The Open Microbiology Journal




ISSN: 1874-2858 ― Volume 13, 2019
REVIEW ARTICLE

Methicillin Resistant Staphylococcus aureus and Extended Spectrum Beta-lactamase Producing Enterobacteriaceae: A Therapeutic Challenge in the 21st Century



Eric S. Donkor1, *, Francis S. Codjoe2, 3
1 Department of Medical Microbiology, School of Biomedical & Allied Health Sciences, College of Health Sciences, University of Ghana, Korle Bu KB 143Accra, Ghana
2 Department of Medical Laboratory Sciences, School of Biomedical & Allied Health Sciences, College of Health Sciences, University of Ghana, Korle Bu KB 143Accra, Ghana
3 Biomolecular Science Research Centre, Sheffield Hallam University, Sheffield, S1 1WB, UK

Abstract

Antimicrobial resistance is one of the greatest global threats to human health in recent times and it limits the achievement of several of the Sustainable Development Goals. Methicillin-Resistant Staphylococcus aureus (MRSA) and Extended-Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae are among the most important multidrug resistant bacterial pathogens. MRSA and ESBL-producing Enterobacteriaceae have evolved significantly over the last few decades with important clinical and epidemiological implications. Given the slow progress of development of new antibiotics in recent times, it is likely that these multidrug resistant pathogens will have a greater impact on public health in the 21st Century, unless other effective control measures are instituted. Effective infection control strategies coupled with antibiotic stewardship programs are required to limit the spread and burden of MRSA and ESBL-producing Enterobacteriacae.

Keywords: Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Methicillin, ESBL, AMR.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 94
Last Page: 100
Publisher Id: TOMICROJ-13-94
DOI: 10.2174/1874285801913010094

Article History:

Received Date: 10/01/2019
Revision Received Date: 20/03/2019
Acceptance Date: 05/04/2019
Electronic publication date: 30/04/2019
Collection year: 2019

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© 2019 Donkor and Codjoe.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Medical Microbiology, School of Biomedical & Allied Health Sciences, College of Health Sciences, University of Ghana, Korle Bu KB 143 Accra, Ghana;
Tel: +233553527140; E-mail: esampane-donkor@ug.edu.gh





1. INTRODUCTION

The World Health Organization (WHO) considers Antimicrobial Resistance (AMR) to be one of the greatest threats to human health in the 21st Century. It is estimated that by 2050 if the AMR threat were not properly tackled, it would lead to 10 million people dying every year and a reduction of 2-3.5% in Gross Domestic Product (GDP) with an overall cost of 100 trillion USD [1Review on Antimicrobial Resistance Tackling a crisis for the health and wealth of nations 2014.]. This burden is expected to be relatively higher in sub-Saharan Africa with a drop in GDP of US $2895 billion, representing 20% of the region’s total economic output [1Review on Antimicrobial Resistance Tackling a crisis for the health and wealth of nations 2014.]. Antimicrobial resistance limits the achievement of several of the Sustainable Development Goals (SDGs). In particular, SDG3 (Ensure healthy lives and promote well-being for all at all ages) is severely impacted by AMR, as several of the adopted targets in this health-dedicated SDG will be impossible to achieve without the availability of effective antibiotics [2Laxminarayan R, Matsoso P, Pant S, et al. Access to effective antimicrobials: A worldwide challenge. Lancet 2016; 387(10014): 168-75.[http://dx.doi.org/10.1016/S0140-6736(15)00474-2] [PMID: 26603 918] , 3World Health Organization Health in 2015: From MDGs to SDGs 2015.].

