Beta-lactamases and Their Global Health Implications-Two: Resistance Profile and Global Health Risk
Sunday Akidarju Mamza1, *, Godwin Onyemaechi Egwu1, Gideon Dauda Mshelia2
1Department of Veterinary Medicine, University of Maiduguri, Maiduguri, Nigeria
2Department of surgery and Theriogenology, University of Maiduguri, Maiduguri, Nigeria
To cite this article:
Sunday Akidarju Mamza, Godwin Onyemaechi Egwu, Gideon Dauda Mshelia. Beta-lactamases and Their Global Health Implications-Two: Resistance Profile and Global Health Risk.Science Journal of Public Health.Vol.3, No. 5, 2015, pp. 797-803. doi: 10.11648/j.sjph.20150305.39
Abstract: Beta-lactamases are enzymes produced by some bacteria, which make them resistant to β-lactam antibiotics such as penicillins, cephalosporins, cephamycins and carbapenems. In this article, global health implications, resistance profile and treatment options were reviewed. Extended-spectrum β–lactamases produced by enterobacteria and methicillinases produced by Staphylococci have been shown to constitute the growing strains of bacteria that confer resistances to all β–lactam agents and many non–β–lactam antimicrobials, including fluoroquinolones. Their continued detection in animal species and food products poses a great challenge to diagnosis and treatment of resulting infections, thus, emanating to serious global health implications. Although a lot of works on β-lactamases have been directed towards the search for molecules which can inhibit these enzymes, the beta-lactamase producting bacteria are not leaving any stone to chance. Investigations targeted at identifying the carriers of these enzymes and intercepting their transmission will help curb the emergence and spread of the β–lactamases and their menace to public health.
Keywords: Beta-lactamase, Escherichia coli, Staphylococcus aureus, Epidemiology, Resistance, Health Implications
One of the most important mechanisms of resistance in bacteria is the production of β –lactamases, which inhibit protein transpeptidases and carboxypeptidases participating in bacterial cell wall synthesis, thereby disrupting cell wall formation of the pathogen (Pitout et al., 1998; Ritu et al., 2006; Kolar et al., 2010).
Much of work on β-lactamases over the past decades has been directed to the search for molecules that can resist β-lactamase-producing organisms, or which can inhibit these enzymes (Brad and Edward, 2008). β-lactam antibiotics have recently been on the list of the most frequently prescribed drugs used worldwide in the control of S. aureus and E. coli infections, but the efficacy of these antimicrobials have suffered set back by the growing trend of multidrug resistant (MDR) strains of these β-lactamase-producing bacteria (Jensen and Lyon, 2009).
The present paper focused on resistance profiles and global health implications of β-lactamases, with overview of the control options. There was a relieve in the therapy of bacterial infections during the late nineteenth century when the third-generation cephalosporin were first introduced into clinical practice in both human and veterinary medicine. But sooner than realised, after the development and widespread use of these oxyimino-cephalosporins there was an emergence of extended-spectrum beta–lactamases (ESBLs) in bacteria that hydrolyze both penicillins and the extended-spectrum cephalosporins and aztreonam (Ritu et al., 2006; Brad and Edward, 2008; Mirzaee et al., 2009). These emergent resistant ESBLs in various bacterial organisms, is creating a huge public health concern worldwide. Resistance by β-lactamase-producing strains of Enterobacteriaceae against the extended-spectrum cephaolosporins have widely been studied and documented in human isolates, and increasing reports in isolates from food-producing animals (Paterson and Bonomo, 2005), companion animals (Sidjabat et al., 2007) and wildlife (Carmen and Myrian, 2007; Pinto et al., 2010). Resistance to β-lactam antibiotics by E. coli is by the production of ESBLs and AmpC type β-lactamases that confer resistance to the penicillins, cephalosporins and aztreonam, and cephamycins (Ritu et al., 2006). The extended-spectrum cephalosporins-resistant strains of E. coli often carry integrons that encode resistance to fluoroquinolones and many newer antibiotics (Lorena and Alvaro, 2007), which further sabotages therapeutic options.
