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SYSTEMATIC REVIEW
Year : 2023 | Volume
: 30
| Issue : 1 | Page : 1-11
A systematic review of the current status of carbapenem resistance in Nigeria: Its public health implication for national intervention
Musa Yakubu Tula1, Onaiwu Idahosa Enabulele2, Endurance Anthony Ophori2, Abumhere Samuel Aziegbemhin2, Osaretin Iyoha3, Joel Filgona4
1 Department of Biological Science Technology, Federal Polytechnic, Mubi, Adamawa State, Nigeria
2 Department of Microbiology, Faculty of Life Sciences, University of Benin, Benin City, Edo State, Nigeria
3 Department of Medical Microbiology, School of Medicine, College of Medical Sciences, University of Benin Teaching Hospital, Benin City, Edo State, Nigeria
4 Department of Microbiology, Adamawa State University, Mubi, Adamawa State, Nigeria
Correspondence Address:
Musa Yakubu Tula
Department of Biological Science Technology, Federal Polytechnic, Mubi, Adamawa State
Nigeria
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/npmj.npmj_240_22
Carbapenem antibiotics are considered one of the most effective and the last-resort antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. However, with the advent of carbapenem resistance, it becomes obvious that quality health-care delivery will be hampered if adequate measure is not put in place. This review assessed the prevalence of carbapenem-resistant Gram-negative bacteria (CR-GNB) and also provided an up-to-date position on carbapenem resistance (CR) in Nigeria. Three electronic databases (Google Scholar, PubMed and African Journal online) were searched for relevant literatures, and 38 articles published between January 2013 and June 2022 that met the criteria for inclusion were recruited into the study. The mean prevalence of CR in Nigeria stands at 21.3%, with the southern and northern regions documenting a mean prevalence of 22.0% and 20.9%, respectively. Most of the reviewed articles were from clinical settings (81.6%), with urine samples (38.7%) constituting the most prevalent clinical sample in which CR-GNB were detected. The preponderance of phenotypic methods (55.3%) over molecular method (44.7%), particularly the use of disk diffusion test breakpoint and Modified Hodge test was documented. The most prevalent carbapenem-resistant bacteria were Escherichia coli (50.0%) and Klebsiella pneumoniae (26.3%). The blaNDM and blaVIM were the major reported carbapenemase-encoded genes, particularly among E. coli, K. pneumoniae and Pseudomonas species. This systematic review revealed a mean prevalence of CR-GNB in Nigeria that required urgent attention. Furthermore, the detection of clinically and epidemiologically important carbapenemase coding genes is of public health importance.
Keywords: Carbapenem, carbapenemase, genes, Nigeria, public health, resistance
An antibiotic is a term that was initially coined from the word 'antibiosis' which indicates 'against life'. Antibiotic was earlier defined as chemical substances or compound of biological source that destroy or stall the proliferation of microbes.[1] This was because antibiotic was thought to be exclusively from microbial source with deleterious effect on other microorganisms. This definition was, however, modified to accommodate antimicrobials that are derived from other sources.[2] To be more specific, antibiotics can be classified as antibacterial, antiviral or antifungal, which shows the group of organisms they act upon.[2],[3]
Soon after the discovery of antibiotics, the populace and clinicians were optimistic that infections caused by biological entities could be checked or prevented optimally. Amazingly, diseases caused by microorganisms, especially bacteria, still stand as the prominent cause of mortality in developing countries. This is because there is an upsurge in the occurrence of new diseases, the recurrence of diseases once subjugated, and, most importantly, the emergence of novel antibacterial resistance.[4]
Resistance to antibiotics by bacteria is the aptitude of the bacterial isolate to live and replicate in the presence of antibiotic dilutions that were initially believed to be active against them.[5] Currently, antibiotic resistance is a global phenomenon, with the scourge much more pronounced in developing than developed countries.[6] This phenomenon is enhanced by bacteria, human and environmental factors.