Antibiotic resistance, which is the most important aspect of AMR, has been attributed to the misuse and overuse of antibiotics which puts selective pressure on bacterial pathogens leading to the emergence of resistance [3World Health Organization Health in 2015: From MDGs to SDGs 2015.-6Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 2010; 74(3): 417-33.[http://dx.doi.org/10.1128/MMBR.00016-10] [PMID: 20805405] ]. Multidrug Resistance (MDR), the phenomenon where microbes become resistant to several drugs, is now common among many bacterial pathogens. Multidrug resistance is of particular concern as it limits treatment options, can be transferred among bacterial pathogens and enhances morbidity and mortality of the superbugs [3World Health Organization Health in 2015: From MDGs to SDGs 2015.-6Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 2010; 74(3): 417-33.[http://dx.doi.org/10.1128/MMBR.00016-10] [PMID: 20805405] ]. Generally, MDR may occur by one of the two mechanisms. Firstly, the bacteria involved may accumulate multiple resistance genes on plasmids, and each of these genes code for resistance to a single drug [6Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 2010; 74(3): 417-33.[http://dx.doi.org/10.1128/MMBR.00016-10] [PMID: 20805405] , 7Nikaido H. Multidrug resistance in bacteria. Annu Rev Biochem 2009; 78: 119-46.[http://dx.doi.org/10.1146/annurev.biochem.78.082907.145923] [PMID: 19231985] ]. Secondly, multidrug resistance may occur by increased expression of genes that encode multidrug efflux pumps, thereby extruding different types of drugs [6Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 2010; 74(3): 417-33.[http://dx.doi.org/10.1128/MMBR.00016-10] [PMID: 20805405] , 7Nikaido H. Multidrug resistance in bacteria. Annu Rev Biochem 2009; 78: 119-46.[http://dx.doi.org/10.1146/annurev.biochem.78.082907.145923] [PMID: 19231985] ]. In the last few decades, several epidemiologically significant MDR bacterial pathogens have emerged including Methicillin-resistant Staphylococcus aureus (MRSA) and Extended-Spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. MRSA is resistant to all beta-lactam antibiotics and many commonly used antibiotic groups including, aminoglycosides, macrolides, fluoroquinolones, chloramphenicol and tetracyclines [8Chambers HF. Methicillin resistance in staphylococci: Molecular and biochemical basis and clinical implications. Clin Microbiol Rev 1997; 10(4): 781-91.[http://dx.doi.org/10.1128/CMR.10.4.781] [PMID: 9336672] -10Han LL, McDougal LK, Gorwitz RJ, et al. High frequencies of clindamycin and tetracycline resistance in methicillin-resistant Staphylococcus aureus pulsed-field type USA300 isolates collected at a Boston ambulatory health center. J Clin Microbiol 2007; 45(4): 1350-2.[http://dx.doi.org/10.1128/JCM.02274-06] [PMID: 17287335] ]. ESBL-producing Enterobacteriaceae are resistant to third generation cephalosporins and monobactams [11Coque TM, Baquero F, Canton R. Increasing prevalence of ESBL-producing Enterobacteriaceae in Europe. Euro Surveill 2008; 13(47): 1-11.[PMID: 19021958] ]. Together MRSA and ESBL-producing Enterobacteriaceae constitute a serious emerging therapeutic challenge in the management of bacterial infections in the 21st century. Though, there is a plethora of review articles on antibiotic resistance, relatively few of them have focused on MDR organisms in recent times; MRSA and ESBL-producing Enterobacteriaceae seem to have received some attention, but in many cases, these are covered to limited scope [12Liakopoulos A, Mevius D, Ceccarelli D. A review of SHV Extended-Spectrum β-lactamases: Neglected yet ubiquitous. Front Microbiol 2016; 7: 1374.[http://dx.doi.org/10.3389/fmicb.2016.01374] [PMID: 27656166] -14Turner NA, Sharma-Kuinkel BK, Maskarinec SA, et al. Methicillin-resistant Staphylococcus aureus: An overview of basic and clinical research. Nat Rev Microbiol 2019; 17(4): 203-18.[http://dx.doi.org/10.1038/s41579-018-0147-4] [PMID: 30737488] ]. To help address some of these gaps, in this paper, we aimed to review the problem of MRSA and ESBL-producing Enterobacteriaceae with emphasis on the clinical and epidemiological aspects. This review covers selected relevant articles on antibiotic resistance spanning the period from 1963-2019.

2. METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS

Staphylococcus aureus is considered as both a commensal and a human pathogen. As a pathogen, S. aureus is implicated in several infections including meningitis, septicaemia, pneumonia, endocarditis and osteomyelitis [15Todar K. Todar’s Online Textbook of Bacteriology 2006.]. Although S. aureus can be carried to several body sites as part of the normal flora (commensal), its ecological niche is the anterior nares of the nose [16Wertheim HF, Melles DC, Vos MC, et al. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis 2005; 5(12): 751-62.[http://dx.doi.org/10.1016/S1473-3099(05)70295-4] [PMID: 16310 147] -18Coates R, Moran J, Horsburgh MJ. Staphylococci: Colonizers and pathogens of human skin. Future Microbiol 2014; 9(1): 75-91.[http://dx.doi.org/10.2217/fmb.13.145] [PMID: 24328382] ]. S. aureus occurs principally in the anterior nares because it tends to thrive in conditions of high osmotic pressure and low moisture [19Williams REO. Healthy carriage of Staphylococcus aureus: its prevalence and importance. Bacteriol Rev 1963; 27: 56-71.[PMID: 14000926] ]. It is known that about 50% of the general population are rarely colonized by S. aureus, 20% are persistent carriers, while the other 30% carry the organisms intermittently [20Nouwen JL, Fieren MW, Snijders S, Verbrugh HA, van Belkum A. Persistent (not intermittent) nasal carriage of Staphylococcus aureus is the determinant of CPD-related infections. Kidney Int 2005; 67(3): 1084-92.[http://dx.doi.org/10.1111/j.1523-1755.2005.00174.x] [PMID: 15698 449] -22Eriksen NH, Espersen F, Rosdahl VT, Jensen K. Carriage of Staphylococcus aureus among 104 healthy persons during a 19-month period. Epidemiol Infect 1995; 115(1): 51-60.[http://dx.doi.org/10.1017/S0950268800058118] [PMID: 7641838] ]. S. aureus colonization is a major risk factor for the development of invasive disease of the organism in humans [18Coates R, Moran J, Horsburgh MJ. Staphylococci: Colonizers and pathogens of human skin. Future Microbiol 2014; 9(1): 75-91.[http://dx.doi.org/10.2217/fmb.13.145] [PMID: 24328382] , 23Verhoeven PO, Gagnaire J, Botelho-Nevers E, et al. Detection and clinical relevance of Staphylococcus aureus nasal carriage: An update. Expert Rev Anti Infect Ther 2014; 12(1): 75-89.[http://dx.doi.org/10.1586/14787210.2014.859985] [PMID: 24308709] ].