S. aureus exhibit resistance to β-lactam antibiotics by the expression of a low-affinity penicillin-binding protein (PBP2a) encoding the resistance gene, mecA, or by the production of the chromosomally-mediated β-lactamases (Ritu et al., 2006; Kolar et al., 2010). The ability of β-lactamase-producing strains of S. aureus to exhibit multi-resistance to antibiotics is largely determined by the location, kinetics, quantity, Physiochemical conditions and interplay of the produced enzyme or expressed PBP2a (McCallum et al., 2010), as well as, the capacity of the enzyme to hydrolyze the ß-lactam ring of ß-lactam antibiotics and inactivates them, thereby rendering the cells resistant to ß-lactam antibiotics (Bywater, 1991).
2. Health Implications
The production of β–lactamase enzymes has been reported to be the most common cause of bacterial resistance to β–lactam antibiotics in both humans and animals. β –lactam antibiotics are widely used in humans and veterinary medicine to treat human and animal infections (Briǹas et al., 2002). This wide spread use of these antibiotics could be associated with the selection of antibiotic resistance mechanisms in both pathogenic and nonpathogenic bacteria, as well as, the production of β–lactamases.
There are now well over 200 recognized ESBLs in a variety of Gram-negative bacteria, conferring resistance to penicillins, cephalosporins, monobactams and even carbapenems (Brad and Edward, 2008). The ESBLs represents an impressive example of the ability of Gram-negative bacteria to develop new antibiotics resistance mechanisms in the face of introduction of new ones (Paterson and Bonomo, 2005). Plasmids responsible for ESBLs production frequently carry genes encoding resistance to other drug classes such as aminoglycosides, sulfanamides, chloramphenicol, rifampin, aminoquinolones or quinolones (Paterson and Bonomo, 2005; Ferran and Elisanda, 2007). The resistance plasmids can also be transferred to other bacteria, not necessarily of the same species, conferring resistance to them. Resistance plasmids or transposons have been reported to transmit multiple resistance traits among Enterobacteriaceae (Carattoli, 2001). This implies that therapeutic options in the treatment of ESBLs–producing organisms are extremely limited (Paterson and Bonomo, 2005; Cuzon et al., 2010). The use of extended–spectrum antibiotics have been said to exert a selective pressure for the emergence of ESBLs–producing bacteria. Involvement of many bacteria organisms producing ESBLs and the emergence of multiple β–lactamases–producing strains of some bacteria are of grave global health implication (Thomson, 2001; Kim et al., 2009). Organisms resistant to multiple antibiotics pose a special threat particularly among transplant patients (Mlynarczyk et al., 2009). The intestine of healthy animals is a reservoir for bacteria carrying CTX–M, mainly E. coli, and transmission to humans through the food chain have been emphasized (Carmen and Myrian, 2007). The enzymes of CTX–M and SHV–12 family are implicated mainly in urinary tract infections (Lorena and Alvaro, 2007). Epidemic clones of these enzymes and their dissemination from a specific group of enzymes have been described to be through the mobile elements called integrons (Lorena and Alvaro, 2007). This implies possible dissemination of these β–lactamases from food animals to humans can occur, since both enzymes have been reported in healthy animals destined for human consumption including chickens (Carmen and Myrian, 2007). Integrons are important, both in terms of the mechanisms of resistance and the dissemination of resistance genes within or outside the health care setting (Gupta, 2007). Integrons are also known to be associated with multiple-drug resistance in enteric organisms (Zhao et al., 2001) and have been reported to be implicated in the dissemination of ESBLs in gram-negative bacteria (Jacoby and Munoz-Price, 2005; Poirel et al. 2010). The transmission of resistance between bacteria haboured within the gut can occur both horizontally through the movement of these mobile genetic elements (integrons), and vertically through proliferation and subsequent dissemination of resistant bacterial strains (Deborah et al., 2005). These mobile elements can thus diffuse resistance genes to many other antibiotics (Ferran and Elisanda, 2007).