Carbapenem has potent activity against wide spectrum of bacterial species, and its exclusive structure consisting of carbapenem attached to a β-lactam ring bestows fortification against the majority of β lactamases such as metallo-β-lactamase and extended-spectrum β-lactamases. As a result, carbapenems are respected as one of the most dependable and last resort antibiotics for the treatment of infections involving multidrug-resistant (MDR) Gram-negative bacteria.[7] However, with the incident of carbapenem resistance (CR), particularly among Gram-negative bacteria, it became obvious and a matter of concern that the next line of antibiotics to be used against carbapenemase-producing Gram-negative bacteria will be marginal, lost or need to be sought after. Presently, the global occurrence of carbapenem resistance, especially among Escherichia coli and Klebsiella pneumoniae species in the community and health-care facilities, including livestock, constitutes a colossal liability and may impede quality health-care delivery.[8],[9]
Although several studies have reported the occurrence of CR in Nigeria, nonetheless, there is a dearth of information on the detailed analysis of the molecular, distributions and epidemiology of CR in Nigeria, and their liability on our health-care facilities. This study will tremendously help healthcare policy makers and clinician, particularly those incharge of antibiotic stewardship in guiding appropriate use of this class of antibiotics. This study also illustrates the present position of CR in Nigeria, underlining their sources, methods of detection, regional prevalence, and the most common Gram-negative bacteria species with carbapenem-degrading enzymes and or genes.
MethodsLiterature review and sources of data
The literature search was performed using Google Scholar, PubMed and African Journals Online databases. The search criteria were based on 'prevalence of carbapenem resistance in Nigeria', 'carbapenem-resistant determinants in Nigeria', 'phenotypic and molecular detection of carbapenem resistance in Nigeria'. The keywords and search terms employed include, but are not limited to, 'carbapenem resistance and Gram-negative bacteria', 'carbapenem resistance and Enterobacteriaceae', 'carbapenem resistance and north-east Nigeria', 'carbapenem resistance and north-west Nigeria,' 'carbapenem resistance and north-central Nigeria', 'carbapenem resistance and south-east Nigeria', 'carbapenem resistance and south-west Nigeria', 'carbapenem resistance and south-south Nigeria', 'carbapenem resistance and clinical samples in Nigeria', 'carbapenem resistance and environmental samples in Nigeria', 'carbapenem resistance and livestock in Nigeria'. For each case, the search outcomes were reviewed by the authors.
Study selection criteria
Full-text cross-sectional research articles reporting the prevalence of carbapenem-resistant Gram-negative bacteria (CR-GNB) isolated from clinical sources, non-clinical sources such as domestic water, wastewater and fomites from the hospital environment in the 36 States of Nigeria, including the Federal Capital Territory (FCT) Abuja were included for this study. Only studies that gave details of the bacterial study population, including the number of carbapenem-resistant bacterial isolates identified, methods used to detect CR and identified carbapenemase genes, were included. However, case reports and review articles were excluded from this systematic review.[9],[10]
Data extraction
A database was created, in which study location, publication year, sample collection period, dominant carbapenem-resistant bacterial species, number of isolates tested for carbapenem, CR prevalence, carbapenemase genes and methods used were included [Table 1] and [Table 2].
Table 1: Sample distribution of carbapenem-resistant bacteria in Nigeria
Table 2: Carbapenem resistance in Nigeria showing prevalent methods used, prevalent carbapenemase genes and bacterial isolatesData analysis
Data were presented in percentages and were analysed by odds ratio (OR) using SPSS Statistics for windows, Version 17.0. (Chicago; Inc.). A P < 0.05 indicated a statistically significant difference.
