ENZYMATIC INACTIVATION OF PENICILLINS: AN EMERGING THREAT TO GLOBAL PUBLIC HEALTHHTML Full Text
ENZYMATIC INACTIVATION OF PENICILLINS: AN EMERGING THREAT TO GLOBAL PUBLIC HEALTH
Ukpai A Eze * 1, Ngozi M. Eze, 2 and Adam Mustapha 3
Department of Medical Laboratory Sciences 1, College of Health Sciences, Ebonyi State University, Abakaliki, Nigeria
Directorate of Nursing Services 2, Ministry of Health, Abakaliki, Ebonyi State, Nigeria
Department of Microbiology 3, University of Maiduguri, Borno State, Nigeria
ABSTRACT: Penicillin antibiotics have been the main-stay armamentarium in the fight against bacterial diseases due to their availability and ease of use. Penicillin resistance has been attributed to modification of penicillin-binding proteins, production of β-lactamases, overexpression of efflux pumps and reduced permeability. In the past 10 years, research was centred on Gram-positive bacteria, particularly Methicillin-Resistant Staphylococcus aureus (MRSA). The key determinant of resistance in MRSA strains is the penicillin-binding protein (PBP2a). Currently, the production of β-lactamases by Gram-negative bacteria has garnered a degree of attention that seems to be rising rapidly. Gram-negative bacteria pose the greatest risk to public health because of the global emergence and spread of metallo-β-lactamases, including Imipenemase (IMP-types), Verona integrin-encoded-metallo-β–lactamases (VIM-types) and New Delhi metallo-β-lactamases (NDM-types). Not only is the increase in resistance of Gram-negative bacteria to beta-lactams faster than in Gram-positive bacteria, but also there are no current and developmental antibiotics active against metallo-β-lactamase-producing Gram-negative bacteria. This review critically examines the current issues in beta-lactamases responsible for penicillins resistance in relation to the current clinically important bacteria pathogens.
Penicillins Resistance, β-lactamases, Gram-positive bacteria, Gram-negative bacteria, Public Health
INTRODUCTION: Penicillin antibiotics have been major agents in the treatment of most bacterial infections since their introduction in 1941. They mainly act by inhibiting the transpeptidases (penicillin binding proteins-PBPs) which are responsible for the cross-linkage of the peptidoglycan layer of the bacterial cell wall 1. Bacterial resistance to penicillins is mainly as a result of the production of beta-lactamases or by modification and/ or production of defective penicillin-binding proteins.
The modification or inhibition of PBPs could then lead to reduced cell wall permeability and increase in efflux pumps activity. The modification of target site is the most frequent resistance mechanism in Gram-positive cocci such as MRSA, penicillin-resistant Streptococcus pneumoniae, and penicillin-resistant Neisseria gonorrhoeae. Resistance in MRSA is as a result of the production a low affinity PBP2a (Fig. 1) whereas alteration in PBP2b is the major cause of penicillin resistance in Streptococcus pneumoniae 1.
In contrast, penicillin resistance in Gram-negative bacteria is the production of intrinsic or horizontally acquired beta-lactamases, which destroys the amide bond of the beta-lactam ring of penicillins rendering them ineffective 2. This poses serious threat to public health and a concerted global action is required to contain this emerging antibiotics resistance 29, 30, 31.
In the past 10 years, research has been focused on Gram-positive bacteria, particularly MRSA which are resistant to penicillins as a result of the presence of PBP2a 1. Currently, production of β-lactamases by Gram-negative bacteria has garnered a degree of attention that seems to be rising rapidly. However, the most significant contributory factor to penicillins resistance in bacteria is “the enzymatic inactivation." This review critically examines the current clinically relevant issues on penicillins resistance in order to evaluate the degree of risks posed by both Gram-positive and Gram-negative bacteria to global public health.
FIG.1: STRUCTURE OF SAUPBP2a*
Classification of β-lactamases:
Generally, β-lactamases are a group of enzymes that hydrolyses β-lactam antibiotics by opening of the β-lactam ring and turning the antibiotic inactive 3. There are two predominantly β-lactamases classification schemes:
- Ambler classification system: this classification is based on the sequence of amino acids and tend to group β-lactamases into class A, B, C and D enzymes.These groups are further sub-divided into metal-dependent (Zn2 +- requiring class B) and metal-independent (serine utilising classes A, C and D), and
- Bush-Jacoby-Medeiros system: this is an updated classification system and is also known as the functional classification scheme. The classification is based on the substrates and inhibitors of the beta-lactamase enzymes such as clavulanic acid, sulbactam, and Tazobactam 4. Here, numbers are assigned to the groupings.