Resistance in bacteria isolated from food animals is in itself not a problem, but the possible transfer of resistance elements to zoonotic pathogens within the gut has serious public health implications (Deborah et al., 2005). The strain of E. coli producing CTX–M has been described as the most frequent cause of community–acquired urinary tract infections, and its increase is mostly due to the dissemination of Inck plasmids among E. coli isolates (Aránzazu et al., 2009). CTX–M β–lactamases, which show a high cefotaxime hydrolytic activity, constitute the most prevalent ESBL type found among clinical isolates of E. coli (Angela et al., 2008), and these enzymes have emerged as the most common type of ESBLs globally (James et al., 2010), and are therefore, of global health risk. TEM–52, SHV–2 and CTX–M–1 isolated from chickens and SHV–12 isolated from swine were observed to exhibit high clonal diversity, and contain transferable blaESBL genes which might be acquired by humans via the food chain (Elisabete et al., 2008). Infections caused by ESBL–producing strains of gram-negative bacteria have been on the increase, and were associated with higher morbidity and mortality in humans (Lorena and Alvaro, 2007; Cuzon et al., 2010), particularly the worldwide growing carbapenemase-producing organisms (Dortet et al., 2008). Treatments of such infections have been reported to be associated with high failure rates (Paterson and Bonomo, 2005). The possession of additional fluoroquinolones resistance by some ESBLs-producing bacteria has further undermined therapeutic options.
Clonal outbreaks of CTX–M–15–producing
Enterobacteriaceae, most frequently involving E. coli have been reported in France, Italy, Spain, Portugal, Austria, Norway, the UK, Tunisia, South Korea and Canada (Teresa et al., 2008). Plasmids encoding [bla.SubCTX–M–15] have been reported from clinical isolates of E. coli in France, Spain, Portugal, UK, Canada, India, Pakistan, south Korea, Taiwan, The United Arab emirates and Honduras (Noyais et al., 2007).
Infection caused by plasmid AmpC–producing isolates was said to significantly increase treatment failure at 72 hrs and that prior use of an oxyimino–cephalosporins is said to be a risk factor for infections caused by plasmid AmpC–producing Enterobacteriaceae (Park et al., 2009). AmpC β–lactamases are typically associated with broad–spectrum multi-drug resistance, which usually is a consequence of genes for other antibiotics resistance mechanisms residing on the same plasmids as the ESBL and AmpC genes (Thomson, 2001).
Methicillinase-producing S. aureus strains have gradually become resistant to almost all hospital disinfectants, and bacteria which survive attacks by biocides are becoming ultra-resistant super bugs (Ippolito et al., 2010). Molecular studies of animal isolates of β–lactamase–producing S. aureus has demonstrated that MRSA producing the mecA gene had similar nucleotide substitutions at same positions in their mecI genes as those described previously in humans (Lee, 2006). These alterations within the mec genes of animal MRSA strains which are homologous to that occurring in human MRSA strains, signals a transfer of such genes between humans and animals, possibly through the food chain. The risk of transfer of MRSA from animals and animal products has been described (Kwon et al., 2006), and the transfer of both resistance and genetic markers from poultry to humans has been reported (Saeed et al., 2000), as well as, the transmission of MRSA between dogs and humans (Mamian, 2003) and between humans and horses (Seguin et al., 1999). MRSA infections thus have zoonotic potential to portend serious human health dangers. Although Staphylococci isolated from animals are generally thought to be host-adapted, the MRSA similar to human epidemic cluster 257 was isolated from fistula of a dog in The Netherlands (van Duijkeren et al., 2004). The MRSA transmitted to the community by foodstuffs such as chicken meat and cow milk, still has the potential of causing human infections (Kwon et al., 2006).
A serious challenge facing clinical laboratories is that clinically relevant ESBLs–mediated resistance is not always detectable in routine susceptibility tests (Thomson, 2001); and most hospitals in rural settlements do not even use routine diagnostic tests for detecting resistant organisms, especially ß–lactamase–producers (Stevenson et al., 2003). Such laboratories may also lack the resources to prevent the spread of these resistance mechanisms. This lack of resources according to Thomson (2001) is particularly responsible for a continuous failure to address the rapid global spread or dissemination of pathogens producing these enzymes.