ResultsDistribution of articles describing carbapenem resistance in Nigeria
Electronic database searches yielded a total of 85 articles. A total of 38 publications that matched the described inclusion benchmark were finally used for this study [Figure 1]. The northern and southern regions had 44.7% (17/38) and 55.3% (21/38) articles, respectively. These articles were from 17 States of the Federation in addition to 1 from FCT Abuja, making a total of 18 States in all. From each geopolitical zone, the 38 articles were distributed thus; 2 (5.3%) from the northeast (NE), 11 (28.9%) from northwest (NW), 4 (10.5%) from northcentral (NC), 3 (7.9%) from the southeast (SE), 13 (34.2%) from southwest (SW) and 5 (13.2%) from south-south (SS) Nigeria [Figure 2].
Figure 1: Flow diagram summarising the process of literature search and selection. AJOL: African Journal online
Figure 2: Distribution of articles included in the study based on Nigeria geopolitical zonesThe two articles from the NE were studies from Adamawa and Borno States only with one article each. CR in NW was centred only in 3 out of the 6 States. Six works of literature (54.5%) were from Kano, while 3 (27.3%) and 2 (18.2%) articles were documented in Sokoto and Kaduna States, respectively. From the NC States, the four articles that reported the prevalence of CR were, one (25.0%) each from Plateau, Kogi, Benue States and the FCT Abuja. The three articles from the southeastern States were all from Anambra State. In the southwestern States, 13 articles were included in this study, of which six were from Lagos, three from Oyo, and one from Ogun States. One literature documented combined prevalence from Ekiti, Osun and Oyo States, one literature also documented CR from Ogun, Oyo and Osun States, while another documented CR from Oyo and Lagos States. The five articles from SS included in this study include 2 (40.0%) each from Edo and Cross-River States, and 1 (20.0%) from Rivers State [Table 1]. Data from States not mentioned (19 States) in each geopolitical zone were either not encountered or could not meet the inclusion criteria for the systematic review. The Odds (OR = 1.375, confidence interval [CI] = 0.376-5.032, P=0.630) showed that states in southern Nigeria reported CR 1.375 times higher than states in northern Nigeria, but with no statistical difference.
Prevalence of Carbapenem-Resistant Gram-Negative Bacteria in NigeriaReported prevalence
From the sampled articles, various prevalence rates were reported across all the six geopolitical zones, which range from 6.8%–12.4%, 4.5%–77.0% and 2.4%–100%, respectively, in NE, NW, and NC. Similarly, the prevalence rates between 28.0%–53.3%, 2.2%–93.8% and 4.1%–70.0% were also reported in the SE, SW and SS, respectively. The highest prevalence of CR (100%) was reported in the NC from a community-based study, while the least was reported in the SW from hospital-based research [Table 1].
Mean prevalence
The result for the mean prevalence showed that from the year 2013–2022, Eight thousand six hundred and fifty-eight Gram-negative bacterial isolates were screened for CR by both phenotypic and molecular methods. Of these, only 1845 were found to be carbapenem-resistant; this account for the mean prevalence of 21.3%. The result also showed that the northern region has a mean prevalence of 20.97% (1203/5736), with a documented mean prevalence of 7.5%, 31.2% and 19.2% for the NE, NW and NC, respectively. Similarly, the southern region has a mean prevalence of 22.0%, with a documented mean prevalence of 25.4%, 24.3% and 14.7% for SE, SW and SS. Of the 6 geopolitical zones, the NW recorded the highest mean prevalence rate of 31.2%, while the least was recorded in the NE with 7.5%. The mean prevalence of 20.5% and 29.4% were documented for CR-GNB from clinical and non-clinical sources, respectively [Table 1].
Sources of specimens/sample-wise distribution of carbapenem-resistant bacteria
Of the articles reviewed, 31/38 (81.6%) were clinical-based research. From these, 12 (38.7%) of the articles documented urine samples as the most predominant specimen that harboured CR-GNB. From the urinary isolates, carbapenem-resistant K. pneumoniae was documented in 58.3% (7/12) articles, carbapenem-resistant E. coli was documented in 33.3% (4/12) studies and carbapenem-resistant P. aeruginosa was documented in 8.3% (1/12) articles. Other studies, however, documented that CR-GNB were predominantly isolated from catheter tips (3.2%), blood (3.2%), sputum (3.2%) and septic wounds (6.4%).