Methicillin was introduced in 1959 to treat infections caused by penicillin-resistant S. aureus. However, in the early 1960s, MRSA was observed in several European countries [24Jevons MP. Celbenin-resistant Staphylococci. Br Med J 1: 124-5.[http://dx.doi.org/10.1136/bmj.1.5219.124-a] -28Gomes AR, Westh H, de Lencastre H. Origins and evolution of methicillin-resistant Staphylococcus aureus clonal lineages. Antimicrob Agents Chemother 2006; 50(10): 3237-44.[http://dx.doi.org/10.1128/AAC.00521-06] [PMID: 17005800] ]. MRSA now has a worldwide distribution and is endemic in many hospitals particularly, in Asia, Europe and the United States [29Chen CJ, Huang YC. New epidemiology of Staphylococcus aureus infection in Asia. Clin Microbiol Infect 2014; 20(7): 605-23.[http://dx.doi.org/10.1111/1469-0691.12705] [PMID: 24888414] -31Panlilio AL, Culver DH, Gaynes RP, et al. Methicillin-resistant Staphylococcus aureus in U.S. hospitals, 1975-1991. Infect Control Hosp Epidemiol 1992; 13(10): 582-6.[http://dx.doi.org/10.2307/30148460] [PMID: 1469266] ]. A systematic review of MRSA carriage among healthcare workers in the United States and Europe in 2014 reported a prevalence of 4.6% [32Dulon M, Peters C, Schablon A, Nienhaus A. MRSA carriage among healthcare workers in non-outbreak settings in Europe and the United States: a systematic review. BMC Infect Dis 2014; 14: 363.[http://dx.doi.org/10.1186/1471-2334-14-363] [PMID: 24996225] ]. In MRSA, the methicillin resistance gene encodes a methicillin-resistant penicillin-binding protein, which is carried on the staphylococcal cassette chromosome mec, of which more than ten types have been described so far [33Classification of staphylococcal cassette chromosome mec (SCCmec): guidelines for reporting novel SCCmec elements. Antimicrob Agents Chemother 2009; 53(12): 4961-7.[http://dx.doi.org/10.1128/AAC.00579-09] [PMID: 19721075] ]. In addition to its extensive resistance to antibiotics, MRSA is of serious concern due to the high prevalence of its infections and association with persistent outbreaks, which have serious economic implications [34Hall GS. MRSA: Lab detection, epidemiology, and infection control. Microbiology. Frontline 2003; 3: 1-6.]. The annual incidence of invasive MRSA infections in the United States is estimated to be 94,360, with 18,650 deaths [35Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298(15): 1763-71.[http://dx.doi.org/10.1001/jama.298.15.1763] [PMID: 17940231] ]. Additionally, hospital stays for MRSA infections in the United States cost $14,000, in comparison with $7,600 for all other stays, with twice the length of hospitalization [36Elixhauser A, Steiner C. Infections with methicillin-resistant Staphylococcus aureus (MRSA) in US hospitals, 1993–2005: statistical brief #35 2007.]. In Europe, data from thirty-one countries reported 27,711 episodes of MRSA blood stream infections, which were associated with 5,503 deaths and 255,683 days of hospitalization between July 2007 and June 2008. The estimated cost of this length of hospital stay was 44 million Euros [37de Kraker ME, Wolkewitz M, Davey PG, et al. Clinical impact of antimicrobial resistance in European hospitals: Excess mortality and length of hospital stay related to methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother 2011; 55(4): 1598-605.[http://dx.doi.org/10.1128/AAC.01157-10] [PMID: 21220533] ]. Relatively, there is a scarcity of MRSA data in developing countries, especially on economic costs. In a hospital-based study involving nine African countries, MRSA was detected in 213 (15%) of the 1440 S. aureus isolates screened; the prevalence was relatively higher in Cameroon, Kenya and Nigeria (21-30%), and below 10% in Tunisia, Malta, and Algeria [38Kesah C, Ben Redjeb S, Odugbemi TO, et al. Prevalence of methicillin-resistant Staphylococcus aureus in eight African hospitals and Malta. Clin Microbiol Infect 2003; 9(2): 153-6.[http://dx.doi.org/10.1046/j.1469-0691.2003.00531.x] [PMID: 12588 338] ]. In Asia, the MRSA prevalence is much higher and countries such as Taiwan, Korea and Japan have recorded Healthcare-Associated HA-MRSA prevalence of >40% [39Chen CJ, Huang YC. New epidemiology of Staphylococcus aureus infection in Asia. Clin Microbiol Infect 2014; 20(7): 605-23.[http://dx.doi.org/10.1111/1469-0691.12705] [PMID: 24888414] ].

