No doubt you’re aware of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcal infections. But perhaps you haven’t heard of another type of drug-resistant infection—one that poses a special challenge because of its relatively low profile and ability to elude laboratory detection.
This increasingly common drug resistance stems from enzymes called extended-spectrum beta-lactamases (ESBLs). ESBL-related infections, which are linked to poor patient outcomes, range from urinary tract and respiratory infections to life-threatening bacteremias. Previously confined to acute-care settings, they are now emerging in community settings as well.
Increasing your knowledge of these infections will help you better understand your patients’ microbiology reports, collaborate with physicians about treatment, and help control infection spread. This article reviews the ABCs of ESBLs—awareness of the problem, basic ESBL microbiology, and control measures.
Awareness of the problem
Almost from the time antibiotics were introduced in the 1940s, pathogenic organisms have mutated to thwart the effects of these drugs. Fifty years ago, scientists discovered that certain staphylococci resist naturally occurring penicillin G. In 1983, organisms that produce beta-lactamase enzymes were discovered in strains of Klebsiella species from Germany; these organisms resisted cephalosporins.
In the United States, ESBLs emerged in 1988. According to the Centers for Disease Control and Prevention (CDC), nationwide prevalence of ESBLs is now about 3%. From the mid- to late-1990s, resistant Escherichia coli strains increased a staggering 48%. Many countries have reported that about 10% to 40% of E. coli and Klebsiella pneumoniae strains produce ESBL enzymes that render certain antibiotics useless. ESBL infections carry a high mortality—from about 42% to 100% in misdiagnosed patients who continue to receive third-generation cephalosporins.
Basic ESBL microbiology
Normally, the backbone of a bacterial cell wall consists of alternating complex sugar chains—
N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Between the layers of NAG and NAM sugars are protein cross-linked bridges, which form a relatively strong wall around the organism. Several enzymes work within the cell wall to insert more NAG and NAM sugar chains and more cross-linked bridges. As this foundation is laid, bacteria flourish.
Gram-negative bacteria (the largest group of human pathogens) have thinner cells walls than gram-positive bacteria. But they have an additional layer composed of lipids (fats) and sugars, called lipopolysaccharide (LPS). The lipid component of LPS is called lipid A. Gram-negative pathogenicity is linked to lipid A presence. When the cell wall of a gram-negative organism disintegrates and the organism dies, lipid A is released, causing many signs and symptoms, such as fever, vasodilation, inflammation, shock, and blood-clotting problems.
Ruining the antibiotic ring
Bacteria can grow resistant to antibiotics in several ways. One way is to produce beta-lactamase, an enzyme that destroys the beta-lactam ring—the functional portion—of various antibiotics and renders these antibiotics ineffective. Beta-lactamases are more prevalent in gram-negative than gram-positive organisms. More than 340 beta-lactamases have been documented. E. coli and K. pneumoniae are the most common ESBL producers.
Penicillins, early cephalosporins, and aztreonam—antibiotics with beta-lactam rings—worked well to destroy nonresistant pathogens. They interfered with enzymes that inserted the protein cross-linked bridges needed by the bacterial cell wall. Because the bacteria could no longer create cross-bridges, cell-wall integrity was disrupted and the cell ruptured, causing the microorganism to die.
However, once bacteria began to mutate and produce beta-lactamase enzymes, drug-resistant pathogenic strains emerged, and more efficient antibiotics had to be developed to overcome them. Second- and third-generation cephalosporins were designed to keep up with these ever-changing pathogens.
In 1988, with the discovery of ESBL-producing organisms, the war against antibiotic resistance changed yet again, as these organisms mutated and acquired actions against wider numbers and classes of antibiotics. ESBLs deactivate penicillins (ampicillin, amoxicillin, and piperacillin), first-generation cephalosporins (such as cefazolin), extended-spectrum (third-generation) cephalosporins (such as ceftazidime, cefotaxime, and ceftriaxone), and monobactams (such as aztreonam).
Recognizing risk factors can help prevent and control ESBL-related infections. The most important risk factor is extensive use of third-generation cephalosporins. These drugs are the most commonly used antibiotic class in acute-care settings; they’re also frequently prescribed in community settings. Persistent exposure to antibiotics helps organisms grow resistant to drugs. To decrease the risk of bacterial overexposure to antibiotics, practitioners must alter their prescribing practices.