From this systematic review, five articles exclusively documented CR from non-clinical sources. Whereas two articles documented CR in both clinical and non-clinical samples. Of the two articles that reported CR from both sources, one reported CR in animals [Table 1].
Method of detection of carbapenem resistance
This study observed that two basic methods were used for the detection of CR in Nigeria: phenotypic and molecular methods.
Phenotypic methods
The detection of carbapenem-resistant organisms by phenotypic methods alone was documented in 55.3% (21/38) articles. Of these, 54.1% (12/21) and 42.9% (9/21) articles were from southern and northern Nigeria, respectively. Going by geopolitical zone, the phenotypic method was registered in 38.1% (8/21) studies from the SW, while it was reported in 33.3% (7/21), 14.3% (3/21), 9.5% (2/21) and 4.8% (1/21) studies from NW, SS, NC and SE respectively. The odds (OR = 1.185, CI = 0.328–4.289, P = 0.796) are 1.185 times higher that detection of CR by a phenotypic method is much more pronounced in southern than in northern Nigeria, but with no statistical difference.
There were eight phenotypic methods documented in the whole reviewed articles for the detection of CR among Gram-negative bacteria. These include disk diffusion breakpoint assay, Carba Nordmann-Poirel test (Carba NP), carbapenemase detection kit (MASTDISCS), Chromatic™ CRE method, Modified Hodges Test, Minimum inhibitory concentrations (MIC) breakpoint, combined disk test (CDT) and carbapenemase inactivation method (CIM).
From the phenotypic method, the disk diffusion test (DDT) alone was reported in 61.9% (13/21), of which 38.5% (5/13) and 61.5% (8/13) studies were from northern and southern Nigeria, respectively. Of these, 38.5% (5/13) were acknowledged from the SW, while 23.1% (3/13) were acknowledged from the NW. More so, DDT assay was acknowledged in 15.4% (2/13) articles each from NC and SS, and 7.7% (1/13) articles from the SE [Table 2].
More to this, the use of DDT in combination with other phenotypic methods alone (DDT + MHT, DDT + CIM and DDT + CDT) was documented in 38.1% (8/21) articles, of which 50.0% (4/8) articles each were documented in northern and southern Nigeria. From these, DDT in combination with MHT was acknowledged in 75.0% (6/8) studies, of which 66.7% (4/6) and 33.3% (2/6) were reported in the NW and SW, respectively. The combination of DDT + CDT and DDT + CIM alone was reported in an article each (12.5%) from the SW and SS, respectively [Table 2]. The odds (OR = 1.600, CI = 0.270–9.490, P = 0.604) was 1.600 times higher that detection of CR by disk diffusion method alone is much more pronounced in southern than in northern Nigeria, but with no statistical difference [Table 3].
The use of the carbapenem disk singly and or in combination was reflected in 91.7% (35/38) of the articles. The reported antibiotic disk used for the preliminary detection of CR in Gram-negative isolates from the articles includes meropenem (MEM), ertapenem (ERT) and imipenem [IPM]), which were used singly or in combination. The carbapenem disks were used in seven different patterns (MEM + IPM + ERT, MEM + IPM, MEM + ERT, IPM + ERT, MEM, IPM and ERT). The combination of MEM + IPM occurred in 25.7% (9/35) of the articles, of which 66.7% (6/9) were from the NW. However, the use of MEM disk alone was documented in 22.9% (8/35) of the articles, of which 50.0% (4/8) were from the SW. Furthermore, the use of IPM disk singly and MEM + ERT was acknowledged each in 18.2% (6/33) of the articles [Table 2].