Table 1 compares the structural classifications schemes (Ambler classification system) with the functional classification scheme (Bush et. al classification). It can be seen that there are still some important issues particularly with the functional classification scheme despite the updates; the hydrolysis of a particular β-lactam class and inactivation properties of the inhibitors are still retained. Also, it is obvious that the functional classification scheme overlaps with structural classification despite its diverse new sub-groups. For instance, the functional classification group 2 contains molecular classes A and D which represent large groups of β-lactamases.
However, structural β-lactamase classification scheme provides a much comprehensive and encompassing format for classifying new and emerging enzymes. This is because enzymes continue to evolve but through use of new molecular techniques such as Polymerase Chain Reaction (PCR) and other methods of genetic analysis, they can be discovered and subsequently classified. Of particular concern here are the classes of enzymes that readily confer resistance to penicillins and other structurally related antibiotics in the Ambler classification and pathogens of clinical relevance.
TABLE 1: CLASSIFICATION SCHEMES FOR BACTERIAL β-LACTAMASES, ADAPTED FROM BUSH AND JACOBY 4.
Resistance mechanisms to penicillins in selected bacteria:
(i). Haemophilus influenza: Haemophilus influenzae is one of the major bacteria causing opportunistic infections in children, including tonsillitis, sinusitis, pneumonia, epiglottitis, meningitis and sepsis. The introduction of Hib conjugate vaccine in developed countries has reduced the morbidity and mortality linked to H. influenzae. In developing countries where the Hib vaccine is not readily available, H. influenzae is still a frequent cause of morbidity and mortality, especially in children less than 5 years of age 2. In addition, the wide spread use of pneumococcal conjugate vaccine in children has led to a sudden increase in pneumonia caused by non-typeable H. influenzae.
Therefore, penicillin antibiotic medication became the last resort for the treatment of these infections. This sudden increase in resistance is thought to be caused by the production of β-lactamases, a major resistance mechanism in H. influenzae. The β-lactamase producing rate varies worldwide. The β-lactamase-producing strains of H. influenzae have been shown to be 42% in USA, 35.8% in Kenya, 52.4% in Korea, 55% in Taiwan, 48.5% in Thailand and 35.8% in China 2. H. influenzae resistance to ampicillin has been linked to the β-lactamase-producing genes, blaTEM-1 and blaROB-1 2. Thus, the resistance of this opportunistic bacterium to penicillins is enhanced leading to increase in morbidity and mortality associated with its infection.
(ii) Escherichia coli:
- coli is a Gram-negative rod and has been associated with bacteraemia, urinary tract infections, peritonitis, neonatal meningitis, skin and soft tissue infections and food-borne infections. There was an increase in resistance of E. coli to aminopenicillins in Europe in 2011 5. Its resistance to penicillins is usually mediated by plasmid coded β-lactamases, mainly of the TEM type and to a lesser extent, the SHV type 6. It is also resistant to carbapenems through the mediation of metallo- β-lactamases or serine-carbapenemases and this could lead to resistance to most or all available beta-lactam antibiotics. Extended spectrum beta-lactamases (ESBLs) have also been identified in E. coli 6. The production of Verona integrin-encoded-4 (VIM-4) metallo- β –lactamase and CTX-M-15 extended-spectrum β –lactamase was identified in an E. coli isolate from a urine sample in Russia and their presence were found to be mediated by plasmids 7. About 90% of ESBL-producing E. coli isolates from urine of 28 patients from Innsbruck, Austria and 34 patients from Bolzano, Italy contained CTX-M group 1 enzymes 6. Similarly, isolates of the Enterobacteriaceae group producing TEM, SHV, OXA, CTX-M have been reported in Nigeria 32, 33. Kluytmans et al. 8 also reported the isolation of ESBL-producing E. coli from retail meat in Netherlands. The presence of extended-spectrum β–lactamases from broiler chickens and turkey have been reported in United Kingdom 9 and in Czech Republic, respectively 10.
