Multidrug-Resistant Bacteria

1 What is multidrug resistance?

Antibiotic classes include the β-lactams, aminoglycosides, quinolones, tetracyclines, sulfonamides, polymyxins, glycopeptides, and the newer agents with gram-positive bacterial activity such as the lipopeptides, oxazolidinones, streptogramins, and lipoglycopeptides. The definition of multidrug-resistant (MDR) bacteria has not been universally agreed on but generally denotes bacteria that are resistant to at least three of these classes.

2 Why are MDR bacteria such a concern?

With increasing bacterial resistance our therapeutic options lessen. Patients with antimicrobial resistance have been shown to have higher rates of hospital-acquired infections, higher APACHE (Acute Physiology, Age, and Chronic Health Evaluation) III scores, longer hospital stays, increased intensive care unit (ICU) admissions, increased mortality, and higher hospital costs. Increasing antibiotic resistance has become a serious public health issue. In contrast to a large number of newer gram-positive coccal (GPC) agents that have been developed over the past 15 years, very few new agents are in the pharmaceutical pipeline with activity against MDR gram-negative rods (GNR). The development of new GNR agents may take 8 to 10 years and cost billions of dollars.

3 What are the risk factors for MDR infections?

Major risk factors for colonization or infection with MDR organisms are as follows:

4 How do mutations in cell wall synthesis contribute to MDR?

Almost all bacteria have cell walls that are located outside of the inner membrane and are composed of repeating carbohydrate units of N-acetylmuramic acid and N-acetylglucosamine. See Figure 36-1. The key structural stabilizing step is the cross-linking between the carbohydrate layers. Penicillin-binding proteins (PBP) are the bacterial enzymes that accomplish this cross-linkage. β-Lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) bind to PBP, inactivating them, thus interfering with the cross-linkage. Gram-positive bacteria can become MDR by mutations in the PBP such that the β-lactam cannot bind to them. Methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococcus (VRE) all have evolved mutated PBP.

Figure 36-1 Structure of the bacterial cell showing inner and outer membranes, cell wall, and protein synthesis in the ribosomes. β-Lactam antibiotics interfere with cell wall synthesis. Most other classes of antibiotics interfere with protein synthesis. Antibiotic resistance can occur by bacterial production of β-lactamases, mutated penicillin-binding proteins, or porin channels and antibiotic efflux pumps.

5 Why are β-lactamases so important in causing MDR infections?

β-Lactamases are bacterial enzymes that inactivate β-lactam antibiotics by opening the amide bond of the β-lactam ring. See Figure 36-1. These enzymes are the most common cause of MDR in GNR. The β-lactamases causing the most common MDR in the ICU include the following:

6 What other resistance mechanisms cause MDR in the ICU?