Multidrug-Resistant Bacteria

Chapter 36 Multidrug-Resistant Bacteria



Christopher Grace, MD, FACP




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:



image Long-term antibiotic exposure


image Prolonged ICU stay


image Nursing home residency


image Severe illness


image Residence in an institution with high rates of ceftazidime and other third-generation cephalosporin use


image Instrumentation or catheterization



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.


image

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:



image Extended-spectrum β-lactamases (ESBL) cause resistance to most β-lactam antibiotics with the exceptions of the cephamycins (cefoxitin, cefotetan) and carbapenems. The most common bacteria carrying ESBL are Klebsiella spp. and Escherichia coli. Less commonly Enterobacter, Serratia, Morganella, Proteus, and Pseudomonas aeruginosa spp. may harbor these genes. The genes for these enzymes are carried on chromosomes or plasmids and are thus transferrable between bacteria. ESBL-producing bacteria are also often resistant to aminoglycosides and quinolones. These enzymes are usually inhibited by β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam.


image AmpC cephalosporinases are β-lactamases that confer resistance to cephalosporin antibiotics (including cephamycins) by Enterobacter, Nitrobacteria, Morganella, Serratia, and P. aeruginosa. In contrast to ESBL enzymes, they are most often chromosomally encoded and not transferable. Paradoxically they are inducible by third-generation cephalosporins. More recently these genes have been found on transferable plasmids but are not inducible. These enzymes are often resistant to β-lactamase inhibitors.


image Carbapenemases are enzymes that can inactivate the carbapenems (meropenem, imipenem-cilastatin, ertapenem, and doripenem). These enzymes may also be able to inactivate all classes of β-lactam antibiotics and are resistant to β-lactamase inhibitors. Organisms found to carry these MDR genes include P. aeruginosa, Acinetobacter, Stenotrophomonas, Klebsiella, Serratia, Enterobacter, E. coli, and Citrobacter. In 2009, a new carbapenemase was isolated in pathogens from New Delhi, India, called the New Delhi metallo-β-lactamase-1 (NDM-1). Bacteria harboring the NDM-1 include Klebsiella, E. coli, Enterobacter, Nitrobacteria, Morganella, Providencia, Acinetobacter, and P. aeruginosa. The resistance gene is carried by a plasmid and is thus transferable between bacteria. Isolates have now been found in Europe and the United States. Transmission of aminoglycoside and quinolone resistance may be carried by other genes on the plasmid.



6 What other resistance mechanisms cause MDR in the ICU?


Bacterial enzymes can modify aminoglycosides, chloramphenicol, macrolides, or tetracyclines before the antibiotic reaches its ribosomal target. Decreased permeability of carbapenems through the porin channel of the GNR outer membrane can occur. Removal of the antibiotic by bacterial efflux pumps can cause resistance to tetracyclines, macrolides, β-lactams, quinolones, and linezolid. Alteration of the bacterial ribosomes leads to resistance to tetracyclines, macrolides, aminoglycosides, and linezolid. Mutations of the bacterial DNA topoisomerase cause resistance to all quinolones. Sulfonamides lose activity when mutations of the bacterial dihydropteroate synthetase occur.

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Jul 6, 2016 | Posted by in CRITICAL CARE | Comments Off on Multidrug-Resistant Bacteria

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