Traditionally, MRSA is regarded as a major nosocomial pathogen in healthcare facilities, and is referred to as healthcare-associated MRSA (HA-MRSA) [40Durai R, Ng PC, Hoque H. Methicillin-resistant Staphylococcus aureus: An update. AORN J 2010; 91(5): 599-606.[http://dx.doi.org/10.1016/j.aorn.2009.11.065] [PMID: 20451002] , 41Boyce JM. Are the epidemiology and microbiology of methicillin-resistant Staphylococcus aureus changing? JAMA 1998; 279(8): 623-4.[http://dx.doi.org/10.1001/jama.279.8.623] [PMID: 9486761] ]. Only a few of the known HA-MRSA clones are responsible for the majority of infections, and different clones dominate in different geographical regions. For example, the ST239-SCCmecIII clone predominates in South America, Asia, and Africa [42Feil EJ, Nickerson EK, Chantratita N, et al. Rapid detection of the pandemic methicillin-resistant Staphylococcus aureus clone ST 239, a dominant strain in Asian hospitals. J Clin Microbiol 2008; 46(4): 1520-2.[http://dx.doi.org/10.1128/JCM.02238-07] [PMID: 18234867] , 43Abdulgader SM, Shittu AO, Nicol MP, Kaba M. Molecular epidemiology of Methicillin-resistant Staphylococcus aureus in Africa: A systematic review. Front Microbiol 2015; 6: 348.[http://dx.doi.org/10.3389/fmicb.2015.00348] [PMID: 25983721] ]. The predominant clone in the United States is CC5-SCCmecII (USA100) [44Roberts RB, Chung M, de Lencastre H, et al. Distribution of methicillin-resistant Staphylococcus aureus clones among health care facilities in Connecticut, New Jersey, and Pennsylvania. Microb Drug Resist 2000; 6(3): 245-51.[http://dx.doi.org/10.1089/mdr.2000.6.245] [PMID: 11144425] , 45Pardos de la Gandara M, Curry M, Berger J, et al. MRSA causing infections in hospitals in greater metropolitan New York: Major shift in the dominant clonal type between 1996 and 2014. PLoS One 2016; 11(6): e0156924.[http://dx.doi.org/10.1371/journal.pone.0156924] [PMID: 27272665] ], while in Europe it is CC22-SCCmecIV (EMRSA-15) [46Denis O, Deplano A, Nonhoff C, et al. National surveillance of methicillin-resistant Staphylococcus aureus in Belgian hospitals indicates rapid diversification of epidemic clones. Antimicrob Agents Chemother 2004; 48(9): 3625-9.[http://dx.doi.org/10.1128/AAC.48.9.3625-3629.2004] [PMID: 1532 8144] -50Pérez-Roth E, Lorenzo-Díaz F, Batista N, Moreno A, Méndez-Alvarez S. Tracking methicillin-resistant Staphylococcus aureus clones during a 5-year period (1998 to 2002) in a Spanish hospital. J Clin Microbiol 2004; 42(10): 4649-56.[http://dx.doi.org/10.1128/JCM.42.10.4649-4656.2004] [PMID: 1547 2324] ]. It is important to note that the replacement of these clones keep occurring in several geographical regions [51Aires-de-Sousa M, Correia B, de Lencastre H. Changing patterns in frequency of recovery of five methicillin-resistant Staphylococcus aureus clones in Portuguese hospitals: Surveillance over a 16-year period. J Clin Microbiol 2008; 46(9): 2912-7.[http://dx.doi.org/10.1128/JCM.00692-08] [PMID: 18614664] -53Knight GM, Budd EL, Whitney L, et al. Shift in dominant hospital-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) clones over time. J Antimicrob Chemother 2012; 67(10): 2514-22.[http://dx.doi.org/10.1093/jac/dks245] [PMID: 22761331] ]. Studies on the evolution of the major HA-MRSA clones indicate strong evidence for a wide range of antibiotic-resistant mutations and mobile genetic elements that are associated with the emergence of these clones in hospital epidemics [54Hsu LY, Harris SR, Chlebowicz MA, et al. Evolutionary dynamics of methicillin-resistant Staphylococcus aureus within a healthcare system. Genome Biol 2015; 16: 81.[http://dx.doi.org/10.1186/s13059-015-0643-z] [PMID: 25903077] , 55DeLeo FR, Chambers HF. Reemergence of antibiotic-resistant Staphylococcus aureus in the genomics era. J Clin Invest 2009; 119(9): 2464-74.[http://dx.doi.org/10.1172/JCI38226] [PMID: 19729844] ]. Though MRSA is considered a nosocomial pathogen traditionally, it has emerged in the community in the last two decades and is responsible for several types of community-acquired infections [56Durai R, Ng PC, Hoque H. Methicillin-resistant Staphylococcus aureus: An update. AORN J 2010; 91(5): 599-606.[http://dx.doi.org/10.1016/j.aorn.2009.11.065] [PMID: 20451002] -59Akram J, Glatt AE. True community-acquired methicillin-resistant Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol 1998; 19(2): 106-7.[http://dx.doi.org/10.2307/30141998] [PMID: 9510108] ]. Epidemiologically, CA-MRSA and HA-MRSA are considered to be different from each other [60Popovich KJ, Weinstein RA, Hota B. Are community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains replacing traditional nosocomial MRSA strains? Clin Infect Dis 2008; 46(6): 787-94.[http://dx.doi.org/10.1086/528716] [PMID: 18266611] , 61Bassetti M, Nicco E, Mikulska M. Why is community-associated MRSA spreading across the world and how will it change clinical practice? Int J Antimicrob Agents 2009; 34(Suppl. 1): S15-9.[http://dx.doi.org/10.1016/S0924-8579(09)70544-8] [PMID: 19560 669] ], and Table 1 shows some clinical and genetic differences between them. However, this epidemiological distinction can be blurred by the fact that CA-MRSA and HA-MRSA genotypes are being observed in healthcare and community infections respectively [62Bal AM, Coombs GW, Holden MTG, et al. Genomic insights into the emergence and spread of international clones of healthcare-, community and livestock-associated meticillin-resistant Staphylococcus aureus: Blurring of the traditional definitions. J Glob Antimicrob Resist 2016; 6: 95-101.[http://dx.doi.org/10.1016/j.jgar.2016.04.004] [PMID: 27530849] ]. CA-MRSA infections could also be caused by livestock-associated MRSA (LA-MRSA) [63Cuny C, Wieler LH, Witte W. Livestock-associated MRSA: The impact on humans. antibiotics (Basel) 2015; 4(4): 521-43.[http://dx.doi.org/10.3390/antibiotics4040521] [PMID: 27025639] ]. LA-MRSA is initially associated with livestock (such as pigs, cattle, and chicken) and differs genotypically from HA-MRSA and CA-MRSA [63Cuny C, Wieler LH, Witte W. Livestock-associated MRSA: The impact on humans. antibiotics (Basel) 2015; 4(4): 521-43.[http://dx.doi.org/10.3390/antibiotics4040521] [PMID: 27025639] ]. Globally, among the known LA-MRSA strains, CC398 is most widely disseminated, followed by CC9 [63Cuny C, Wieler LH, Witte W. Livestock-associated MRSA: The impact on humans. antibiotics (Basel) 2015; 4(4): 521-43.[http://dx.doi.org/10.3390/antibiotics4040521] [PMID: 27025639] ].