Molecular method
Molecular method for detecting CR among Gram-negative bacteria was acknowledged in 44.7% (17/38) of the articles, of which 47.1% (8/17) and 52.9% (9/17) studies were from the northern and southern regions, respectively. Of these, 29.4% (5/17) and 23.4% (4/17) of studies were from the SW and NW, respectively, whereas 11.8% (2/17) studies each were documented in NE, NC, SE and SS [Table 2]. The molecular methods used for the detection of CR among Gram-negative bacteria in this study were the polymerase chain reaction (PCR) method, and whole-genome sequence (WGS). PCR singly was mentioned in 80.0% (13/17) of the articles, whereas WGS alone, and PCR + WGS were used in 5.9% (1/17) and 17.6% (3/17) of the articles, respectively [Table 2].
The carbapenem-resistant genes were amplified in 13 (76.5%) out of the 17 pieces of literature that carried out molecular studies. Five carbapenem-resistant genes amplified were documented as follows: New Delhi Metallo-β-lactamases (NDM), Verona integron-encoded Metallo-β-lactamase (VIM), variants of Oxacillinases like enzymes [OXA]), K. pneumoniae carbapenemase (KPC) and Guiana-Extended-spectrum β-lactamase (GES). The encoding gene for NDM was reported in 61.5% (8/13) studies (two studies each from NE, NW, and SW, and one literature each from SS and SE). The encoding gene for VIM was documented in 53.8% (7/13) studies; 2 (28.6%) each from NE, NW and SW, including 1 (14.3%) from NC. The OXA variants were reported in 4 (30.8%) studies; 2 (50.0%) studies from the SW, and 1 (25.0%) each from the SE and SS. Whereas KPC was acknowledged in only 3 (23.1%) studies; 1 (33.3%) each from NE, NW and SS. GES was only documented in a study from the SW [Table 2].
However, carbapenem genes were not amplified in 23.5% (4/17) studies that studied CR by molecular method. These include two studies (one in the SE and the other in the SW) that documented the use of the combination MEM + ERT in the phenotypic detection of carbapenem resistance, and the other in the NW that documented the use of Carba NP in the phenotypic detection of carbapenem resistance, and another study in NC that documented the use of MIC breakpoint for MEM, ERT, IPM and CIM.
Species distribution of carbapenem-resistant Gram-negative bacteria
The most predominant CR-GNB reported in the reviewed articles varies. However, 19 out of 38 articles (50.0%) documented E. coli as the most predominant carbapenem-resistant bacteria. This was followed by K. pneumoniae which was documented in 10 out of the 38 articles (26.3%). The preponderance of Pseudomonas spp. and Acinetobacter baumannii was documented in 3 (7.9%) and 2 (5.3%) studies, all in Southwestern Nigeria [Table 1].
The preponderance of CR in E. coli was 100% in all the studies from NW, 66.7% in the SE, 50.0% in the NC, 30.8% in the SW and none in SS and NE. More so, the preponderance of carbapenem-resistant K. pneumoniae was 50% in the NE, 38.5% in the SW, 33.3% in the SE, 40.0% in SS, 25.0% in NC and none in the NW. One study each reported the preponderance of CR in Salmonella enterica (NC), Enterobacter aerogenes and Escherichia fergusonii (SW), Aeromonas and Serratia spp (SS) and Klebsiella quasipneumoniae (NC).
The preponderance of E. coli and K. pneumoniae was reported more in clinical than non-clinical samples. A species each of E. coli, Pseudomonas putida, S. enterica, K. pneumoniae, K. quasipneumoniae, Aeromonas spp. and Serratia spp., was reported as the most prevalent CR-GNB from non-clinical sources of the reviewed articles.
DiscussionIn Nigeria, there is a paucity of data on the trend, spread, and magnitude of carbapenem resistance. This is enhanced by the lack of a sustainable framework for national antimicrobial resistance surveillance and stewardship programmes. The results showed that studies on CR were more carried out in the southern than in the northern States, despite the north having a greater number of States. The highest number of studies was documented from the SW and the least from NE Nigeria. The reason for this disparity is rather obscure.