What’s more, identifying ESBL-producing organisms in laboratories is no easy task. The Clinical and Laboratory Standards Institute (CLSI) has published standards (available at www.nccls.org) to help microbiologists and infection control specialists seeking to identify ESBL producers. Bacterial growth that continues in a clinical isolate despite exposure to aztreonam or at least one of four extended-spectrum cephalosporins (ceftazidime, ceftriaxone, cefpodoxime, or cefotaxime) suggests an ESBL-producing organism. For further confirmation, clavulanic acid (a beta-lactamase inhibitor) can be added to the testing regimen; decreased bacterial growth after this addition confirms ESBLs. However, the CLSI standards are recommended only to confirm ESBL-producing K. pneumoniae and E. coli. Many additional species of ESBL-producing organisms exist; worldwide, more than 150 have been identified.
In addition, ESBLs can produce many strains of enzymes within one bacterium, making detection even more challenging. Even if testing shows an organism is susceptible to third-generation cephalosporins, CDC urges clinicians not to use these drugs to treat ESBL infections. Many microbiology laboratories mistakenly report pathogens as susceptible to particular antibiotics because of difficulty identifying beta-lactamases. In one study, 21% of laboratories failed to detect inefficacy of extended-spectrum cephalosporins and aztreonam to ESBL-producing organisms. In fact, susceptibility testing commonly indicates that a patient’s treatment regimen is adequate—yet the patient doesn’t improve clinically.
Even if early susceptibility results are positive, to promote the best patient outcomes, clinicians and microbiology personnel should consider ESBL infections resistant to all penicillins, cephalosporins, and aztreonam. Susceptibility reports should include a notation that ESBL-producing organisms are present. Once these organisms are confirmed, healthcare providers should take appropriate precautions, such as patient isolation, good hand hygiene, and other measures specified by facility policy.
Which drugs work
The mainstay of treatment for ESBL infections are carbapenems, such as imipenem and meropenem. These broad-spectrum antibiotics destroy various gram-positive, gram-negative, and anaerobic bacteria. Nonetheless, they can cause serious adverse effects, such as phlebitis at the I.V. site, nausea and vomiting, rash, hypotension, pseudomembranous colitis, seizures, and anaphylaxis.
Beta-lactam/beta-lactamase inhibitor combinations (such as amoxicillin/clavulanic acid, ampicillin/sulbactam, and piperacillin/tazobactam) have been used with some success in treating ESBL infections of the lower urinary tract. However, they’re not preferred for serious ESBL infections. Aminoglycosides and fluoroquinolones are somewhat effective in varying dosages and combinations, but aren’t considered first-line treatment.
Preventing ESBL infections
Prescribers can help prevent development of ESBL resistance and control the spread of resistant infections. Third-generation cephalosporins are prescribed too often or incorrectly in acute-care settings—especially intensive care units (ICUs). A study of a 17-bed neurosurgical ICU over a 10-month period found these drugs were used inappropriately 63% of the time. After the infection prevention and control team limited their use, prescribers switched to imipenem for patients with respiratory infections involving ESBL-producing K. pneumoniae. This prescribing change significantly lowered the incidence of ESBL-producing K. pneumoniae isolates. Although contact isolation wasn’t used in this study, such isolation may be warranted in some patients with ESBL infections.
Both indirect and direct transmission modes are linked to ESBL outbreaks. Indirect modes include patient contact with fomites, such as contaminated thermometers, oxygen probes, blood pressure cuffs, patient sink basins, and ultrasound gel, as well as cockroaches.
Direct transmission can occur via a healthcare worker’s contaminated hands. Always practice good hand hygiene, including a 15-second handwash or appropriate use of an alcohol-based rub.
Be sure to adhere to your facility’s policies regarding hand hygiene and patient isolation. Patient segregation has been shown to effectively control outbreaks of ESBL infections. Physician preference and facility policy dictate whether contact isolation should be used; some facilities use it in conjunction with face masks if the ESBL infection has been isolated in the patient’s sputum. Bowel incontinence also may warrant isolation.
More than any other healthcare providers, nurses have the greatest opportunity to detect possible ESBL infection sources, prevent transmission, and identify early signs and symptoms of infection. Armed with knowledge, you’ll be better prepared to collaborate with other clinicians in obtaining proper cultures, discussing treatment regimens, and controlling the spread of ESBL infections.
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Krista A. White is a Nursing Instructor at Lancaster General College of Nursing & Health Sciences in Lancaster, Pa. She has 22 years of experience in critical care and 15 years in nursing education. Currently, she is pursuing her PhD in nursing at the University of Nevada, Las Vegas.
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