These are potential risks factors for the transmission of resistant ESBL-producing bacteria and antibiotic-resistance genes to humans through the food chain. It could also serve as a source for the outbreak of multidrug resistant pathogens in the human population since most of the resistance genes are plasmid encoded. Besides these, CTM-M and SHV extended-spectrum β–lactamases have been identified in E. coli isolates from dogs and cats 11 and CMY-2 and CTX-M-15 extended-spectrum β –lactamases have been found in E. coli from wild birds (seagull and pelican faeces) in USA12. Extended-spectrum-β-lactamase-producing and plasmid-mediated AmpC β –lactamase-producing E. coli from dogs have also been reported in South Korea 13 whereas multi-drug resistant E. coli producing extended-spectrum β-lactamases have been isolated from the faeces of wild animals in central Europe 14. ces of wild animals in central Europe 14. The colonisation of companion animals, wild animals and birds by resistant E. coli can become important reservoirs and vectors for human infection and the possibility of transferring resistance by conjugation to human strains is unavoidable.
More recently, the discovery of New Delhi Metallo- β-lactmase-1 (NDM-I) in E. coli and Klebsiella pneumoniae worldwide (Fig. 2), especially in United Kingdom, India, Pakistan 15, 34, Australia 16 , Canada 21, and South Africa 28, 35 is a major concern. The NDM-1 is mediated by plasmids carrying blaNDM-1 gene and these plasmids harbours “numerous resistance genes associated with other carbapenemase genes (Oxacillinase-48), plasmid-mediated cephalosporinase genes, ESBLs genes, aminoglycoside resistance genes (16S RNA methylase), macrolide resistance (esterase), rifampin (rifampin-modifying enzymes) and sulfamethoxazole resistance as a source of multidrug resistance and pan-drug resistance” 17.
FIG.2: GEOGRAPHIC DISTRIBUTION OF NEW DELHI METALLO-Β-LACTAMASE-1 PRODUCERS, JULY 15, 2011. STAR SIZE INDICATES NUMBER OF CASES REPORTED. RED STARS INDICATE INFECTIONS TRACED BACK TO INDIA, PAKISTAN, OR BANGLADESH, GREEN STARS INDICATE INFECTIONS TRACED BACK TO THE BALKAN STATES OR THE MIDDLE EAST, AND BLACK STARS INDICATE CONTAMINATIONS OF UNKNOWN ORIGIN SOURCE: Nordmann et al. 17.
(iii) Klebsiella pneumonia:
The metallo-β-lactamases and extended-spectrum β-lactamases are also present in K. pneumoniae. These isolates are common in neonatal intensive care units and are major causes of hospital-acquired infections in this group 18. Nosocomial outbreaks in a neonatal intensive care unit attributed to extended-spectrum-β-lactamase-producing K. pneumoniae have been reported 19. In cultures of clinical samples from Neonatal care unit, the hands of healthcare workers and the environment, Lin et al. 18 reported that 2.6% of the neonates had infections while 4.5% had colonisation with extended-spectrum-β-lactamase-producing K. pneumoniae. In addition, 44.9% of the environmental samples yielded extended-spectrum-β-lactamase-producing K. pneumoniae. The relatively immature immune system of these neonates and the absence of passive antibodies through the placenta and breast feeding tend to increase the risk of neonatal colonisation by multi-drug resistant K. pneumoniae.
DISCUSSION: Even though there was an increased attention on resistant Gram-positive organisms such as MRSA, Penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus species in the past 10 years, 15 there is now a continuous decline of MRSA resistance, especially in UK 5. This decrease in infections by resistant Gram-positive organisms in the UK is attributed to the implementation of different programmes, including hand washing by hospital staff as well as enhanced surveillance of MRSA in hospitals. The mecA gene acquired by MRSA is responsible for the expression of PBP2a which has low affinity to beta-lactam antibiotics and penicillins. Penicillins PBP1a, PBP2x and PBP2b are also known to be responsible for penicillin resistance in Streptococcus pneumoniae 1.
