Source: https://ajlmonline.org/index.php/ajlm/article/view/778/1217
Timestamp: 2019-04-26 14:49:10+00:00

Document:
Background: The World Health Assembly adopted the Global Action Plan on Antimicrobial Resistance, which includes improving the knowledge base through surveillance and research. Noteworthily, the World Health Organization has advocated a Global Antimicrobial Resistance Surveillance System to address the plan’s surveillance objective, with most African countries enrolling in or after 2017.
Aim: The aim of this article was to review prior data on antimicrobial resistance of Vibrio cholerae from sub-Saharan Africa with a view for future control and intervention strategies.
Methods: We used the Preferred Reporting Items for Systematic Review and Meta-Analysis (or ‘PRISMA’) guidelines to search the PubMed and African Journals Online databases, as well as additional articles provided by the Nigeria Centre for Disease Control, for articles reporting on the antibiotic susceptibility of V. cholerae between January 2000 and December 2017.
Results: We identified 340 publications, of which only 25 (reporting from 16 countries within the sub-Saharan African region) were eligible. The majority (20; 80.0%) of the cholera toxigenic V. cholerae isolates were of the serogroup O1 of the El Tor biotype with Ogawa and Inaba serotypes predominating. Resistance was predominantly documented to trimethoprim-sulphamethoxazole (50% of the studies), ampicillin (43.3% of the studies), chloramphenicol (43.3% of the studies) and streptomycin (30% of the studies). Resistance mechanisms were reported in 40% of the studies.
Conclusion: Our results demonstrate a documented antimicrobial resistance of V. cholerae to multiple antibiotic classes, including cell wall active agents and antimetabolites with evidence of phenotypic/genotypic resistance to fluoroquinolones.
Upon commissioning from the Nigeria Centre for Disease Control (NCDC), we set out to review data on the antimicrobial resistance of V. cholerae from publications done in sub-Saharan Africa, in order to provide evidence that may serve as a yardstick for future control programmes and interventions.
This systematic review was done using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (or ‘PRISMA’) guidelines.9 The protocol for the study was developed in conjunction with the NCDC panel of experts and a more detailed version of the protocol is available on request.
We searched Medline using PubMed for articles published in English between 01 January 2000 and 31 December 2017 with the search terms ‘antimicrobial resistance’, ‘antibiotic resistance’, ‘Vibrio cholerae’ and the names of the individual countries of sub-Saharan Africa. Additional searches were done in the African Journals Online database, using an additional search term of ‘antimicrobial susceptibility’. We also scanned a list of articles obtained from the NCDC to select eligible articles that conformed with our search terms.
Articles were included for this review provided they reported on the antimicrobial susceptibility profile of V. cholerae isolates from clinical specimens in sub-Saharan Africa and were published between January 2000 and December 2017. We included articles irrespective of whether the isolates were obtained as part of an outbreak investigation or from a hospital-based site using cross-sectional survey, provided they were from human specimens.
The titles and abstracts of all search results were listed and were thereafter reviewed to identify papers for full text review. The selection procedure is outlined in Figure 1. Forty-five papers were excluded, because all attempts to secure full text versions were unsuccessful. Names of authors from articles were not blinded before or after the full text review. We used predetermined inclusion and exclusion criteria to select papers for full review. Papers selected for full review after abstract review were retrieved as full manuscript papers through PubMed, HINARI, from the NCDC or by personal communication with the corresponding authors. Seventy-six review articles were excluded, and 45 papers did not report on the susceptibility pattern of V. cholerae and were also excluded. Twenty-eight papers were on environmental samples; hence, they were excluded. Nineteen articles were not from sub-Saharan Africa and 15 articles evaluated susceptibility to plant extracts and, consequently, they were all excluded. Eight articles were in French and six articles used isolates from animal sources and they were all excluded.
FIGURE 1: Summary of study selection procedure.
A database was created in which the study name, study period, susceptibility pattern, biochemical properties, genes and virulence factors of the V. cholerae isolates from countries of sub-Saharan Africa were recorded where applicable (Table 1). We could not adequately carry out a quantitative study, because most of the susceptibility patterns of the isolates were not recorded in actual numerical values. Most of the studies also did not report on the quality control procedure they used and some of the studies relied only on molecular detection of resistance genes.