Sample-wise distribution of carbapenem-resistant Gram-negative bacteria
This systematic review revealed that CR-GNB is highly detected in clinical than non-clinical samples. This could be attributed to the fact that most of the published articles were hospital-based studies. This implies that most interest in CR in Nigeria is clinically based. From the clinical sources, carbapenem-resistant bacteria were predominantly detected in urine than in other clinical sources. This contradicts observations from East Africa that reported the preponderance of carbapenem-resistant bacteria in respiratory tract samples more than other samples.[9] The preponderance of carbapenem-resistant bacteria in blood and septic wound samples, as reported in some articles included in this study, corroborates previous reports from India and the United State of America.[9],[49]
The non-clinical sources encountered in this systematic review include water, wetland samples, stool from community-based studies, hospital fomites and samples from animal sources. This suggests that carbapenem-resistant bacteria in Nigeria are not limited to clinical samples alone. Studies have shown that the movement of mobile genetic elements from clinical to environmental bacteria may occur inside the hospital environment, hereafter advancing the emergence of new resistant bacteria strains. In addition, carbapenem-resistant bacteria in the hospital environment may spill into the food chain, hence becoming one of the sources of community-acquired-resistant pathogens.[9] Isolates from livestock in this study were also found to be resistant to carbapenem antibiotics. This corroborates several studies from Algeria, Egypt, India, China, France, the USA and other parts of the world as documented in a systematic review article.[50] A systematic review from East Africa reported a lack of studies on the detection of carbapenem-resistant bacteria in livestock,[9] to which this study has an edge.
Prevalence of carbapenem resistance
Variable prevalence rates were reported in Nigeria, between 2.2% and 100%. The lowest is 2.2% from the SW (Lagos) and the highest is 100% from NC (Kogi State). However, the mean prevalence of CR in Nigeria going by the available data from 2013 to 2022 in this systematic review, stands at 21.3%. This is quite lower than the prevalence rates of 35%, 40.0% and 68% reported in East Africa,[9] Egypt[51] and South Africa,[52] respectively. In Uganda, a prevalence of 28.6% was reported.[53] The highest prevalence rate was recorded in southern than northern Nigeria. This could be because a higher number of researches on CR were recorded in the southern than northern region. Of the six geopolitical zones, the least prevalence of 7.5% recorded from the NE could be influenced by the significant paucity of data on the subject matter in the region. Although the number of studies on CR in the SW was higher than in the other geopolitical zones, however, the mean prevalence of CR among Gram-negative bacteria was highest in northwestern Nigeria than in the other sub-region. This could be attributed to the higher proportion of positive carbapenem-resistant bacteria detected in the region when compared with the number of bacteria screened. More so, the higher prevalence of carbapenem-resistant organisms recorded in non-clinical than clinical samples could be attributed to the fewer number of studies with non-clinical samples. This implies that CR-GNB and their determinants are spreading quietly and unknowingly in the community or environment.
Methods of detection of carbapenem-resistant Gram-negative bacteria
Phenotypic detection of CR among Gram-negative bacteria was the most common method employed as shown in the reviewed articles. The use of the method was more pronounced in southern than northern Nigeria. This could be explained by the elevated number of studies in the southern region than in the northern region. The DDT followed by MHT are the most commonly used phenotypic method in Nigeria, as shown by the reviewed articles. The frequent use of phenotypic methods alone in Nigeria could be majorly due to resource constraints, as most of the studies were self-sponsored. It may also be because phenotypic methods are rapid, result-oriented and reproducible, it has wider acceptability, are cost-saving, materials are accessible and is not tedious.
Only three antibiotics disks were encountered in the reviewed articles, and include MEM, IPM and ERT disks. The IPM disk was the disk commonly used singly, while MEM and IPM were the disks commonly used in combination. The use of these disks may be influenced by personal interest, accessibility and the commonly reported used antibiotic disk in literature. The preponderance of the disk method alone in the southern region may be connected with a greater number of studies in the south than in the north.
