|Year : 2018 | Volume
| Issue : 2 | Page : 176-182
Resistance Pattern and Detection of Metallo-beta-lactamase Genes in Clinical Isolates of Pseudomonas aeruginosa in a Central Nigeria Tertiary Hospital
KO Zubair, KC Iregbu
Department of Medical Microbiology, National Hospital Abuja, Abuja, Nigeria
|Date of Acceptance||26-Oct-2017|
|Date of Web Publication||21-Feb-2018|
Dr. K O Zubair
Department of Medical Microbiology, National Hospital Abuja, Abuja
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Acquired metallo-β-lactamases (MBLs) pose serious problem both in terms of treatment and infection control in the hospitals and report across the world showed an increase in their prevalence. However, there is a paucity of data from Africa, and their report is rare in Nigeria. Aim: This study aimed to determine the prevalence of acquired MBL-resistant genes in carbapenem-resistant Pseudomonas aeruginosa in Abuja, North Central Nigeria. Materials and Methods: Two hundred nonduplicate, consecutive isolates of P. aeruginosa from clinical samples submitted to the Medical Microbiology Laboratory of National Hospital, Abuja were screened for carbapenem resistance using imipenem and meropenem. Phenotypic detection of MBL-producing strains was determined using Total MBL confirm kits and E-test strips on isolates that were resistant to both Imipenem and meropenem. The MBL genes were detected using multiplex polymerase chain reaction, while the gene variant was determined by sequencing. Results: Twenty-two MBL-producing strains were detected phenotypically, but only 5 harbored the blaVIM-1 gene, giving a prevalence of 2.5%. These 5 strains were resistant to all the antipseudomonal antibiotics tested except Aztreonam and Colistin. Other common MBL-genes were not detected. Conclusion: The prevalence of MBL-producing strains of P. aeruginosa which poses serious challenge for therapeutics and infection control is currently low in Abuja, North Central, Nigeria. Therefore, rational use of the carbapenems and other antipseudomonal antibiotics, regular surveillance and adequate infection control measures should be instituted to limit further spread.
Keywords: Abuja, carbapenem-resistance, metallo-β-lactamases, Pseudomonas aeruginosa
|How to cite this article:|
Zubair K O, Iregbu K C. Resistance Pattern and Detection of Metallo-beta-lactamase Genes in Clinical Isolates of Pseudomonas aeruginosa in a Central Nigeria Tertiary Hospital. Niger J Clin Pract 2018;21:176-82
|How to cite this URL:|
Zubair K O, Iregbu K C. Resistance Pattern and Detection of Metallo-beta-lactamase Genes in Clinical Isolates of Pseudomonas aeruginosa in a Central Nigeria Tertiary Hospital. Niger J Clin Pract [serial online] 2018 [cited 2022 Jul 3];21:176-82. Available from: https://www.njcponline.com/text.asp?2018/21/2/176/225937
| Introduction|| |
Pseudomonas aeruginosa, an organism widespread in nature, is an important cause of healthcare-associated infection, especially in patients with compromised host defense.,,, Its infections are associated with relatively high treatment failures and mortality due to its intrinsic and acquired resistance to commonly available antibiotics, particularly in patients hospitalized with burns, malignancies, and those with cystic fibrosis, as well as in those with fulminant infections such as sepsis and pneumonia, most of which are fatal with high mortality rate, often >50%.,
With increasing inappropriate use of antimicrobials both in human and veterinary medicine, microorganisms are rapidly evolving from susceptible into resistant strains to various antibiotics with consequent therapeutic failures ,, At present, a number of pathogenic bacteria are being described as multidrug-resistant (MDR), extensively-drug-resistant, or pan-drug-resistant pathogens because they have developed or acquired resistance to a number of clinically useful antibiotics.,,P. aeruginosa has been identified in all the three categories.
The carbapenems used to be the empirical agent of last resort when dealing with MDR Gram-negative bacteria, but there are increasing reports of resistance to them, especially in P. aeruginosa. In Nigeria, different researchers in Zaria, Lagos, and Kano have reported P. aeruginosa carbapenem resistance of between 20% and 60% using phenotypic methods of Detection.,, This organism employs different mechanisms such as reduced outer membrane permeability, target site modification, efflux pumps over-expression, expression of chromosomal AmpC β-lactamases, and the acquisition of β-lactamases to become resistant to this group of antibiotics., Of all these, the most worrisome is the emergence of strains of P. aeruginosa with acquired metallo-β-lactamases (MBLs) which present the most clinically challenging situation both in terms of treatment and infection control.