3. Treatment and Control
ESBL-producing bacteria have shown some susceptibility level to cephamycins and carbapenems in vitro (Jacoby and careras, 1990). Some TEM and SHV type ESBL-organisms have in vitro susceptibility to cefepime and piperacillin/tazobactam, but both drugs have exhibited diminished susceptibility alongside inoculum effect (Thomson and Moland, 2000). Bacterial strains possessing some CTX–M–type and OXA–type ESBLs were found to be resistant to cefepime on testing, despite the use of a standard inoculum (Ritu et al., 2006; Brad and Eward, 2008; Mirzae et al., 2009). AmpC–producing strains typically shown to resist oxyimino–cephalosporins and cephamycins were initially susceptible to carbapenems, but were however, shown resistant to the carbapenems due to loss of membrane porins (Briǹas et al., 2002). Strains possessing IMP–, VIM– and OXA– type carbapenemases are said to be susceptible to aztreonam whilst resistance to non–ß–lactam antibiotics is said to be common in strains producing any of these enzymes, such that alternative options for non–ß–lactam therapy needed to be determined by direct susceptibility testing (Pfaller and Segreti, 2006). Infections caused by ESBL–producing E. coli and K. pneumoniae have been treated with the best outcomes in terms of survival and bacteriologic clearance using imipenem or meropenem (Jonathan et al., 2006); whilst in vitro resistance to cefotaxime, ceftazidime and aztreonam have been shown in some strains of ESBLs (Pitout et al., 1998). But KPC–producing bacteria have been shown to inactivate carbapenems and other ß–lactam antibiotics, and have also demonstrated typical resistance to trimethoprim-sulfamethoxazole, quinolones, and aminoglycosides, thereby making these pathogens truly multi-drug resistant (Jonathan et al., 2006). Some resistance profiles are shown in table 1 below.
Similarly, the ß–lactamases produced by S. aureus have shown resistance to a wide variety of ß–lactam antibiotics and many non-ß–lactam antibiotics as well (Mansouri and khaleghi, 1997; Kwon et al., 2006; Mamza et al. 2010). However, some strains have shown in vitro sensitivity to vancomycin and teicoplanin (van Duijkeren et al., 2004; Lee, 2006), but surprisingly, however, several newly discovered strains of methicillinase-producing S. aureus have been reported to resist vancomycin and teicoplanin (Diep et al., 2006). This new evolution of ß–lactamase S. aureus have been dubbed vancomycin–intermediate resistant Staphylococcus aureus or VISA (Diep et al., 2006). Monitoring and control of extended–spectrum cephalosporins usage, and regular surveillance of antibiotics resistance patterns, as well as efforts to decrease the use of empirical therapy have been recommended to help curb (control) the spread of ß–lactamase–producing organisms. The need for extensive research into plant materials that could elicit permanent activity against these growing ß–lactamase–producing strains of bacteria is also a prerequisite.
(*) A: ampicillin, Ac: amoxiclav, Ce: cefepime, Cx: cefotaxime, Fx: cefoxitin, No: norfloxacin, St: sulfamethoxazole-trimethoprim, K: kanamycin, T:tetracycline, C: chloramphenicol, G: gentamicin, Cz: ceftazidime, Ct: ceftriazone, CT: cefotatan, At: aztreonam, P: penicillin, pi: piperacillin, Tz: piperacillin/tazobactam, I: imipenem, M: meropenem, Cp: ciprofloxacin, Ax: amoxicillin, S: streptomycin, An: andriamycin, Ox: oxacillin, Co: cloxacillin, Cd: cefamandole, Cf: cefazoline, Cn: cephalexin, Cm:c efuroxime
Bacterial organisms have adapted to both broad–spectrum and ß–lactam antibiotics by modifying substrate spectrum of common plasmid–mediated ß–lactamases, and by mobilizing resistance–promoting chromosomal ß–lactamase genes into plasmids, thereby enhancing their spread to new hosts. The persistence of β–lactamase–producing bacteria in our healthcare centres and the emergence of same in the Veterinary field is a global threat to both therapeutic and healthcare services. Although the precise cause and route of β–lactamase-producing strains into the Veterinary field could not be determined, it is clear that β–lactamases-producing bacterial strains do exist, and are being transmitted regardless of the use of ß–lactam antibiotics in this field. Also, the relative ease with which these bacteria organisms become resistant to newly developed antibiotics and the alarming global dissemination of β–lactamases highlights the need for continued epidemiological monitoring of these enzymes and prudent use of antibiotics. Investigations aimed at identifying the carriers of ß–lactamases and intercepting their transmission will play a vital role in curbing the emergence and spread of these β–lactamases and further enzymes, and their menace to global health.
We are grateful to our well wishers for encouraging us to pursue this review to its logical end. We acknowledge the typesetting work.