-lactam structure

Clavulanate, sulbactam and tazobactam irreversibly inactivate plasmid-encoded beta-lactamases, often found in Staphylococcus, Neisseria, E. Coli, Klebsiella, Salmonella and Shigella. They can’t inactivate chromosomal beta-lactamases or metallo-beta-lactamases.

Beta-lactamase inhibitors with non-beta-lactam structure

Avibactam and vaborbactam have broader spectrum than the previously mentioned drugs. In addition to plasmid-encoded beta-lactamases they can also inactivate chromosomal beta-lactamases. They still cannot inactivate metallo-beta-lactamases, but they can inactivate KPC.

Beta-lactamase inhibitors	Drugs	Plasmid beta-lactamases	Chromosomal beta-lactamases	KPC	Metallo-beta-lactamases
Beta-lactam structure	Clavulanate, sulbactam, tazobactam	Effective	Ineffective	Ineffective	Ineffective
Non-beta-lactam structure	Avibactam, vaborbactam	Effective	Effective	Effective	Ineffective