MBLs are carbapenemases with capability of hydrolyzing the penicillins, cephalosporins, cephamycins, and the carbapenems but not monobactams. In addition, pathogens that harbor MBL genes tend to carry co-resistance genes for other classes of antibiotics. MBL genes are usually borne on mobile genetic elements such as integrons, transposons, plasmids, or associated with insertion sequences which confer it with the propensity to spread not just within a species but also between different species. MBLs have been reported in more than 28 species of Gram-negative bacteria from more than forty countries. The mortality attributable to infections caused by MBL-producing P. aeruginosa is estimated to range from 70% to 90%.,
Since resistance is driven by antibiotics use,, there is increasing report of these strains, and the possibility of rising prevalence exist with escalating use of the carbapenems as they become more available for clinical use, even as better methods of detection of MBL producing strain are becoming available in clinical microbiology laboratories. A number of studies in Nigeria have reported antibiotics resistance in P. aeruginosa, but, there is a paucity of data on MBL-induced resistance.,,,,,,, In Abuja, the federal capital territory of Nigeria, neither the prevalence rate of MBL-producing strains of P. aeruginosa nor the MBL gene type harbored by any of such strains has been reported.
This study was carried out to determine the prevalence of MBL-producing strains of P. aeruginosa in a tertiary health-care setting in Abuja as well as characterize the common resistance gene-types harbored by the strains as a way of generating local data for planning and advocacy with respect to empiric therapy, antibiotic stewardship, and infection control.
| Materials and Methods|| |
This was a cross-sectional study carried out over a 34-month period ranging from February 2013 to November 2015 at the National Hospital Abuja (NHA), a 400-bed tertiary health-care institution located in Abuja, North Central Region of Nigeria. Two hundred consecutive, nonduplicate, isolates of P. aeruginosa from all samples except stool submitted to the Medical Microbiology Laboratory of NHA were identified using standard techniques, and further subjected to a temperature of 42 °C to eliminate the other members of the fluorescence group of Pseudomonads. Antibiotics Susceptibility Testing was performed using Modified Kirby–Bauer disc diffusion method, in accordance with the CLSI standards. Antibiotics tested were piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem, gentamicin, amikacin, ciprofloxacin, and colistin. P. aeruginosa that showed resistance to imipenem and or meropenem were subjected to phenotypic MBL confirmation using Total MBL Confirm Kit from ROSCO Diagnostica (ROSCO Diagnostica A/S, Taastrupgaardsvej, Denmark) in accordance with the manufacturer's instructions. The sensitivity and specificity of total MBL confirm kit from ROSCO Diagnositica is 97.7% and 100%, respectively. Further confirmation of MBLs was done with E-test strip from Liofilchem (Liofilchem, Roseto degli Abruzzi, Italy). A positive MBL test is indicated by the ratio of the MIC of IMP: IMD or MRP: MRD ≥8 (IMP/IMD ≥8 or MRP/MRD ≥8) or the presence of a phantom zone. P. aeruginosa ATCC 27853 was used as control strain for these procedures. Phenotypically confirmed MBL producers were stored at 20°C in 50% glycerol stock until they were further analyzed at the DNA Labs, Kaduna, for molecular confirmation. Using the following primers: blaIMP- types, blaVIM- types, blaGIM-1, blaSPM-1, blaSIM-1 and blaNDM-1, multiplex polymerase chain reaction (PCR) was used to detect the specific type of MBL gene harbored by the MBL-producing strains of P. aeruginosa. In addition, one pair of class 1 integron primer was included to detect the presence of class 1 integron. DNA sequencing using Bechmann coulter CEQ-8000 (Beckman Coulter, Kraemer Boulevard, Brea, CA, USA) was carried out on sample No. 22. The resulting nucleotide sequence was analyzed using the BLAST program on NCBI website (http://blast.ncbi.nlm.nih.gov/Blast.cgi) which shows the nucleotide sequence as 99% identical to blaVIM-1 gene with E-value of 6 × 10−180 and accession numbers KF975369 in the GenBank. This resulting nucleotide sequence was used as the positive control for the multiplex PCR while all the PCR reaction mixture without a primer was used as negative control as shown in [Figure 1] in the result section.