All molecular methods in this study were carried out after a preliminary investigation of CR by phenotypic methods. This is of great importance as it helps to direct and or guide the researcher on the choice of appropriate isolates with the potential of harbouring carbapenem-resistant genes. It also helps to eliminate or reduce labour and cost. The use of molecular studies in the detection of carbapenem-resistant genes was documented in less than half of the reviewed articles. In addition, only four articles documented the use of WGS. This could be due to resource constraints as earlier explained. This suggests that more robust studies on CR by the molecular method are required to determine the genotypic characteristics of the carbapenem-resistant encoding genes and the nature of their spread in the country for epidemiologic surveillance.
Prevalent carbapenem-resistant Gram-negative bacteria
The most prevalent CR-GNB reported in the reviewed articles was E. coli, followed by K. pneumoniae. These organisms were also found to be higher in clinical than non-clinical sources of the sample. This may be because most of the studies on CR in Nigeria were from clinical settings. It could also be because some of the studies were centred on Enterobacteriaceae or more precisely, on either E. coli or K. pneumoniae or both. The finding of this study was consistent with a similar systematic review from East Africa, where E. coli and K. pneumoniae were reported as the most detected CR-GNB.[9] It is also in agreement with the global data about carbapenem resistance.[54] In South Africa, however, K. pneumoniae and A. baumannii were reported as the most dominant CR-GNB.[55] Furthermore, the growing incidence of CR among oxidase-positive, non-lactose-fermenting organisms such as Pseudomonas species, as shown in the review articles, corroborates reports from previous studies.[9],[54],[56] The southern States were reported to harbour a higher number of carbapenem-resistant bacteria than the northern States because quite a number of studies on CR were carried out in the south than in northern Nigeria.
Carbapenem-resistant bacteria isolated from non-clinical sources such as community studies, hospital environments and water sources showed species diversity compared to isolates from clinical sources. This may be because these sources serve as a suitable environment for the proliferation of diverse species of bacteria. It equally suggests that carbapenem-resistant bacteria are on the increase, not only in the clinical settings but also in the environment, water sources, and among livestock in Nigeria.
Carbapenem-resistant genes
The carbapenemase genes, such as blaNDM-1, blaKPC, blaVIM, variants of blaOXA,blaGES, were reported in this study. Much of these genes were from the human or clinical setting. This corroborates a previous report from Nigeria.[57] More so, these carbapenemase genes have been documented in several African countries.[57],[58],[59] These genes detected in Nigeria are the most epidemiological and clinically important carbapenemase genes, as previously observed.[57],[60] From the reviewed articles, blaNDM and blaVIM are the most detected carbapenemase genes in Nigeria. Other studies in South Africa and other African countries reported the preponderance of blaNDM and blaOXA.[55],[57],[61] In Tanzania, however, blaIMP and blaVIM were reported as the principal carbapenem-resistant genes.[62] The difference between the comparative and the present study could be due to differences in the regional prevalence of dominant CR genes. These dominant genes in Nigeria were mostly detected in either E. coli or K. pneumoniae. This is in agreement with several other studies in Kenya and South Africa.[61],[63] The study also showed that blaVIM is the predominant carbapenem gene detected in the Pseudomonas species. This is consistent with a study from South Africa.[61] The finding of this systematic review, therefore, implies that CR in Nigeria is mostly mediated by carbapenemase enzymes.
