What are the mechanisms of intrinsic and acquired resistance of bacteria?

From the Guidelines

Bacterial resistance to antibiotics is a major concern and occurs through both intrinsic and acquired mechanisms, with intrinsic resistance referring to the natural ability of bacteria to resist certain antibiotics and acquired resistance developing through genetic changes. Intrinsic resistance is often seen in Gram-negative bacteria, which naturally resist vancomycin due to their outer membrane preventing the large antibiotic molecule from reaching its target in the cell wall 1. Pseudomonas aeruginosa possesses intrinsic resistance to many antibiotics due to its low-permeability outer membrane and efflux pumps that expel drugs 1. On the other hand, acquired resistance develops when previously susceptible bacteria become resistant through genetic changes, which can occur via mutations in bacterial chromosomes or through horizontal gene transfer mechanisms like conjugation, transformation, and transduction 1. Common acquired resistance mechanisms include enzymatic inactivation of antibiotics, alteration of antibiotic targets, decreased permeability to antibiotics, and enhanced efflux pump activity 1. Understanding these resistance mechanisms is crucial for appropriate antibiotic selection in clinical practice and highlights the importance of antimicrobial stewardship to prevent further resistance development through practices like avoiding unnecessary antibiotic use and completing prescribed antibiotic courses 1. Some bacteria, such as Klebsiella, Enterobacter, and Serratia species, are intrinsically resistant to certain antibiotics and can acquire resistance to others through the production of extended-spectrum beta-lactamases (ESBLs) or other mechanisms 1. The use of broad-spectrum antibiotics can contribute to the development of resistance, and it is essential to use antibiotics judiciously and follow guidelines for their use to minimize the risk of resistance development 1. In the context of intra-abdominal infections, the choice of empiric antibiotic regimens should be based on the clinical condition of the patients, the individual risk for infection by resistant pathogens, and the local resistance epidemiology 1. The selection of appropriate empiric antibiotic therapy is critical for preventing unnecessary morbidity and mortality from intra-abdominal infections, and clinicians should always consider the pathophysiological status of the patient as well as the pharmacokinetic properties of the employed antibiotics. In patients with complicated intra-abdominal infections, a short course of antibiotic therapy (3-5 days) after adequate source control is a reasonable option, but in critically ill patients with ongoing sepsis, an individualized approach should be always mandatory, and patient’s inflammatory response should be monitored regularly 1. The recent challenges of treating multidrug-resistant gram-negative infections have renewed interest in the use of “old” antibiotics such as polymyxins and fosfomycin, now routinely used for treatment of MDR bacteria in critical ill patients 1. New antibiotics, such as ceftolozone/tazobactam and ceftazidime/avibactam, have been approved for treatment of complicated intra-abdominal infections, including infection by ESBLs producing Enterobacteriaceae and P. aeruginosa, and will be valuable for treating infections caused by MDR gram-negative bacteria in order to preserve carbapenems 1. Overall, the management of intra-abdominal infections requires a comprehensive approach that takes into account the patient's clinical condition, the risk of resistance, and the local epidemiology of resistant pathogens, and the use of antibiotics should always be guided by the principles of antimicrobial stewardship to minimize the risk of resistance development and ensure the best possible outcomes for patients.

From the FDA Drug Label

There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases).

The mechanisms of intrinsic and acquired resistance of bacteria to meropenem include:

• Intrinsic resistance: decreased permeability of the outer membrane of gram-negative bacteria, reduced affinity of the target PBPs, increased expression of efflux pump components
• Acquired resistance: production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases) 2

From the Research

Intrinsic Resistance of Bacteria

• Intrinsic resistance is a trait of bacteria that is independent of previous antibiotic exposure and is not caused by horizontal gene transfer 3
• Intrinsic resistance genes are involved in this process and can provide attractive therapeutic targets for the development of novel drugs 3
• Examples of intrinsic resistance include the impermeability of cellular envelopes, the activity of multidrug efflux pumps, and the lack of drug targets 3
• Transferases and enzymes involved in basic bacterial metabolic processes can also confer intrinsic resistance in certain bacteria, such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus 3

Acquired Resistance of Bacteria

• Acquired resistance occurs when bacteria develop resistance to antibiotics through horizontal gene transfer or spontaneous mutation 3
• Methicillin-resistant Staphylococcus aureus (MRSA) is an example of a bacterium that has acquired resistance to multiple antibiotics, including methicillin and other beta-lactams 4, 5, 6
• MRSA is a significant clinical threat, with high morbidity and mortality, and requires evaluation of novel antimicrobials and adjunctive aspects of care for successful treatment 5

Mechanisms of Resistance

• The cell wall of Gram-negative bacteria is a significant barrier to antibiotic penetration, and its composition and resulting mechanisms of resistance must be considered when developing new therapies 7
• The outer membrane structure, porins, and efflux pumps are all potential targets for antibiotic development to overcome intrinsic and acquired resistance mechanisms 7
• The acquisition of additional resistance determinants can further complicate the eradication of MRSA and other multidrug-resistant bacteria 6

Overcoming Resistance

• Developing new antibiotics and adjuvant therapies is crucial to overcoming antibiotic resistance 5, 7, 6
• Understanding the mechanisms of intrinsic and acquired resistance is essential for the development of effective treatments 3, 7
• Evaluating novel antimicrobials and adjunctive aspects of care is necessary for successful treatment of MRSA and other multidrug-resistant infections 5