|Figure 1: Agarose gel electrophoresis result for multiplex polymerase chain reaction product for the detection of metallo-β-lactamase genes. Lane 1 = Strain no: 10, 5 = 54, 13 = 112, 20 = 152, 22 = 185. PC: Positive Control, NC: Negative Control. NB: The bands in lane 1, 5, 13, 20, and 22 are the specific (positive) bands while the second band in lane 5 is a nonspecific band which should be ignored|
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Ethical approval was given by the Ethical Committee of NHA while informed consent was obtained from patient using standard consent form.
| Results|| |
Distribution of clinical samples/isolates
The 200 isolates of P. aeruginosa from various clinical samples were distributed as follows: wound swab/biopsy 103 (51.5%); ear swab 32 (16%); urine 27 (13.5%); and blood culture 20 (10%) [Table 1].
|Table 1: Distribution of isolates of P. aeruginosa in various clinical samples|
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Antibiotics susceptibility profile of Pseudomonas aeruginosa
Of the 200 isolates 176 (88%), 169 (84.5%), 168 (84%), and 146 (73%) were susceptible to imipenem, piperacillin/tazobactam, colistin, and cefepime, respectively [Table 2]. In addition, 139 (69.5%) isolates were susceptible to amikacin, 133 (66.5%) to gentamicin, 135 (67.5%) to ciprofloxacin, and 128 out of the 178 tested (71.9%) susceptible to meropenem. One hundred and two isolates (51%) were resistant to ceftazidime.
|Table 2: Susceptibility of P. aeruginosa isolates to antipseudomonal antibiotics|
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Multiplex polymerase chain reaction result of metallo-β-lactamases-Pseudomonas aeruginosa and resistant pattern
Out of the 22 phenotypically detected MBL-P. aeruginosa, the blaVIM-1 gene was detected in only five  [Table 3]. The agarose gel electrophoresis result for the blaVIM-1 gene is shown in [Figure 1].
|Table 3: Microbiological and molecular characteristics of Carbapenem-Resistance P. aeruginosa isolates|
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| Discussion|| |
Antibiotics susceptibility profile
Results of antibiotics susceptibility testing revealed that isolates of P. aeruginosa were most susceptible to imipenem, piperacillin-tazobactam, colistin, and cefepime but were largely resistant to ceftazidime. The previous retrospective studies conducted in this center also showed that imipenem had the highest susceptibility against P. aeruginosa in the range of 80%–90%, but with reduced susceptibility to ceftazidime, one-third-generation cephalosporin that was heavily relied on for its antipseudomonal activity.,,, The concordance of the retrospective studies with this prospective one implies that there has been little or no change in the antibiotics susceptibility pattern of P. aeruginosa between 2010 and 2015 in this locality.
The studies, however, revealed that ceftazidime could no longer be suitable as an agent for empiric therapy in serious infections suspected to be caused by P. aeruginosa. Ceftazidime has been the “workhorse” for the treatment of severe infections caused by P. aeruginosa in many tertiary healthcare institutions in Nigeria for over two decades, and this may account for the high resistance profile. This reduced susceptibility to ceftazidime and other commonly prescribed antipseudomonal antibiotics had previously been reported in studies from other tertiary health-care institutions in other parts of Nigeria.,,, Similar reason stated above may be adduced for these susceptibility patterns. However, a well-designed multicenter research may provide more representative data.
Imipenem and the carbapenems generally, are not commonly prescribed in our center, implying less exposure and pressure on this pathogen to these antibiotics; hence, the relatively high susceptibility profile. Similarly, piperacillin-tazobactam, cefepime, and colistin are not commonly prescribed, were not usually included in routine antibiotics susceptibility testing as reflected in the retrospective studies. Therefore, on the basis of this susceptibility profile, imipenem and piperacillin/tazobactam, would appear to be the most appropriate choices for empiric therapy in the treatment of patients with serious infections in which P. aeruginosa is suspected while colistin and cefepime should be reserved as last drugs of choice. Notwithstanding, the commonly prescribed antipseudomonal agents are still clinically useful, provided their selection is based on an appropriate antibiogram and regular surveillance.