The antibiotic, ceftaroline has recently been approved in the US for the treatment of acute bacterial skin and skin-structure infections, including community-acquired bacterial infections whilst in Europe, it's been approved for the treatment of complicated and soft tissue infections, and community-acquired pneumonia 1. Ceftaroline has high efficacy in the treatment of infections caused by MRSA and penicillin-resistant Streptococcus pneumoniae as result of its strong affinity for PBP2a, mostly found in MRSA and PBP1a, PBP1b, PBP1x, PBP2a/b and PBP3 proteins responsible for antibiotics resistance in MRSA and penicillin-resistant Streptococcus pneumoniae 1. For antibiotics resistance in MRSA and penicillin-resistant Streptococcus pneumoniae 1. Consequently, the global threat initially posed by MRSA and penicillin-resistant Streptococcus pneumoniae is becoming a thing of the past due to development of this antibiotic.
The spread of multidrug-resistant Gram negative bacteria, especially the Enterobacteriaceae are a major threat to public health 15. This is because of the global spread of resistance genes among Gram-negative bacteria through horizontal gene transfer mainly mediated by plasmids, transposons and integrons 16. The emergence of metallo-β-lactamase-producing Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli, and their isolation from life-threatening infections, has increased globally.
Metallo-β-lactamases are mainly of two types; Imipenemase (IMP) and Verona integrin-encoded metallo-β-lactamases (VIM). The enzymes of the IMP-type metallo-β-lactamase were first described in a strain of Serratia marcescens from Japan and they were able to hydrolyse all β-lactams, except monobactams 17. The IMP-type metallo-β-lactamases have been identified in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae and reported worldwide 5. The VIM-type was described in an isolate of Pseudomonas aeruginosa in Italy, also hydrolyses all β-lactams, except monobactams 20. Several VIM-type enzymes; VIM-1, VIM-2, VIM-3, VIM-4, VIM-5, VIM-6 and VIM-7 have been discovered in P. aeruginosa, K. pneumoniae, and E. coli isolates worldwide (Fig.3), with high incidence in Europe and Far East 7, 20.
In a recent study in Thailand, Piyakul et al. 20 reported the prevalence of 17.3% of P. aeruginosa-producing metallo-β-lactamases with both IMP-14 and VIM-2 enzymes. They further reported that all the IMP-14 strains were identical or closely related suggesting clonal dissemination.
The major challenge in the antibiotics armamentarium is the emergence of New Delhi Metallo-β-lactamases (NDM) in Enterobacteriaceae. NDM-1 was first detected in a strain of Klebsiella pneumoniae isolated in 2008 in a patient returning to Sweden from India, where NDM-1 is widespread in Enterobacteriaceae 7. Kumarasamy et al. 15 identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan even though NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111).
The 37 isolates with NDM-1 in UK were identified as K. pneumoniae (21), E. coli (7), Enterobacter spp. (5), Citrobacter freundii (2), Morganella morganii (1) and Providencia spp. (1). These isolates were from urine, blood, burn or wound swab, sputum, central line tip and throat swab. It is disturbing as most of the Indian isolates from Chennai and Haryana were from community-acquired infections, suggesting that blaNDM-1 is widespread in the environment. This is corroborated by the isolation of NDM-1 β-lactamase-producing bacteria from 2 of 50 (4%) water and 51 of 171 (30%) sewage seepage samples in India indicating that the environment can be a potential source for dissemination 36.
Since India act as a medical tourism centre for Europeans, Americans and Africans, blaNDM-1 will likely spread worldwide. This is true because Multidrug-resistant Klebsiella pneumoniae and Escherichia coli isolates harboring New Delhi metallo-β-lactamase (NDM-1) have been isolated from a patient who had returned to Canada from India 21. In the same vein, Poirel et al. 26 reported seven carbapenem-resistant NDM-1-positive Klebsiella pneumoniae isolates recovered from patients hospitalised between 2007 and 2009 in different wards at a referral and tertiary care center in Nairobi, Kenya. In Australia, an E. coli isolate from the urine produced NDM-1 metallo-β-lactamase 16. In addition, this E. coli isolate expressed the extended-spectrum-β-lactamase CTX-M-15, together with two 16S rRNA methylases, namely, ArmA and RmtB, conferring a high level of resistance to aminoglycosides. Similarly, K. pneumoniae-producing NDM-1 which was also carrying genes for CTX-M 15, TEM-1 and SHV-11 has been reported in Malaysia 27 while K. pneumoniae-producing NDM-1 was detected in South Africa 28.
