Antibacterial resistance is one of the most persistent challenges to modern medical care in America. Given the ever-changing nature of antibacterial resistance, knowledge of this major health issue and recent associated trends is essential for both the treatment of infected patients and for prevention of further resistance. Methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile are only two examples of today's challenges in antibiotic therapy.
This review focuses on two particular strains of resistant bacteria, vancomycin-resistant Enterococcus (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA). The common link between the two is their resistance to vancomycin, a common glycopeptide antibiotic whose injudicious use in past decades has weakened its scope of efficacy. VRE is notable in part because of the resilience of the gram-positive, anaerobic Enterococcus genus; it is able to survive in much tougher environments than other bacteria can endure. Special care should be taken with patients who are infected with VRE, since this bacteria species is associated with markedly increased rates of morbidity and mortality, especially among the immunosuppressed population. VRSA, on the other hand, is a newer but just as threatening progression in the advancement of antibiotic resistance, owing its creation to the combined presence of VRE and MRSA.
Etiology & Epidemiology
As with many other drug-resistant bacteria, VRE's recent presence in the news belies a longer history. The first case of VRE was documented in 1986. This was more than three decades after the first use of the antibiotic use in hospitals to treat penicillin-resistant staphylococci.1 A microbe's ability to develop resistance lies within its genes and the changes that occur therein. A number of gene cluster types, or operons, can be found in VRE and are represented by the name Van. Within this Van group, multiple phenotypes are denoted by the addition of a letter for that particular phenotype. Of these phenotypes, VanA and VanB convey the strongest and broadest resistance to vancomycin.
These gene clusters change vancomycin-susceptible peptidoglycan chains into vancomycin-resistant forms. Other phenotypes exist, such as VanC and VanD, which cause a different chain mutation and tend to be less pathogenic than VanA or VanB.1 Of all of these operons, VanA is implicated as the one that provides enterococci with the greatest level of vancomycin and teicoplanin resistance. A number of other genes are suspected or proven to be involved with vancomycin resistance, such as the esp-gene and hyl-gene.2
About 30% to 33% of enterococcal infections in American hospitals may be resistant to vancomycin.3,4 VRE isolates are typically either E faecalis or E faecium, though a number of other species may colonize or infect a patient. A patient is considered colonized when he or she has a series of positive rectal swab cultures. A patient is classified as infected when an active pathogenic process occurs locally or systemically, most likely in the urinary tract.2,5 Of the two typical species found in the United States, E faecalis is considered to be more pathogenic, yet E faecium is more common, causing approximately 80% of enterococcal infections.3. In the nosocomial setting, a VRE outbreak is often the result of clonal strains that have adapted specifically to the hospital environment and spread rapidly.4 An estimated 10% of patients admitted to intensive care units may already be colonized with VRE, and a similar number of them may become colonized or infected.7 Beyond the hospital environment, VRE may also be found in human wastewater, suggesting that it has migrated into the community setting.5
Bacteria may exchange genetic information through the process of plasmid-mediated conjugation. VRE is able to spread its vancomycin resistance to MRSA via VanA, resulting in the creation of VRSA.9 VRSA was first seen about 15 years ago and is associated with a high probability of treatment failure.2 The possibility of MRSA developing into VRSA is problematic because of the extensive spread of MRSA within the community and hospital settings. Some studies of inpatient populations have shown rates of co-colonization between VRE and MRSA as high as 20%, highlighting the risk of potentially developing VRSA.9 Although cases of VRSA have been sporadic and rare, its mere existence poses a threat to clinical practice and stands as a testament to the persistent evolution of microbial resistance.
VRE may colonize or infect any patient, but special attentiveness should be given to patients who are hospitalized for a prolonged period, who are immunosuppressed, who are on dialysis, and who have taken a third-generation cephalosporin, which can select for resistant bacteria.10,11 Beyond a urinary tract infection, other presentations include the development of an abdominal abscess, bacterial endocarditis or bacteremia .2,10,12 Patients who are colonized or infected with one resistant microbe are at an increased risk to contract additional microbes, so patients who are known to be carriers or who are immunosuppressed must be monitored closely.
Laboratory Evaluation and Screening
Current screening procedures for VRE colonization involve the use of serial rectal swab samples tested directly upon bile esculin azide agar plates and treated with 6 µg/mL vancomycin.8 There is a concern that due to the time these tests take - possibly as long as 5 days for the culture method - a mild hospital outbreak may escalate before patients can be adequately and accurately placed under contact precautions.5,6 Further laboratory studies will elucidate the specific species as well as the minimum inhibitory concentration of vancomycin for the sample.
