What is the introduction to Antimicrobial Resistance (AMR) in Gram-positive and Gram-negative bacteria?

From the Guidelines

Antimicrobial resistance (AMR) in bacteria is a growing global health concern that differs between Gram-positive and Gram-negative organisms due to their distinct cell wall structures, with Gram-negative bacteria being particularly challenging to treat due to their additional outer membrane and sophisticated resistance mechanisms, as highlighted in a recent study 1.

Introduction to AMR in Gram-Positive and Gram-Negative Bacteria

Antimicrobial resistance (AMR) is a major public health concern worldwide, and it is essential to understand the differences in resistance mechanisms between Gram-positive and Gram-negative bacteria. Gram-positive bacteria have a thick peptidoglycan layer that allows certain antibiotics like vancomycin to target cell wall synthesis effectively. Common resistance mechanisms in Gram-positive bacteria include target modification (as seen in MRSA with altered penicillin-binding proteins), enzymatic inactivation (such as beta-lactamases in Staphylococcus), and efflux pumps.

Gram-Negative Bacteria Resistance Mechanisms

In contrast, Gram-negative bacteria possess an additional outer membrane that creates an inherent permeability barrier, making them naturally resistant to many antibiotics that work well against Gram-positive organisms. Gram-negative resistance mechanisms include production of extended-spectrum beta-lactamases (ESBLs) and carbapenemases, porin channel modifications that reduce antibiotic entry, and sophisticated efflux pump systems. The genetic elements encoding resistance can be chromosomal or carried on mobile genetic elements like plasmids, which facilitate rapid spread of resistance between bacteria.

Clinical Implications

Understanding these distinct resistance mechanisms is essential for appropriate antibiotic selection and development of new antimicrobial strategies. The choice of empiric antibiotic regimens in patients with intra-abdominal infections (IAIs) should be based on the clinical condition of the patients, the individual risk for infection by resistant pathogens, and the local resistance epidemiology, as recommended by the 2017 WSES guidelines for management of IAIs 1. In patients with healthcare-associated infections (HA-IAIs), antibiotic regimens with broader spectra of activity are preferred, and the use of carbapenems should be limited to preserve their activity against multidrug-resistant infections.

Key Points

• AMR is a growing global health concern that differs between Gram-positive and Gram-negative organisms.
• Gram-negative bacteria are particularly challenging to treat due to their additional outer membrane and sophisticated resistance mechanisms.
• Understanding resistance mechanisms is essential for appropriate antibiotic selection and development of new antimicrobial strategies.
• The choice of empiric antibiotic regimens in patients with IAIs should be based on the clinical condition of the patients, the individual risk for infection by resistant pathogens, and the local resistance epidemiology.
• The use of carbapenems should be limited to preserve their activity against multidrug-resistant infections, as recommended by recent guidelines 1.

From the FDA Drug Label

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding-protein (PBP) targets. The avibactam component of AVYCAZ is a non-beta-lactam beta-lactamase inhibitor that inactivates certain beta-lactamases that degrade ceftazidime. AVYCAZ demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC, and certain oxacillinases (OXA).

Introduction to AMR in Gram-Positive and Gram-Negative Bacteria

• Mechanisms of Resistance: There are several mechanisms of resistance to carbapenems, including decreased permeability of the outer membrane of gram-negative bacteria, reduced affinity of the target PBPs, increased expression of efflux pump components, and production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases).
• Antimicrobial Resistance (AMR): AMR occurs when microorganisms develop mechanisms to survive the effects of an antimicrobial agent, making the agent ineffective against the microorganism.
• Gram-Positive and Gram-Negative Bacteria: Both types of bacteria can develop resistance to antimicrobial agents, but the mechanisms of resistance may differ between the two types.
• Key Points:
  • Meropenem is effective against most gram-positive and gram-negative bacteria.
  • Avibactam is a non-beta-lactam beta-lactamase inhibitor that inactivates certain beta-lactamases.
  • AVYCAZ (ceftazidime and avibactam) has in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and ESBLs.
  • Resistance to carbapenems can occur through various mechanisms, including decreased permeability, reduced affinity, increased efflux, and production of drug-destroying enzymes. 2 3

From the Research

Introduction to AMR in Gram-Positive and Gram-Negative Bacteria

• Antimicrobial resistance (AMR) is a significant concern in both Gram-positive and Gram-negative bacteria, with severe consequences for patient outcomes and public health 4, 5.
• Gram-negative bacteria, such as Acinetobacter baumannii, Enterobacterales, and Pseudomonas aeruginosa, are particularly problematic due to their ability to develop resistance to multiple antibiotics, making treatment challenging 4.
• Gram-positive bacteria, including Staphylococcus aureus and Enterococcus spp., are also major contributors to AMR, with methicillin-resistant S. aureus (MRSA) being a notable example 6, 5, 7, 8.

Gram-Negative Bacteria and AMR

• The development of new antibiotics, such as β-lactam/β-lactamase inhibitor combinations, eravacycline, plazomicin, and cefiderocol, offers hope for improving treatment options for multidrug-resistant Gram-negative infections 4.
• The emergence of carbapenem-resistant Gram-negative bacteria has significant implications for patient care, particularly in critically ill and immunocompromised hosts 4.

Gram-Positive Bacteria and AMR

• MRSA is a leading cause of bacteraemia, endocarditis, skin and soft tissue infections, bone and joint infections, and hospital-acquired infections, with high morbidity and mortality rates 7, 8.
• The treatment of MRSA infections requires careful evaluation of novel antimicrobials and adjunctive aspects of care, such as infectious disease consultation and source control 7.
• The development of new antimicrobials, including oxazolidinones, lipopeptides, and glycylcyclines, is crucial for combating AMR in Gram-positive bacteria 5.