Multidrug-Resistant Bacteria

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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:

Long-term antibiotic exposure

Prolonged ICU stay

Nursing home residency

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

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.

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:

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.

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.

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.

7 How do bacteria become multiresistant?

Bacteria become resistant to antibiotics by DNA mutation at select points or by insertions or deletions that alter microbial enzymes or the antibiotic targets. Genetic material can be transferred between bacteria by plasmids (extrachromosomal double-stranded circular DNA) via direct cell-to-cell contact. Bacteria may also acquire new resistance genes by infection with bacteriophage viruses that carry resistance genes with them when they infect bacteria. Once bacteria develop or acquire new resistance genes they have a selective advantage when antibiotics are used. As more mutations or transferred genetic material accumulates, the more classes of antibiotics the bacteria become resistant to, inducing MDR.

8 What MDR gram-positive bacteria pose the greatest risk in the ICU?

MRSA is resistant to all penicillins and cephalosporins and often resistant to clindamycin and quinolones. Long known as a nosocomial pathogen, MRSA is now appearing as community-acquired infections. MRSA can cause pneumonias, severe abscesses with cellulitis, and bloodstream and central line infections. It is not a classic urinary pathogen, and its presence in the urine should raise the suspicion of bacteremia. Vancomycin remains the “go to” drug although resistance is emerging more commonly. For those isolates with a minimum inhibitory concentration of > 1 mcg/mL, vancomycin may not be effective, especially for endocarditis, bloodstream infections, and pneumonia.

VRE have become increasingly common. They can be part of bowel flora and colonize the urinary tract. They can be nosocomial pathogens causing blood, urinary tract, and central catheter infections and endocarditis.

9 What are the treatment options for these MDR gram positives?

Vancomycin interferes with bacterial cell wall synthesis by blocking penicillin-binding proteins. It is active against MRSA and vancomycin-sensitive enterococci. Vancomycin-intermediate S. aureus (VISA) isolates have been found clinically, and fear remains concerning vancomycin-resistant S. aureus (VRSA) isolates.

Daptomycin is the first of a new class of antibiotics called lipopeptides that interfere with gram-positive bacterial cell membrane function. It has activity against MRSA, some VISA, and VRE. Daptomycin may cause myositis, and creatine phosphokinase levels need to be monitored. Daptomycin is inactivated by pulmonary surfactant and should not be used to treat pneumonia.

Linezolid is the first oxazolidinone antibiotic. It interferes with bacterial protein synthesis by binding to the 50 S ribosome. It is bacteriostatic with activity against MRSA and VRE. It can be used orally or intravenously. Linezolid can cause thrombocytopenia.

Quinupristin-dalfopristin (Synercid) is a combination streptogramin antibiotic that interferes with the bacterial 50 S ribosome. It has activity against MRSA. Although it does not have activity against Enterococcus faecalis, it does work against Enterococcus faecium including VRE.

Ceftaroline fosamil is a new cephalosporin with activity against MRSA and penicillin-resistant S. pneumoniae. As with all cephalosporins, there is no enterococcal activity including VRE.

Televancin is a new lipoglycopeptide antibiotic that inhibits cell wall synthesis and disrupts bacterial cell membrane function. It has activity against MRSA and enterococci but not VRE.

Older agents, such as doxycycline, may have activity against both MRSA and VRE. Trimethoprim-sulfamethoxazole (TMP-SMX) may have activity against MRSA. Clindamycin may have MRSA activity, but it is important to check for erythromycin resistance because that may predict inducible clindamycin resistance.

10 What MDR gram-negative bacteria pose the greatest risk in the ICU?

Enterobacteriaceae that have increasing MDR include E. coli, Klebsiella, and Enterobacter. Resistance is most often conferred by ESBL, AmpC cephalosporinases, and carbapenemases. These organisms may be urinary, wound, or respiratory colonizers but also cause a wide array of nosocomial infections including pneumonia, bacteremia, and urinary tract infections. Agents with possible activity include carbapenems, aminoglycosides, tigecycline, and colistin.

P. aeruginosa has the greatest ability to develop resistance. It has minimal nutritional requirements, which accounts for its successful growth in many environments and its ability to colonize endotracheal tubes and urinary catheters in the ICU. P. aeruginosa may cause pulmonary, bloodstream, central line, and urinary tract infections. In the host with neutropenia, necrotic skin lesions, ecthyma gangrenosum, can occur. Resistance is mediated by ESBL, AmpC cephalosporinases, carbapenemases, efflux pumps, and outer membrane porin mutations. See Figure 36-1. No evidence exists that using two antibiotics for synergy improves outcomes or reduces emerging resistance. Antibiotics that may retain activity against MDR P. aeruginosa include colistin and, in some situations, doripenem.