Multiplex PCR and gel electrophoresis can be used to determine the resistance genotype of the sample; that is, whether the sample contains VanA, VanB, VanC, etc.9,13 Other important tests are Disk diffusion for antimicrobial susceptibility, Etest to determine minimum inhibitory concentrations, electrophoresis, and broth microdilution.2,11 At present, there are no set guidelines for screening pregnant women for VRE, but studies have shown the present threat of VRE is not high enough to warrant standardized prenatal screening.14 However, vancomycin is one of the treatments for pregnant penicillin-allergic patients who are colonized with S agalactiae. This pathogen is has shown greater resistance to antibiotics such as clindamycin and erythromycin, and it is possible for vancomycin resistance to soon follow.14
Once the presence of colonizing or infectious VRE has been established, contact precautions should be undertaken immediately. This can be done by adhering to stringent hand washing, gowning and gloving, disinfection of surfaces with an aldehyde solution, and using personalized equipment for only that patient.10 The monetary cost of contact precautions should be considered, including the cost of serial swabbing, patient-specific instruments and protective wear, but a hospital experiencing an outbreak may judge these as necessary expenses. Researchers and medical practitioners have had to be creative with antibiotic usage as the upward trend of drug resistance has continued. Enterococci are by nature robust and adaptive. The majority of enterococci species cannot be easily eliminated through the use of beta-lactam antibiotics because of the presence of low-affinity PBP in the enterococci. Further, enterococci may also gain resistance to such common antibiotics as aminoglycosides, erythromycin, fluoroquinolones and nitrofurantoin, leaving the practitioner with fewer options.12 Beyond that, VRE isolates may exhibit an "intermediate resistance" to such antimicrobials as tetracyclines, bacitracin, and chloramphenicol, which suggests that even these antimicrobials are consistently reliable and effective.
Pharmacological treatment of VRE may be initiated using any of several options. For urinary tract infections, removal of any indwelling catheters usually produces a highly favorable outcome; however, in cases of lingering VRE presence, nitrofurantoin may be used.7 In cases where E faecium has been confirmed, the streptogramin drug quinupristin/dalfopristin has proven to be effective parenterally at 7.5 mg/kg three times a day. Dose-related side effects of quinupristin/dalfopristin are typically arthralgia and myalgia. Some resistance to linezolid (another antibiotic used for VRE) and quinupristin/dalfopristin has already been reported, so this must be kept in mind when treating patients with these drugs.2,15 Alternatively, linezolid may also be used for E faecium, though this is not always effective.15 Treatment with linezolid for E faecium is recommended at 600 mg administered orally or intravenously twice a day for 2 to 4 weeks. Likewise, in cases of E faecalis, linezolid can be successful, though quinupristin/dalfopristin has not been shown to be effective.
Teicoplanin is a drug in the glycopeptide class. Although it is not available in the United States, it is notable because it is also rendered useless against VRE in the presence of VanA, and has lowered efficacy in enterococci with VanB or VanC. For skin manifestations of VRE infection, tigecycline may be used and daptomycin has had success in E faecium skin treatment in an in vitro setting.12 Tigecycline may also be used in abdominal manifestations of VRE infection.10 For the treatment of VRE infection in a pregnant patient, great care must be taken to avoid teratogenic effects, yet still clear the patient of the infection. For this purpose, the pregnancy category B drugs daptomycin or nitrofurantoin can be successful and nonteratogenic.16
The prevention of VRE may be undertaken in a number of ways. One of the simplest prevention strategies is to judiciously monitor the use of vancomycin within hospitals and clinics, since these are the classic environments for the development and spread of VRE. The aforementioned contact precautions should be implemented immediately once a positive diagnosis has been made.
Studies in a major French hospital system showed favorable results when a long-term program aimed at reducing multidrug resistance was implemented.17 The parameters of such a program involve the rapid reporting of any recognized VRE case, the restriction of transport and contact with VRE positive patients, patient screening for VRE, and tracking of the VRE cases post-discharge.10 Hospital staff should also be educated and encouraged to use antibiotics with discretion, to use alcohol-based hand scrub frequently, and to not treat cases of simple colonization.
Retrospective studies of programs such as these document a sharp decrease in the number of observed VRE cases after implementation.17 As enterococci may live on dry surfaces for as long as 16 weeks7, surface disinfectant use is important. Successful prevention can be attained when a hospital dedicates certain inpatient rooms for VRE-positive patients only, helping to stop the spread of residual surface VRE to successive noninfected patients.5 Although the majority of colonizations or infections of the skin and colorectal region are caused by other, more common entities, such as S aureus, MRSA and C difficle, it is important to consider VRE and VRSA in the patient's differential because of their propensity to worsen patient outcomes and cause outbreaks in hospital settings.