The dissemination of this novel carbapenemase gene is considered a serious threat since the reservoir of NDM-1 producers is at least in part related to the Indian subcontinent, which is inhabited by the second-largest population in the world and where NDM-1 producers are reported also in community-acquired infections. These NDM-1 variants have been shown to possess high hydrolytic activity to carbapenems and various cephalosporins 25. Currently, seven variants of NDM (NDM-1 to -7) have been detected in various countries 37.
FIG. 3: WORLDWIDE (A) AND EUROPEAN (B) GEOGRAPHIC DISTRIBUTION OF VERONA INTEGRON–ENCODED METALLO-Β-LACTAMASE (VIM) AND IMP ENTEROBACTERIAL PRODUCERS SOURCE: Nordmann et al. 17
Despite the widespread discovery of NDM-1, NDM-2-producing A. baumannii isolates have been reported from Egypt and Israel 22, 23. NDM-2 differs from NDM-1 by a single amino acid substitution
(Pro28Ala) located in the leader peptide of the enzyme 23. In contrast to the spread of NDM-1 which is associated with travel to the Indian subcontinent, the five (5) A. baumannii isolates producing NDM-2 enzymes reported in Israel were not associated with international travel. Consequently, there is a possibility for the NDM-2 to spread globally since Israel is a country where many Christians from different parts of the world sojourn for pilgrimage. In addition, NDM-4 and NDM-5 have been reported from Escherichia coli isolates from United Kingdom, India and Japan 24, 25, 30. Another variant, NDM-6 with a point mutation at position 698 (C to T) was identified in an E. coli isolate in New Zealand 38 whereas NDM-7 have been reported in Germany and this differ from NDM-1 as a result of mutations at positions 388 (G to A) and 460 (A to C) corresponding to amino acid substitutions Asp130Asn and Met154Leu, respectively 39.
The continuous spread of metallo-β-lactamases across Enterobacteriaceae and Pseudomonas aeruginosa is worrisome because there is no current drug for the management of infections caused by these super bugs, although colistin, fosfomycin and tigecycline has shown promising activity 40, 41, 42.
CONCLUSION: Bacteria from clinical and non-clinical environments are becoming increasingly resistant to conventional antibiotics, including penicillins. Resistance to penicillins is usually due to modification of target site, inactivation of the beta-lactam ring, and/or presence of efflux pumps. In the past 10 years, concern was centred on Gram-positive bacteria, particularly meticillin-resistant Staphylococcus aureus, Streptococcus pneumoniae and vancomycin-resistant Enterococcus spp which are resistant as a result of modified target. Now, however, clinical microbiologists increasingly agree that multidrug resistant Gram-negative bacteria pose the greatest risk to public health as a result of the emergence of metallo-β-lactamases, including IMP-types, VIM-types and NDM-types. Not only is the increase in resistance of Gram-negative bacteria faster than in Gram-positive bacteria, but also there are no current and developmental antibiotics active against metallo-β-lactamase-producing Gram-negative bacteria.
ACKNOWLEDGEMENTS: The authors sincerely give thanks to the entire academic staff members of Department of Medical Laboratory Sciences, College of Health Sciences, Ebonyi State University, Abakaliki for help and useful comments on the manuscript. We also thank Dr. Prosper Kanyong (Ulster University, Northern Ireland, UK) for finding time to proof-read the manuscript and also making useful comments.
- Kosowska-Shick K, McGhee PL and Appelbaum P C: Affinity of ceftaroline and other β-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrobial Agents and Chemotherapy 2010; 54(5): 1670-1677.
- Luo C, Xia Y, Liu Q, Chu L, Fu X, Jing C, Chen D, Liu L and Shi Y: Antibiotic resistance and molecular epidemiology of beta-lactamase-producing Haemophilus influenzae isolated in Chonquing, China. APMIS 2012; 120: 926-934.
- Zhang H-M and Hao Q: Crystal structure of NDM-1 reveals a common β-lactam hydrolysis mechanism. The FASED Journal 2011; 25:.2574-2582.