Acinetobacter calcoaceticus (80% of clinical isolates) and Acinetobacter baumannii have limited nutritional requirements, are resistant to many disinfectants, and can easily contaminate environmental surfaces. Approximately 25% of the healthy population are colonized. All of these factors contribute to colonization and infection in the ICU. Infections may occur in the lung, bloodstream, urinary tract, and traumatic wounds. Acinetobacter have multiple β-lactamases, loss of outer-membrane porin channels, and efflux pumps causing MDR to most β-lactams, quinolones, and aminoglycosides. Isolates may be sensitive to carbapenems, tigecycline, ampicillin-sulbactam, TMP-SMX, rifampicin, and colistin.

Stenotrophomonas maltophilia is most often encountered in the nosocomial setting in patients with prior broad-spectrum antibiotic exposure. It is often isolated in patients with cystic fibrosis. The most common infections include bacteremias related to central venous catheters and pneumonia. Resistance is mediated through β-lactamases, efflux pumps, and outer-membrane porin channel mutations. Although TMP-SMX and ticarcillin-clavulanic acid are often effective, reports are increasing of TMP-SMX resistance. Other agents that may have activity include ceftazidime, aztreonam, minocycline, tigecycline, and ciprofloxacin.

11 What are the treatment options for these MDR gram negatives?

Carbapenems should remain active against ESBL and AmpC-producing bacteria. Rates of P. aeruginosa, Acinetobacter, and S. maltophilia resistance are increasing.

Colistin is polymyxin E, a cationic polypeptide antibiotic that binds to the lipopolysaccharides of the GNR outer membrane to disrupt it and cause cell death. It has been used successfully intravenously and as an aerosol to treat MDR Acinetobacter. It may be used for MDR P. aeruginosa and carbapenemase-producing Enterobacteriaceae. Serratia, Proteus, and S. maltophilia are resistant. Nephrotoxicity and neurotoxicity are the major toxicities.

Tigecycline is a parenteral derivative of minocycline. It may have activity against ESBL and carbapenemase-producing Enterobacteriaceae, S. maltophilia, and Acinetobacter. P. aeruginosa and Proteus are resistant. Because of low urinary concentrations, it should not be used to treat urinary tract infections.

12 Control of MDR bacteria

Because the emergence of MDR bacteria is related to selective antibiotic pressure, the best means of reducing or controlling MDR bacteria is by limiting antimicrobial exposure. Although challenging in the ICU setting because of the critical nature of illness, antibiotic usage can be curtailed by careful differentiation of colonization from true infection and narrowing of broad-spectrum empiricism once cultures are available. Minimizing the duration of antimicrobial use will also decrease exposure. Guidance developed by the Infectious Diseases Society of America and the American Thoracic Society suggests that 5 days of an active antibiotic for community-acquired pneumonia and 7 days for uncomplicated hospital- or ventilator-acquired pneumonia are adequate. Limitation of excess culturing can also avoid repeated sampling of universally positive cultures from endotracheal tubes and urinary catheters. Strict use of infection control measures can also limit health care worker transfer of resistant bacteria from one patient to another. This is especially true for hand washing before and after each patient contact. Patients with MDR bacteria (GPC and GNR) should be placed in a private room and contact precautions (gown and gloves) be practiced by all those entering the room. On a more societal level, removing antibiotics from animal feed products will also lessen antibiotic pressure and selection of resistant strains.

MDR bacteria are becoming an increasing threat to ICU patients. Although a large array of agents with activity against the resistant Staphylococcus and Enterococcus now exists, there are very few options for patients infected with MDR GNR. It is feared these options will only become more limited as times goes on. Newer agents to fill the breach are not on the horizon. For the foreseeable future our best defense against this growing menace will be the judicious use of our current limited resources.

Key Points Multidrug-Resistant Bacteria

1. GNR and GPC MDR bacteria are becoming an increasingly greater problem.

2. Increasing bacterial resistance is caused by excessive antibiotic usage both by physicians and in animal feeds.

3. Before initiating antibiotic therapy it is vital to differentiate between colonization and infection.

4. Many new agents exist with activity against MDR staphylococcus and enterococcus.

5. Because of the lack of new agents with activity against MDR GNR, older drugs such as colistin will be required more often.

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