Updated information about the spread and prevalence of VRE may be readily found in a report released by the Centers for Disease Control and Prevention (CDC) detailing the current state and extent of many antibiotic-resistant organisms.4 Further information about the degree of antimicrobial resistance may also be found in a CDC report on nosocomial infection.18 Information about individual state or regional resistance is available at http://cddep.org/resistancemap/use.
VRE, MRSA and many of the other drug-resistant microbes borne in hospitals have now made their way into communities and countries around the world. As for VRSA, we can only speculate about the future behavior and spread of this threat. An aggressive strategy is important now more than ever. Even a general and rudimentary knowledge of drug-resistant trends is enough to be able to begin combating the problem in the clinical setting. Information on this topic is especially valuable to clinicians treating patients in hospitals, the breeding ground for new microbe development and existing outbreaks alike.
It is easy to become alarmed by the resilience, rapid evolution and pathogenicity of these organisms. The best that health care providers can do is attack the issue on all sides with pre-emptive means (e.g., further research into resistance genes, screening swabs and prudent use of antimicrobials) and post-infection strategies (e.g., genetic testing of samples and wise use of effective antibiotics). It is unlikely that we will eradicate the problem we created, but with testing, education and prevention, we can do our best to prevent the next resistant microbe on the horizon.
Jennifer Rockhold is a physician assistant specializing in cardiology at Lima Memorial Health System in Lima, Ohio. Jennifer Childers is an associate professor in the Marietta College physician assistant program in Marietta, Ohio.
1. Levine DP. Vancomycin : a history. Clin Infect Dis. 2006;42(Suppl 1):S5-S12.
2. Bourdon N, et al. Changing Trends in vancomycin-resistant enterococci in French hospitals, 2001-2008. J Antimicrob Chemother. 2011;66(4):713-721.
3. Orsi GB, Ciorba V. Vancomycin resistant enterococci healthcare associated infections. Ann Ig. 2013;25(6):485-492.
4. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Antibiotic resistant threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf
5. Moretti ML, et al. Controlling a vancomycin-resistant enterococci outbreak in a Brazilian teaching hospital. Eur J Clin Microb Infect Dis. 2011;30(3):369-374.
6. Fang H, et al. Screening for vancomycin-resistant enterococci: results of a survey in Stockholm. APMIS. 2010;118(5):413-417.
7. Ziakas PD, et al. Trends and significance of VRE colonization in the ICU: a meta-analysis of published studies. PLoS One. 2013;8(9):e75658.
8. Beier RC, et al. Antibiotic and disinfectant susceptability profiles of vancomycin-resistant Enterococcus faecium (VRE) isolated from community wastewater in Texas. Bull Environ Contam Toxicol. 2008;80(3):188-194.
9. Sharaf E, et al. Trafficking of methicillin-resistant Staphylococci and co-colonization with vancomycin-resistant Enterococci. Med Princip Pract. 2011;20(3):253-258.
10. Oriola S. Understanding VRE is key to prevention. Materials Mgt Healthcare. 2009;18(5):34-36.
11. Alves d'Azevedo P, et al. Rapid detection of vancomycin-resistant Enterococci (VRE) in rectal samples from patients admitted to intensive care units. Braz J Infect Dis. 2009;13(4):289-293.
12. Cetinkaya Y, et al. Vancomycin-resistant Enterococci. Clin Microbiol Rev. 2000;13(4):686-707.
13. Thierfelder C, et al. Vancomycin-resistant Enterococcus. Swiss Med Weekly. 2012;142:w13540
14. Miller M, et al. Prevalence of vancomycin-resistant Enterococcus in prenatal screening cultures. J Clin Microbiol. 2004;42(2):855-857.
15. Sujatha S, Praharaj I. Glycopeptide resistance in gram-positive cocci: a review. Interdisc Perspect Infect Dis. 2012;2012:781679.
16. Shea K, et al. Successful treatment of vancomycin-resistant Enterococcus faecium pyelonephritis with daptomycin during pregnancy. Ann Pharmacother. 2008;42(5):722-725.
17. Fournier S, et al. Twenty years of antimicrobial resistance control programme in a regional multi-hospital institution, with focus on emerging bacteria (VRE and CPE). Antimicrob Resist infect Control. 2012;(1):9.
18. CDC. National nosocomial infections surveillance (NNIS) system report. Data summary from January 1992 through June 2004. http://www.cdc.gov/nhsn/pdfs/datastat/nnis_2004.pdf.