Table 1
Some differences between healthcare-associated MRSA (HA-MRSA) and community-associated MRSA (CA-MRSA).


The advent of Whole Genome Sequencing Analysis (WGSA) has provided us the opportunity of better understanding some of the important MRSA clones. Using WGSA, Strauß et al. [64Strauß L, Stegger M, Akpaka PE, et al. Origin, evolution, and global transmission of community-acquired Staphylococcus aureus ST8. Proc Natl Acad Sci USA 2017; 114(49): E10596-604.[http://dx.doi.org/10.1073/pnas.1702472114] [PMID: 29158405] ] recently provided insights into the evolution and global dissemination of the ST8 clone (USA 300). The study showed that the ancestor of all ST8 S. aureus emerged in Central Europe in the mid-19th century, and then appeared in North America in the early 20th century where it progressively acquired the USA300 features. Starting from North America, USA300 then spread globally, including Africa. In a phylogenetic analysis, Strauß et al. [64Strauß L, Stegger M, Akpaka PE, et al. Origin, evolution, and global transmission of community-acquired Staphylococcus aureus ST8. Proc Natl Acad Sci USA 2017; 114(49): E10596-604.[http://dx.doi.org/10.1073/pnas.1702472114] [PMID: 29158405] ] demonstrated that the African USA300 isolates formed a monophyletic group within the clade of North American USA300, indicating a single introduction event to the African continent, followed by a spread in the local population [64Strauß L, Stegger M, Akpaka PE, et al. Origin, evolution, and global transmission of community-acquired Staphylococcus aureus ST8. Proc Natl Acad Sci USA 2017; 114(49): E10596-604.[http://dx.doi.org/10.1073/pnas.1702472114] [PMID: 29158405] ]. These observations highlight the role international travel may play in the dissemination of antibiotic resistance.