Interestingly, the target of all the articles with molecular studies in this systematic review was the detection of carbapenemase-encoding genes. None of the articles targeted other emerging mechanisms of CR in Gram-negative bacteria. For example, the lack of detection of carbapenemase genes in four studies whose isolates were phenotypically resistant to carbapenem antibiotics by disk diffusion test, suggests the presence of other mechanisms of carbapenem resistance. This implies that organisms that lack carbapenemase determinants might have acquired a silent gene, which enables them to exhibit phenotypic resistance.[60],[64] Studies have shown that in addition to the acquisition of carbapenemase genes, resistance to carbapenem could be mediated by mutations or disruption in the chromosomes that affect regulatory or non-regulatory genes. These genes, in turn, influence or mediate the efflux pump resistance mechanism, which pumps the carbapenem outside the cells, and or porin-mediated resistance that help to limit the uptake of carbapenem antibiotics.[27],[65] CR can also be mediated by β-lactamases enzymes, especially extended-spectrum beta-lactamases (ESBLs) and aminopenicillin cephalosporinase in combination with the mutations of the efflux pump and outer membrane protein structure.[27],[66]
One of the studies in which the carbapenemase gene was not amplified was an animal study. This corroborates a previous study in Nigeria that reported a lack of detection of the carbapenemase gene in bacterial isolates from livestock.[57] This implies that CR among livestock in Nigeria is mediated by the clone of bacterial isolates that mediate resistance to carbapenem by non-carbapenemase mechanism.
Public health implications of CR for national intervention
Carbapenems remain the reliable last line of defence against infections involving multidrug-resistant (MDR) bacteria. However, the rapid emergence of CR among Gram-negative bacteria constitutes a public health concern because the relatively high MIC of carbapenems in these pathogenic bacteria along with exhibiting MDR phenotypes make them difficult to eliminate.[60],[67] Given the length of hospital stay, increased resistance to multiple antibiotics, treatment failure and high mortalities emanating from infections caused by carbapenem-resistant organisms, their public health impact, therefore, is highly significant.[55],[68] With the relentless and undetected nature of these carbapenem-resistant organisms, influenced by the lack of antibiotic surveillance, and routine examination of clinical samples for carbapenem resistance, particularly in our hospitals, there is the likelihood of outbreaks possibly involving hospital staff and patients. If that happens, the possibility of an outbreak in the community is also imminent. More so, with the detection of CR in bacterial isolates from drinking water sources, and among Salmonella species in a community study, as shown in this systematic review, the spread of carbapenem-resistant bacteria in the community through food and water in Nigeria is ensured. The implication is that many people will be exposed unknowingly if an adequate measure is not put in place, and the burden of antibiotic resistance in the community will further be worsened. This calls for national intervention programmes such as establishing public health surveillance programmes, establishing and enforcing antibiotic stewardship programmes, introducing routine CR checks and developing infection control programmes in Nigerian hospitals, and developing alternative but effective therapies to counter bacteria with this kind of resistance.
Carbapenem resistance knowledge gap in Nigeria
Studies worldwide have documented CR mediated by mechanisms (expression of ESBLs in the combination of reduced or loss of outer membrane porin) other than carbapenemases,[69],[70] which was not or rarely reported in Nigeria. More so, the use of high-profile molecular platforms such as WGS for genetic characterisation and epidemiology of different variants of CR coding determinants were rarely documented. Most of the studies in Nigeria were centred in health-care environment, as such, the extent of the spread of CR in the community is largely unknown.
Limitations of the study
The results of the 38 articles reflecting the prevalence of CR by both phenotypic and molecular methods in Nigeria were reviewed in this study. However, the number of studies in the NE and southeast were too scanty to adjudge the true position of CR in these regions. More so, most of the studies reported CR based on the phenotypic method alone. This might have influenced the higher number of CR-GNB in the study. Furthermore, the pattern of the spread of CR-GNB in the community is not elucidated.
ConclusionThis systematic review revealed a mean prevalence of CR in Nigeria that required urgent attention, with E. coli and K. pneumoniae as the most preponderant CR-GNB. The study also highlighted elevated studies of CR in the southern than northern region, particularly from clinical samples. The phenotypic method was the most common technique used for the detection of carbapenemase enzymes as a marker for carbapenem resistance. The detection of clinically and epidemiologically important carbapenemase coding genes is of public health importance.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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