- Bush K and Jacoby GA: Updated functional classification of β-lactamases. Antimicrobial Agents and chemotherapy 2010; 54(3): 969-976.
- European Antimicrobial Surveillance network, EARS-NET: Antimicrobial Resistance Surveillance in Europe. Annual report of the European Antimicrobial Resistance Surveillance Network, 2011. Available at www.ecdc.europa.eu (Accessed March 12, 2014).
- Huemer HP, Eigentler A, Aschbacher R and Larcher C: Dominance of CTX-M group 1 beta-lactamase enzymes in ESBL-producing Escherichia coli from outpatient urines in neighbouring regions in Austria and Italy. The Central European Journal of Medicine 2011; 123: 41-44.
- Schevchenko OV, Mudrak DY, Skleenova EY, Kozyreva VK, Ilina E N, Ikryannikova LN, Alexandrova IA, Sidorenko SV and Edelstein MV: First detection of VIM-4 metallo- β-lactamase-producing Escherichia coli in Russia. Clinical Microbiology and Infection 2012; 18: E214-E217.
- Kluytmans JAW, Overdevest ITMA, Willemsen I, Bergh MFQK, Zwaluw KV, Heck M, Rijnsburger M, Vandenbroucke-Grauls CMJE, Savelkoul PHM, Johnston BD, Gordon D and Johnson JR: Extended-spectrum β-lactamase-producing Escherichia coli from retail chicken meat and humans: comparison of strains, plamids, resistance genes, and virulence factors. Clinical Infectious Diseases 2013; 56 (4): 478-487.
- Rindall LP, Clouting C, Horton RA, Coldham LG, Wu G, Clifton-Hadley FA, Davies RH and Teale CJ: Prevalence of Escherichia coli carrying extended-spectrum- β –lactamases (CTX-M and TEM-52) from broiler chickens and turkeys in Great Britain between 2006 and 2009. Journal of Antimicrobial Chemotherapy 2011; 66: 86-95.
- Dolejska M, Matulova M, Kohoutova L, Literak I, Bardon J and Cizek A: Extended-spectrum beta-lactamase-producing Escherichia coli in turkey meat production farms in Czech Republic: National survey reveals widespread isolates with blaSHV-12 genes on InFII plasmids. Letters in Applied Microbiology 2011; 53: 271-277.
- O’Keefe A, Hutton AT, Schifferli DM and Rankin SC: First detection of CTX-M and SHV Extended-spectrum β-lactamases in Escherichia coli in the urinary tract isolates from dogs and cats in the United States. Antimicrobial Agents and Chemotherapy 2010; 54(8): 3489-3492.
- Poirel L, Potron A, Cuesta CDL, Cleary T, Nordmann P and Munoz-Price LS: Wild coastline birds as reservoirs of broad-spectrum- β-lactamase-producing enterobacteriaceae in Miami Beach, Florida. Antimicrobial Agents and Chemotherapy 2012; 56 (5), pp. 2756-2758.
- Tamang MD, Nam HM, Jang GC, Kim SR, Chae MH, Jung SC, Byun JW, Park YH and Lim SK: Molecular characterization of extended-spectrum- β-lactamase-producing and plasmid-mediated AmpC β-lactamase-producing Escherichia coli isolated from stray dogs in South Korea. Antimicrobial Agents and Chemotherapy 2012; 56(5): 2705-2712.
- Dolejsk LM, Radimersky T, Klimes J, Friedman M, Aarestrup FM, Hasman H and Cizek A: Antimicrobial-resistant faecal Escherichia coli in wild mammals in central Europe: multi-resistant Escherichia coli producing extended-spectrum beta-lactamases in wild boars. Journal of Applied Microbiology 2010; 108: 1702-1711.
- Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, Chaudhary U, Doumith M, Giske CG, Irfan S, Krishnan P, Kumar AV, Maharjan S, Mushtaq S, Noorie T, Paterson DL, Pearson A, Perry C, Pike R, Rao B, Ray U, Sarma JB, Sharma M, Sheridan E, Thirunarayan MA, Turton J, Upadhyay S, Warner M, Welfare W, Livermore DM and Woodford N: Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infectious Disease 2010; 10: 597– 602.