3. EXTENDED SPECTRUM β-LACTAMASE PRODUCING ENTEROBACTERIACEAE

Gram-negative bacteria including Enterobacteriaceae have a relatively higher tendency to become antibiotic-resistant partly due to the presence of an outer membrane which excludes antibiotics from penetrating the cell [65Silhavy TJ, Kahne D, Walker S. The bacterial cell envelope. Cold Spring Harb Perspect Biol 2010; 2(5): a000414.[http://dx.doi.org/10.1101/cshperspect.a000414] [PMID: 20452953] ]. Additionally, these organisms have a great facility for exchanging genetic material (DNA) that may contain antibiotic-resistant genes among strains of the same species and even among different species [66Aminov RI. Horizontal gene exchange in environmental microbiota. Front Microbiol 2011; 2: 158.[http://dx.doi.org/10.3389/fmicb.2011.00158] ]. The discovery of antibiotic resistance in Gram-negative bacteria became apparent soon after ampicillin (first semisynthetic penicillin) was clinically introduced in 1961. The first plasmid-mediated β-lactamase in gram-negative bacteria, TEM-1, was detected in Escherichia coli isolated from a blood culture from a patient in Greece in 1963 [66Aminov RI. Horizontal gene exchange in environmental microbiota. Front Microbiol 2011; 2: 158.[http://dx.doi.org/10.3389/fmicb.2011.00158] ]. Over the years, diverse resistance mechanisms have changed the distribution of plasmids and new mobile genetic features have been contributory in the horizontal transmission of resistance genes, with these multiple genes conferring resistance to many antimicrobials. Among the Enterobacteriaceae, TEM-1 and sulfhydryl variable-1 (SHV-1) β-lactamases were the most prevalent plasmid-mediated enzymes frequently found spreading in countries worldwide [67Medeiros AA. Evolution and dissemination of beta-lactamases accelerated by generations of beta-lactam antibiotics. Clin Infect Dis 1997; 24(Suppl. 1): S19-45.[http://dx.doi.org/10.1093/clinids/24.Supplement_1.S19] [PMID: 899 4778] ]. In the 1970s, resistant Gram-negative bacteria had become more common in most hospital-acquired pathogens with TEM-1 and SHV-1 enzymes. Most of these bacteria carried multiple β-lactamases as well as other multidrug-resistant genes. In the early part of the 1980s, a number of new antimicrobials were clinically introduced in the health-care delivery systems, including the third-generation cephalosporins. Due to misuse of these agents, Germany in 1983 experienced the first Extended-Spectrum β-Lactamase (ESBL) in a species of Klebsiella. Extended-spectrum β-lactamases are resistance enzymes that usually confer resistance in most Gram-negative bacterial pathogens as a result of more-selective pressure from the use of β-lactams: oxyimino-cephalosporins (such as cefotaxime, ceftriaxone, ceftazidime, or cefepime) and monobactams (aztreonam) but not carbapenems, which had undergone hydrolysis and further mutations [68Bush K. The ABCD’s of β-lactamase nomenclature. J Infect Chemother 2013; 19(4): 549-59.[http://dx.doi.org/10.1007/s10156-013-0640-7] [PMID: 23828655] , 69Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJV. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 2015; 13(1): 42-51.[http://dx.doi.org/10.1038/nrmicro3380] [PMID: 25435309] ]. The ESBL enzymes result from a point mutation in the parent β-lactamases, TEM-1 and SHV-1 by one to four amino acid changes which form the basis of resistance presumably due to evolutionary selective pressure from the use of β-lactams, such as oxyimino-cephalosporins and aztreonam. To date, the number of known β-lactamases have increased, and there are now over 1000 that have been identified. The most recognizable among the mutants of SHV-1, named SHV-2, deactivated the extended-spectrum cephalosporin drugs and often carried many other resistance genes on its parent plasmid that conferred reduced susceptibility to other unrelated classes of antimicrobials [70Knothe H, Shah P, Krcmery V, Antal M, Mitsuhashi S. Transferable resistance to cefotaxime, cefoxitin, cefamandole and cefuroxime in clinical isolates of Klebsiella pneumoniae and Serratia marcescens. Infection 1983; 11(6): 315-7.[http://dx.doi.org/10.1007/BF01641355] [PMID: 6321357] , 71Altayb HN, El Amin NM, Mukhtar MM, Salih MA, Siddig MAM. Molecular characterization and in silico analysis of a novel mutation in TEM-1 beta-lactamase gene among pathogenic E. coli infecting a Sudanese patient. Afr J Microbiol Res 2014; 2(6): 217-23.].

Table 2
Beta lactamases classifications, ESBL activity and representative enzymes.