Prevalence of VIM-1 metallo-β-lactamases-Pseudomonas aeruginosa
Although the phenotypic method used in this study detected 22 (11%) MBL-producing P. aeruginosa strains, only five were found to harbor the gene for MBLs when subjected to molecular analyses, and they were all blaVIM-1 sub-types. This gave an overall prevalence of 2.5%. This, to the best of our knowledge, is the first report of the detection of blaVIM-1 in clinical isolate of carbapenem resistance P. aeruginosa in Nigeria. The multiplex PCR did not detect the MBL gene for IMP, NDM, SPM, SIM, and GIM that were assayed for. Most published studies on the detection of MBLs in P. aeruginosa in Nigeria were limited to phenotypic methods only.,,, Studies in Kaduna/Kano, Lagos, and Calabar using the ethylenediaminetetraacetic acid (EDTA) disc synergy method gave prevalence of 21.2%, 8.8% and 4.1%, respectively; whereas an Enugu study gave a prevalence of 10%, similar to the 11% in this study. The differences in the methods used partly accounted for the wide differences in prevalence as the EDTA disc synergy method is of lower specificity than the disc potentiating method used in this and the Enugu studies.
The phenotypic resistance to carbapenems in the absence of relevant genes for their enzyme elaboration, most probably suggests that resistant mechanisms other than MBLs could be at play in the isolates. Efflux pumps, impermeability of the outer membranes, modification of target site and carbapenemases other than MBLs may also mediate carbapenem resistance in P. aeruginosa.,
Interestingly, the findings in this study are a marked contrast from a similar study in Kenya  where all phenotypically detected MBL-producing, carbapenem-resistant P. aeruginosa (CRPA) harbored the blaVIM-2 gene, which is the much more common one while our study detected the much rarer blaVIM-1 gene, suggesting that this is the dominant strain circulating in Abuja, Nigeria. It would appear that blaVIM-2 does not presently exist in Abuja and probably Nigeria as a whole; an issue for further studies for conclusive determination.
The blaVIM-1 was first reported in Verona University Hospital, Italy, in 1999 by Laura Lauretti et al. in an isolate of CRPA. Subsequently, it was frequently reported around the Mediterranean region and has largely remained confined there., Its detection in Abuja may be a case of imported antibiotic resistance strains because many Nigerians frequently visit this region for pilgrimage (Israel, Saudi Arabia, Rome), medical tourism, and work. Two cases of imported MBL-producing P. aeruginosa from Ghana to Norway  and from Egypt to Hungary  have previously been reported and serve to illustrate this phenomenon. These two cases represented the first report of MBL-producing P. aeruginosa harboring blaVIM-2 gene in Norway and Hungary, a scenario which highlighted the significant role of international travel on the spread of antimicrobial resistance across the globe.
blaNDM-1 which has been linked with international travel, especially to the Indian Subcontinent, where it is commonly found, surprisingly was not detected in this study despite the fact that many Nigerians, particularly the inhabitants of Abuja, travel to India for medical care. Although blaNDM-1 gene had been more commonly reported among Enterobacteriaceae than Pseudomonas, the result of this study runs contrary to the common assertion that blaNDM-1 has great propensity for international dissemination as a consequence of international travel, especially to India. It is also possible that the rare blaVIM-1 detected in this study developed de novo.
The strains of P. aeruginosa isolated in this study that harbored blaVIM-1 gene was resistant to all the antipseudomonal antibiotics tested except aztreonam and colistin, but two (strains No. 10 and 185) were also resistant to aztreonam which may be due to additional resistant mechanisms. This reduced susceptibility to a broad array of antipseudomonal antibiotics has been reported by the previous studies and has a grave clinical implication for health care.,
Although it has been reported that blaVIM genes are usually carried on gene cassettes inserted on a Class 1 integron,, it was not found in this study because the Class 1 integron primers used during the multiplex PCR reaction did not detect it.
| Conclusion|| |
Acquired MBL-producing strains of P. aeruginosa poses serious challenge for therapy as well infection control. However, the prevalence rate is currently low in Abuja, North Central Nigeria as reported in this study. With some harbouring the rare blaVIM-1-gene. Hence, rational use of antipseudomonal antibiotics, good infection control practice should be instituted to curb further spread of these strains.
Limitation of study
The limitation of this study was a result of limited resources and time constraint. Other genes responsible for MBL resistance and other mechanisms of resistance in these strains of P. aeruginosa could have been detected using whole gene sequencing. Similarly, gene localization, gene cassette array, and genetic relatedness are information that could be derived from these strains where resources are available.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]