Wednesday, February 13, 2013

The Effect of Horizontal Gene Transfer on the Emergence of Multi-Drug Resistant Bacteria in Nosocomial Infections

Cara N. Wilder, Ph.D.

The discovery of antibiotics in the early twentieth century has revolutionized the treatment of infectious diseases. However in recent decades, the frequency of nosocomial infections caused by multidrug-resistant bacterial strains has steadily escalated worldwide, resulting in increased morbidity, mortality, and health-care expense1-2. This phenomenon can be attributed to a combination of microbial evolution and clinical practices that enhance the transmission of multidrug-resistant strains, including the continuous overuse and misuse of antibiotics, the increased employment of invasive medical devices and procedures, and ineffectual infection control practices3. These selective pressures have required bacterial species to evolve an extraordinary gamut of mechanisms designed to counteract antibiotic function, including the production of antibiotic-modifying and -inactivating enzymes, efflux pumps, and genomic and ribosomal modifications of target sites4-5.

Antibiotic resistance in bacterial strains can be achieved through either genetic mutation or by the acquisition of a laterally transmitted mobile genetic element harboring an antibiotic-resistance gene cassette6. This latter mechanism, termed horizontal gene transfer, can occur through cell contact-dependent DNA transfer (conjugation), the uptake of naked DNA from the surrounding environment (transformation), or by phage-dependent transfer of bacterial genetic elements (transduction). In particular, conjugation has been implicated in a vast number of reports of bacterial gene transfer in the environment, including the horizontal transfer of antibiotic resistance genes. It is predicted that this transfer system may be more predominant as the associated mobile genetic elements transferred are of a very wide host range.

Studies have shown that horizontal gene transfer can occur in both intra- and inter-species populations, with foreign DNA representing up to one-fifth of any given bacterial genome7. This natural selection process has been particularly prominent in the emergence of deadly multidrug-resistant strains such methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae8-10. Numerous surveillance studies have identified the emergence of these resistant strains as a major trend in nosocomial infections among high-risk patients, and are attributed to more than 70% of these infections11-13.

Overall, the worldwide clonal spread of multidrug-resistant organisms within and between hospitals has fueled the extensive rise in resistance, severely limiting therapeutic options and substantially increasing the incidence of incurable infection. Unless this rise in multidrug-resistance can be reversed, the effectiveness and utility of antibiotics may be a matter of years or decades, effectively plunging infection control toward a pre-antibiotic era14.


Prominent Strains of Multidrug-Resistant Bacteria
Extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae Gram-negative bacilli within the Enterobacteriaceae family that produce extended-spectrum β-lactamase. An example of this includes strains of Escherichia coli and Klebsiella pneumoniae that produce New Delhi metallo-β-lactamase-1 (NDM-1). NDM-1 is a carbapenemase β-lactamase that inactivates carbapenem antibiotics as well as a wide range of other antibiotics through the destruction of the β-lactam ring, thus deactivating the antibacterial properties.

ATCC® NDM-1 Strains:
·         Klebsiella pneumoniae (ATCC® BAA-2146™)
·         Enterobacter cloacae (ATCC® BAA-2468™)
·         Escherichia coli (ATCC® BAA-2469™)
·         Klebsiella pneumoniae subsp. pneumoniae (ATCC® BAA-2470™)
·         Klebsiella pneumoniae subsp. pneumoniae (ATCC® BAA-2472™)


Methicillin-resistant Staphylococcus aureus (MRSA) – Any strain of Staphylococcus aureus that has developed resistance to β-lactam antibiotics, including methicillin. These strains harbor the SCCmec genomic island containing the mecA resistance gene, which encodes a penicillin binding protein (PBP) that does not bind methicillin or other β-lactam antibiotics. This enables the PBP to catalyze the transpeptidase reaction, consequently completing cell wall synthesis in the presence of antibiotics.

ATCC® MRSA Strains:
·         Methicillin-Resistant Staphyloccus aureus Panel organized by SCCmec type (MP-2™)
·         Methicillin-Resistant Staphyloccus aureus Panel organized by Pulse-field type (MP-3™)


Vancomycin-resistant enterococci (VRE) – Bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin. This phenotype is possible through the presence of various resistance genes, including vanA, vanB, vanC, vanD, vanE, and vanF. Resistance involves the alteration of vancomycin target sequences: the terminal amino acid residues of NAM/NAG-peptide subunits. Modification of these sequences decreases the binding affinity of vancomycin, allowing antibiotic resistance.
 
ATCC® VRE Strains:
·         Vancomycin-Resistant Enterococci Panel (MP-1™)


References
1.     Harbarth S, et al. Control of multiply resistant cocci: do international comparisons help? Lancet Infect. Dis. 1: 251-261, 2001.
2.     Blondeau JM, Tillotson GS. Antimicrobial susceptibility patterns of respiratory pathogens – a global perspective. Semin. Respir. Infect. 15: 195-207, 2000.
3.     Jones RN, Phaller MA. Bacterial resistance; a worldwide problem. Diagn. Microbial. Infect. Dis. 31: 379-388, 1998.
4.     Levy SB. Active efflux, a common mechanism for biocide and antibiotic resistance. J. Appl. Microbial. Suppl. S1: 65S-71S, 2002.
5.     Gold HS, Moellering RC Jr. Antimicrobial-drug resistance. N. Engl. J. Med. 335: 1445-1453, 1996.
6.     Normark BH, Normark S. Evolution and spread of antibiotic resistance. J. Intern. Med. 252: 91-106, 2002.
7.     Davison J. Genetic exchange between bacteria in the environment. Plasmid 42(2): 73-91, 1999.
8.     Wielders CCL, et al. mecA Gene is Widely Disseminated in Staphylociccus aureus Population. J. Clin. Microbiol. 40(11): 3970-3975, 2002.
9.     Palmer KL, et al. Horizontal Gene Transfer and the Genomics of Enterococcal Antibiotic Resistance. Curr. Opin. Microbial. 13(5): 632-639, 2010.
10.   Bush K, Fisher JF. Epidemiological expansion, structural studies, and clinical challenges of new β-lactamases from Gram-negative bacterial. Annu. Rev. microbial. 65: 455-478, 2011.
11.   Wiener J, et al. Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes. JAMA 281: 517-523, 1999.
12.   Dzidic S, Bedekovic V. Horizontal gene transfer-emerging multidrug resistance in hospital bacteria. Acta. Pharmacol. Sin. 24(6): 519-526, 2003.
13.   Muto CA, et al. SHEA Guideline for Preventing Nosocomial Transmission of Multidrug-Resistant Strains of Staphylococcus aureus and Enterococcus. Infection Control and Hospital Epidemiology 24(5): 362-386, 2003.
14.   Wellington EMH, et al. The role of the natural environment in the emergence of antibiotic resistance in Gram-negative bacteria. Lancet Infec. Dis. 13(2): 155-165, 2013.