TABLE 1: Characterisation of eligible articles that sought resistance of Vibrio cholerae from countries in sub-Saharan Africa.
An attempt to reduce bias within studies and between individual studies was done. The review was also conducted in a group with materials, articles and the papers double-checked by at least two members of the group.
The extracted data were reported as outlined by the authors using the susceptibility categorisation of the pathogens into sensitive, intermediate and resistant. We reported on the biochemical characteristics of the V. cholerae in terms of serogroup, biotype and serotype. We also reported on the clinical diagnosis for isolates in studies where diagnosis was stated. We also highlighted the use of molecular methods, genotyping or virulence features for the characterisation of isolates wherever such data were available.
Our search generated 267 articles after removal of duplicates. During abstract review, we excluded 242 articles, because they did not meet our inclusion criteria. Twenty-five articles were included in the final analysis.
One article reported resistance of V. cholerae from five sub-Saharan African countries and was therefore divided into five for convenience. In all, the articles obtained reported on 16 of the 47 countries within the sub-Saharan African region. One study (3.4% for each) was obtained from each of the following countries: Angola, Chad, Madagascar, Namibia, Senegal, South Africa and Togo. Two studies (6.9% for each) were from each of Cote d’Ivoire, Democratic Republic of the Congo, Ghana, Guinea Bissau, Mozambique, Tanzania and Zambia. Three (10.3%) studies were from Kenya and five (17.2%) were from Nigeria.
Twenty-four (82.8%) of the studies reported serogroup O1 as the only serogroup, while two (6.9%) studies reported the O1 serogroup coexisting with the non-O1/non-O139 serogroup, but even in those studies the O1 serogroup dominated. Three (10.3%) studies did not report on the serogroup status. None of the studies reported the O139 serogroup from any country in the region of sub-Saharan Africa.
Twenty two (75.9%) studies reported the El Tor biotype, while one (3.4%) study reported the existence of the El Tor and the atypical El Tor biotype. Six (20.7%) of the studies did not biotype their isolates. There was no report of the classical biotype from any of the studies.
Eight (27.6%) studies reported the Ogawa serotype as the predominant serotype, three (10.3%) studies reported on Inaba existing alone and six (20.7%) reported the Ogawa/Inaba coexisting together. The coexistence of Inaba/Ogawa/Hikojima was reported from one (3.4%) study. Eleven (37.9%) of the studies did not report on any of the serotypes.
Seventeen studies detected or confirmed cholera toxin and toxin-co-regulated pilus genes (ctxB, ctxA and tcpA).
Table 1 shows the characteristics of eligible articles that investigated resistance of V. cholerae from sub-Saharan Africa. Resistance was documented to trimethoprim-sulphamethoxazole (50% of the studies), ampicillin (43.3%), chloramphenicol (43.3%), streptomycin (30%), nalidixic acid (30%), nitrofurantoin (26.7%), ceftriaxone (20%), spectinomycin (10%), sulfonamide (6.7%), penicillin G (6.7%) and cloxacillin (3.3%). The antibiotics to which susceptible strains were reported were: tetracycline (46.7% of the studies), amoxicilin/clavulanic acid (6.7%), florfenicol (3.3%), azithromycin (3.3%), imipenem (3.3%), ciprofloxacin (3.3%), ofloxacin (3.3%) and erythromycin (3.3%).
Mutations in antibiotic resistance determinants (gyrA, parC, floR, strA, and strB) were detected in nine (31.1%) of the studies, while twenty (68.9%) studies did not conduct genotypic studies on the isolates.
The ICEVchAng2 and ICEVchInd5 were reported from seven (24.1%) of the studies while the other twenty-two (75.9%) studies did not perform this genotypic analysis.
The average prevalence of resistance to cell wall active agents by the V. cholerae organisms from 20 studies was 68.8% (100–0%). However, 25 studies reported on the resistance to fluoroquinolones with their total average of 44.0% (100–0%), while the average prevalence of resistance to inhibitors of nucleic acid, predominantly the sulphonamide and co-trimozaxole, was 92.0% from 25 studies (Table 1).