- Poirel L, Lagrutta E, Taylor P, Pham J and Nordmann P: Emergence of metallo- β-lactamase NDM-1-producing multidrug-resistant Escherichia coli in Australia. Antimicrobial Agents and Chemotherapy 2010; 54(11): 4914-4916.
- Nordmann P, Naas T and Poirel L: Global spread of carbapenamase-producing Enterobacteriaceae. Emerging Infectious Diseases 2011; 17 (10): 1791-1798.
- Lin R, Wu B, Xu XF, Liu XC, Ye H and Ye GY: Extended-spectrum extended-spectrum-β-lactamase-producing pneumonia infection in a neonatal intensive care unit. World Journal of Paediatrics 2012; 8(3): 268-271.
- Rastogi V, Nirwan PS, Jain S and Kapil A: Nosocomial outbreak of septicaemia in neonatal intensive care unit due to extended-spectrum-β-lactamase-producing pneumonia showing multiple mechanisms of drug resistance. Indian Journal of Medical Microbiology 2010; 28: 380-384.
- Piyakul C, Tiyawisutsri R and Boonbumrung K: Emergence of metallo-β-lactamase IMP-14 and VIM-2 in Pseudomonas aeruginosa clinical isolates from a tertiary-level hospital in Thailand. Epidemiology and Infection 2012; 140: 539-541.
- Mulvey MR, Grant JM, Plewes K, Roscoe D and Boyd DA: New Delhi metallo-β-lactamase in Klebsiella pneumoniae and Escherichia coli, Canada. Emerging Infectious Diseases 2011; 17(1): 103-106.
- Kaase M, Nordmann P, Wichelhaus TA, Gatermann SG, Bonnin RA and Poirel L: NDM-2 carbapenemase in Acinetobacter baumannii from Egypt. Journal of Antimicrobial Chemotherapy 2011; 66: 1269-1262.
- Espinal P, Fugazza G, Lopez Y, Kasma M, Lerman Y, Malhotra-Kumar S, Goossens H, Carmeli Y and Vila J: Dissemination of an NDM-2 producing Acinetobacter baumannii clone in an Israeli rehabilitation centre. Antimicrobial Agents and Chemotherapy 2011; 55(11): 5396-5398.
- Horney M, Phee L and Wareham DW: A novel variant NDM-5 of the New Delhi Metallo-β-lactamases in a multidrug resistant Escherichia coli ST648 isolate recovered from a patient in the United Kingdom. Antimicrobial Agents and Chemotherapy 2011; 55(5): 5952-5954.
- Nordman P, Boulanger AE and Poirel L: NDM-4 Metallo-β-lactamase with increased carbapenemase activity from Escherichia coli. Antimicrobial Agents and Chemotherapy 2012; 56(4): 2184-2186.
- Poirel L, Revathi G, Bernabeu S and Nordmann P: Detection of NDM-1-Producing Klebsiella pneumoniae in Kenya. Antimicrobial Agents and Chemotherapy 2011; 55(2): 934-936.
- Ahmad N, Hashim R, Shukor S, Nizam K, Khalid M, Shamsudin F and Hussin H: Characterization of the first isolate of Klebsiella pneumoniae carrying New Delhi metallo-b-lactamase and other extended spectrum b-lactamase genes from Malaysia. Journal of Medical Microbiology 2013; 62: 804-806.
- Lowman W, Sriruttan C, Nana T, Bosman N, Duse A, Venturas J, Clay C and Coetzee J: NDM-1 has arrived: first report of a carbapenem resistance mechanism in South Africa. South African Medical Journal 2011; 101(12): 873-875.
- Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H, Greko C, So AD, Bigdeli M, Tomson G, Woodhouse W, Ombaka E, Peralta AQ, Qamar FN, Mir F, Kariuki S, Bhutta ZA, Coates A, Bergstrom R, Wright GD, Brown ED and Cars O: Antibiotic resistance—the need for global solutions. Lancet Infectious Diseases 2013; 13: 1057–1098.
- Nakano R, Nakano A, Hikosaka K, Kawakami S, Matsunaga N, Asahara M, Ishigaki S, Furukawa T, Suzuki M, Shibayama K and Ono Y: First Report of Metallo-_-Lactamase NDM-5-Producing Escherichia coli in Japan. Antimicrobial Agents and Chemotherapy 2014; 58(12): 7611–7612.