Equally important ESBLs of clinical significance are the CTX-M and AmpC β-lactamases families, as indicated in Table 2. The CTX-M family is classified under classes of β-lactamases as class A ESBLs for the past decade, CTX-M–type ESBL enzymes have become most, prevalent in clinical isolates, mostly in Escherichia coli isolates in Asia, Europe and South America [72Wang G, Huang T, Surendraiah PKM, et al. CTX-M β-lactamase-producing Klebsiella pneumoniae in suburban New York City, New York, USA. Emerg Infect Dis 2013; 19(11): 1803-10.[http://dx.doi.org/10.3201/eid1911.121470] [PMID: 24188126] ]. Earlier, there were confusions as to where MEN-1 and Tolo-1 enzymes belong. CTX-M-1 was subsequently found to be similar to the MEN-1 enzyme; while CTX-M-44 and CTX-M-45 were known to be the same as Toho-1 and Toho-2 respectively [68Bush K. The ABCD’s of β-lactamase nomenclature. J Infect Chemother 2013; 19(4): 549-59.[http://dx.doi.org/10.1007/s10156-013-0640-7] [PMID: 23828655] , 73Ma L, Ishii Y, Ishiguro M, Matsuzawa H, Yamaguchi K. Cloning and sequencing of the gene encoding Toho-2, a class A β-lactamase preferentially inhibited by tazobactam. Antimicrob Agents Chemother 1998; 42(5): 1181-6.[http://dx.doi.org/10.1128/AAC.42.5.1181] [PMID: 9593147] ]. Since CTX-M-1 recognition in clinical circles in the 1980s, over 130 variants have been identified and genetically classified based on amino acid differences into 5 major divisions, CTX-M-1, -2, -8, -9, or -25 mostly identified in Escherichia coli and Klebsiella pneumoniae isolates from varying geographical locations [74Rossolini GM, D’Andrea MM, Mugnaioli C. The spread of CTX-M-type Extended-Spectrum beta-lactamases. Clin Microbiol Infect 2008; 14(Suppl. 1): 33-41.[http://dx.doi.org/10.1111/j.1469-0691.2007.01867.x] [PMID: 1815 4526] , 75Rogers BA, Sidjabat HE, Paterson DL. Escherichia coli O25b-ST131: A pandemic, multiresistant, community-associated strain. J Antimicrob Chemother 2011; 66(1): 1-14.[http://dx.doi.org/10.1093/jac/dkq415] [PMID: 21081548] ]. In 1999, a CTX-M-15 variant was recovered from India; belonging to the CTX-M-1 group, it was shown to have dominance in the clinical setting and also shown to have worldwide distribution. Thus, more allelic variants were subsequently recovered from different Gram-negative bacterial isolates in both clinical and community settings and those yet to arrive are a threat to patients' conditions in the clinical environment [72Wang G, Huang T, Surendraiah PKM, et al. CTX-M β-lactamase-producing Klebsiella pneumoniae in suburban New York City, New York, USA. Emerg Infect Dis 2013; 19(11): 1803-10.[http://dx.doi.org/10.3201/eid1911.121470] [PMID: 24188126] , 76Cantón R, González-Alba JM, Galán JC. CTX-M enzymes: Origin and diffusion. Front Microbiol 2012; 3: 110.[http://dx.doi.org/10.3389/fmicb.2012.00110] [PMID: 22485109] ].

AmpC β-lactamases are also of importance and the enzymes can be chromosome or plasmid-mediated. After sequencing of the AmpC gene from Escherichia coli K-12 strain, it was designated as class C according to Ambler's structural classification of β-lactamases (Table 2). Thus, differences in molecular structures between β-lactamases classes A and B actually determined AmpC gene classification [77Jaurin B, Grundström T. AmpC cephalosporinase of Escherichia coli K-12 has a different evolutionary origin from that of β-lactamases of the penicillinase type. Proc Natl Acad Sci USA 1981; 78(8): 4897-901.[http://dx.doi.org/10.1073/pnas.78.8.4897] [PMID: 6795623] ]. AmpC-like β-lactamases mainly from Enterobacter and Pseudomonas with ESBLs hydrolyse both penicillins and cephalosporins. Of clinical importance, plasmid-mediated AmpC enzymes occurring in Gram-negative bacteria have detection problems with the phenotypic methods, therefore, dissemination associated with ESBLs pose a serious risk of treatment failures [78Rand KH, Turner B, Seifert H, Hansen C, Johnson JA, Zimmer A. Clinical laboratory detection of AmpC β-lactamase: Does it affect patient outcome? Am J Clin Pathol 2011; 135(4): 572-6.[http://dx.doi.org/10.1309/AJCP7VD0NMAMQCWA] [PMID: 2141 1779] ]. AmpC enzymes are inducible, unaffected by EDTA and clavulanic acid inhibitors, usually produced in low quantities and often suppress detection ability. The main mechanisms that initiate acquisition of plasmid-mediated AmpC genes and overexpression in bacterial strains are largely due to mutation at the AmpC attenuator and promotor regions [79Peter-Getzlaff S, Polsfuss S, Poledica M, et al. Detection of AmpC beta-lactamase in Escherichia coli: Comparison of three phenotypic confirmation assays and genetic analysis. J Clin Microbiol 2011; 49(8): 2924-32.[http://dx.doi.org/10.1128/JCM.00091-11] [PMID: 21653764] , 80Lakshmi R, Nusrin KS, Ann GS, Sreelakshmi KS. Role of beta lactamases in antibiotic resistance: A review. Int Res J Pharm 2014; 5(2): 37-40.[http://dx.doi.org/10.7897/2230-8407.050207] ].

A study by [81Cottell JL, Webber MA, Piddock LJ. Persistence of transferable ESBL resistance in the absence of antibiotic pressure. Antimicrob Agents Chemother 2012; 56(9): 4703-6.[http://dx.doi.org/10.1128/AAC.00848-12] [PMID: 22710119] ] earlier reported selective pressure of broad-spectrum cephalosporins such as cefotaxime and ceftazidime as the main cause of production for AmpC types of β-lactamases [81Cottell JL, Webber MA, Piddock LJ. Persistence of transferable ESBL resistance in the absence of antibiotic pressure. Antimicrob Agents Chemother 2012; 56(9): 4703-6.[http://dx.doi.org/10.1128/AAC.00848-12] [PMID: 22710119] ]. This suggestion has been entirely modified following a careful re-evaluation on a number of plasmid-mediated bacteria by the same group of investigators recently, that selective pressure of antimicrobials only increase the number of antimicrobial resistance isolates, and that production of AmpC β-lactamases largely depend on; suitability of plasmid, stability of bacterial strain interactions, complexity of the plasmids, ability to conjugate freely and survival of plasmid at different conditions [82Cottell JL, Saw HTH, Webber MA, Piddock LJV. Functional genomics to identify the factors contributing to successful persistence and global spread of an antibiotic resistance plasmid. BMC Microbiol 2014; 14: 168.[http://dx.doi.org/10.1186/1471-2180-14-168] [PMID: 24961279] ].