Twenty-seven studies reported 43.5% (100–0%) prevalence of resistance to protein synthesis inhibitors of 30S subunit, while the average prevalence of resistance to protein synthesis inhibitors of 50S subunit (Table 1) was 62.5% (100–0%) from 26 eligible studies.
A study done by Quilici et al.24 using the V. cholerae isolates from the September/October 2009 outbreak of acute watery diarrhoea in north-eastern Nigeria and northern Cameroon implicated the serogroup O1 of the El Tor biotype and Ogawa serotype as the causative serotypes. The toxigenic genes of ctxA and ctxB were elaborated, in addition to detected mutations in the genes responsible for quinolone resistance. The ctxB gene was similar to the one detected in India. All of them were resistant to trimethoprim-sulphamethoxazole, ciprofloxacin, sulphonamide and nalidixic acid. All the isolates were resistant to tetracycline, but moderately susceptible to chloramphenicol and ampicillin.24 In 2013, Marin and colleagues25 described V. cholerae that were isolated from cases of acute watery diarrhoea outbreaks in Nigeria from 2009 to 2010. They reported that these toxigenic V. cholerae isolates were mostly of O1 serotype, and that atypical El Tor strains with the integrative conjugative element (ICE) of the sulfamethoxazole and trimethoprim (SXT) element, gyrA, cholera toxin (CTX) phage and cytidine triphosphate (CTP) synthetase clusters showed reduced susceptibility to ciprofloxacin and chloramphenicol.
Cholera outbreaks have been ongoing within sub-Saharan African countries for the past four decades. Unfortunately, the specific strains responsible and their antibiotic resistance patterns are not well studied and elucidated.36 This consequently impacts negatively on the control programmes for cholera across the continent.
An increasing trend of resistance to cotrimoxazole was observed from many studies. Kacou-N’douba11 and Smith et al.12 documented resistance to chloramphenicol and cotrimoxazole from their studies in Cote d’Ivoire, Democratic Republic of the Congo, Guinea Bissau, Mozambique and Namibia.11,12 This is worrisome, because, until now, cotrimoxazole was considered the drug of choice against V. cholerae.
The finding of transferable resistance to almost all of the antibiotics commonly used to treat cholera was documented from many studies. Some of this was documented by Ceccarelli,1 Kaas,2 Dalsgaard4 and Ismail.31 This is of great public health concern and a cause of alarm for the continent.
The most appropriate pictorial representation for meta-analytic data is the forest plot. However, we could not construct one because the studies we included did not provide the component data that is essential for a forest plot.
Antimicrobial resistance exists among V. cholerae isolates from sub-Saharan Africa and includes the most feared fluoroquinolone resistance variety as well as resistance to the cell wall active agents and antimetabolites. The volume of research from countries in sub-Saharan Africa on antimicrobial resistance trends in V. cholerae needs to be expanded and better explored. Guidelines on antimicrobial chemotherapy and standardisation of antimicrobial susceptibility testing need to be strictly adhered to.
We thank the Nigeria Antimicrobial Resistance Technical group for review of an earlier version of this manuscript and we are grateful to Nigeria Centre for Disease Control for commissioning and supporting the research.
The study was supported by the Nigeria Centre for Disease Control, Abuja. The authors carried out the assignment as part of their routine work. I.N.O is a UK Medical Research Council and Department for International Development-supported African research leader.
Y.M. was the project leader, A.O.A., I.N.O. and A.T.O. were responsible for experimental and project design. Y.M. performed most of the experiments. A.O.A., I.N.O. and A.T.O. made conceptual contributions and performed some of the experiments. A.O.A., I.N.O and A.T.O. prepared the samples and calculations were performed by Y.M.
Dalsgaard A, Forslund A, Petersen A, et al. Class 1 Integron-borne, multiple-antibiotic resistance encoded by a 150-kilobase conjugative plasmid in epidemic Vibrio cholerae O1 strains isolated in Guinea-Bissau. J Clin Microbiol. 2000;38:3774–3777.
Urassa WK, Mhando YB, Mhalu FS, Mgonja SJ. Antimicrobial susceptibility pattern of Vibrio Cholerae 01 strains during two cholera outbreaks in Dar Es Salaam, Tanzania. East Afr Med J. 2000;77(7):350–353.

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