- Biedenbach D, Bouchillon S, Hackel M, Hoban D, Kazmierczak K, Hawser S and Badal R: Dissemination of NDM Metallo-_-Lactamase Genes among Clinical Isolates of Enterobacteriaceae Collected during the SMART Global Surveillance Study from 2008 to 2012. Antimicrobial Agents and Chemotherapy 2015; 59(2): 826-830.
- Ogbolu DO, Daini OA, Ogunledun A, Alli AO and Webber MA: High levels of multidrug resistance in clinical isolates of Gram-negative pathogens from Nigeria. International Journal of Antimicrobial Agents 2011; 37: 62–66.
- Iroha IR, Esimone CO, Neumann S, Marlinghaus L, Korte M, Szabados F, Gatermann S and Kaase M: First description of Escherichia coli producing CTX-M-15- extended spectrum beta lactamase (ESBL) in out-patients from south eastern Nigeria. Annals of Clinical Microbiology and Antimicrobials 2012; 11:19.
- Sartor AL, Raza MW, Abbasi SA, Day KM, Perry JD, Paterson DL and Sidjabat HE: Molecular Epidemiology of NDM-1-Producing Enterobacteriaceae and Acinetobacter baumannii Isolates from Pakistan. Antimicrobial Agents and Chemotherapy 2014; 58(9): 5589-5593.
- Rubin JE, Peirano G, Peer AK, Govind CN and Pitout JDD: NDM-1–producing Enterobacteriaceae from South Africa: moving towards endemicity? Diagnostic Microbiology and Infectious Disease 2014; 79: 378-380.
- Walsh TR, Weeks J, Livermore DM and Toleman MA: Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. Lancet Infectious Diseases 2011; 11: 355–362.
- Rahman M, Shukla SK, Prasad KN, Ovejeroc CM, Pati BK, Tripathi A, Singh A, Srivastava AK and Gonzalez-Zorn B: Prevalence and molecular characterisation of New Delhi metallo-lactamases NDM-1, NDM-5, NDM-6 and NDM-7 inmultidrug-resistant Enterobacteriaceae from India. International Journal of Antimicrobial Agents 2014; 44: 30-37.
- Williamson DA, Sidjabat HE, Freeman JT, Roberts SA, Silvey A, Woodhouse R, Mowat E, Dyet K, Paterson DL, Blackmore T, Burnse A and Heffernan H: Identification and molecular characterisation of New Delhi metallo-_-lactamase-1 (NDM-1)- and NDM-6-producing Enterobacteriaceae from New Zealand hospitals. International Journal of Antimicrobial Agents 2012; 39: 529-533.
- Gottig S, Hamprecht AG, Christ S, Kempf VAJ and Wichelhaus TA: Detection of NDM-7 in Germany, a new variant of the New Delhi metallo-b-lactamase with increased carbapenemase activity. Journal of Antimicrobial Chemotherapy 2013; 68: 1737–1740.
- Rogers BA, Sidjabat HE, Silvey A, and Anderson TL, Perera S, Li LJ and Paterson DL: Treatment Options for New Delhi Metallo-Beta-Lactamase-Harboring Enterobacteriaceae. Microbial Drug Resistance 2013; 19(2): 100-103.
- Falagas ME, Karageorgopoulos DE and Nordmann P: Therapeutic options for infections with nterobacteriaceae producing carbapenem-hydrolyzing enzymes. Future Microbiology 2011; 6(6): 653–666.
- Dortet L, Poirel L and Nordmann P: Worldwide dissemination of the NDM-type carbapenemases in Gram-negative bacteria. BioMed research international 2014; Article ID 249856. doi:10.1155/2014/249856 (Accessed on February 17, 2015).
How to cite this article:
Eze, UA, Eze NM and Mustapha A: Enzymatic Inactivation of Penicillins: An Emerging Threat to Global Public Health. Int J Pharm Sci Res 2015; 6(8): 3151-60.doi: 10.13040/IJPSR.0975-8232.6(8).3151-60.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Ukpai A Eze *, Ngozi M Eze and Adam Mustapha
Department of Medical Laboratory Sciences, College of Health Sciences, Ebonyi State University, Abakaliki, Nigeria
14 December, 2014
21 February, 2015
18 April, 2015
01 August, 2015