Epidemiological evidence from the SMART study on urinary isolates between 2009 and 2010 showed that ESBL prevalence among E. coli and K. pneumoniae was 17.6 and 38.9% respectively in Europe, and 8.5 and 8.8% respectively in North America [83Hoban DJ, Lascols C, Nicolle LE, et al. Antimicrobial susceptibility of Enterobacteriaceae, including molecular characterization of extended-spectrum beta-lactamase-producing species, in urinary tract isolates from hospitalized patients in North America and Europe: results from the SMART study 2009-2010. Diagn Microbiol Infect Dis 2012; 74(1): 62-7.[http://dx.doi.org/10.1016/j.diagmicrobio.2012.05.024] [PMID: 2276 3019] ]. In both continents, the class A ESBL gene CTX-M-15 was the most prevalent gene (found in >90% of E. coli isolates and in 35–65.5% of K. pneumoniae), though SHV- and TEM-type genes were also common [83Hoban DJ, Lascols C, Nicolle LE, et al. Antimicrobial susceptibility of Enterobacteriaceae, including molecular characterization of extended-spectrum beta-lactamase-producing species, in urinary tract isolates from hospitalized patients in North America and Europe: results from the SMART study 2009-2010. Diagn Microbiol Infect Dis 2012; 74(1): 62-7.[http://dx.doi.org/10.1016/j.diagmicrobio.2012.05.024] [PMID: 2276 3019] ]. Data from the SENTRY Asia Pacific surveillance program reported that CTX-M genes occurred in 38.2–55.5% of K. pneumoniae and E. coli isolates, and the prevalence of SHV- and TEM-type genes was higher (between 34.3 and 85.3%) [84Bell JM, Chitsaz M, Turnidge JD, Barton M, Walters LJ, Jones RN. Prevalence and significance of a negative Extended-Spectrum Beta-Lactamase (ESBL) confirmation test result after a positive ESBL screening test result for isolates of Escherichia coli and Klebsiella pneumoniae: Results from the SENTRY Asia-Pacific Surveillance Program. J Clin Microbiol 2007; 45(5): 1478-82.[http://dx.doi.org/10.1128/JCM.02470-06] [PMID: 17344367] ]. In Africa, a recent review reported ESBL prevalence ranging from 17.7% in Algeria to 82.8% in Cameroon; ESBLs (classes A and D) are common on the continent with the CTX-M-15 gene being most prevalent [85Storberg V. ESBL-producing Enterobacteriaceae in Africa - a non-systematic literature review of research published 2008-2012. Infect Ecol Epidemiol 2014; 4: 10.[http://dx.doi.org/10.3402/iee.v4.20342] [PMID: 24765249] ]. The available data on ESBLs show considerable geographical differences in prevalence. For example, a study involving 100 European Intensive Care Units (ICUs) reported that the prevalence of ESBLs in Klebsiella ranged from 3% in Sweden to 34% in Portugal [86Hanberger H, Garcia-Rodriguez JA, Gobernado M, Goossens H, Nilsson LE, Struelens MJ. Antibiotic susceptibility among aerobic gram-negative bacilli in intensive care units in 5 European countries. JAMA 1999; 281(1): 67-71.[http://dx.doi.org/10.1001/jama.281.1.67] [PMID: 9892453] ].

CONCLUSION AND RECOMMENDATIONS

Methicillin-resistant S. aureus and ESBL producing Enterobacteriaceae have evolved significantly over the last few decades with important clinical and epidemiological implications. Given the slow progress of development of new antibiotics in recent times, it is likely that these MDR bacterial pathogens will have a greater impact on public health in the 21st Century unless other effective control measures are instituted. Effective infection control strategies coupled with antibiotic stewardship programs are required to limit the spread and burden of MRSA and ESBL-producing Enterobacteriaceae. Additionally, further studies on the transmission mechanisms and local epidemiology of these two MDR bacterial pathogens are needed. In particular, there is a need for surveillance including molecular epidemiology data on MRSA and ESBL-producing Enterobacteriaceae in the developing world, where such efforts have focused mainly on microbes with a greater mortality burden such as Streptococcus pneumoniae, Rotavirus and Mycobacterium tuberculosis [87Global tuberculosis report, 2015 WHO/HTM/TB/201522 2016.-91Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375(9730): 1969-87.[http://dx.doi.org/10.1016/S0140-6736(10)60549-1] [PMID: 20466 419] ].

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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(Indiana University School of Nursing, USA)

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(Indiana University School of Medicine, USA)

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(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


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(National Central University, Taiwan)


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