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Molecular epidemiology of Methicillin-resistant Staphylococcus aureus in Africa: a systematic review

Molecular epidemiology of Methicillin-resistant Staphylococcus aureus in Africa: a systematic review REVIEW published: 30 April 2015 doi: 10.3389/fmicb.2015.00348 Molecular epidemiology of Methicillin-resistant Staphylococcus aureus in Africa: a systematic review 1 2 1, 3, 4 1, 3 Shima M. Abdulgader , Adebayo O. Shittu ,Mark P. Nicol and Mamadou Kaba * Division of Medical Microbiology, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of 2 3 Cape Town, Cape Town, South Africa, Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa, National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious global problem, with considerable impact on patients and substantial health care costs. This systematic review provides an overview on the clonal diversity of MRSA, as well as the prevalence of Panton-Valentine leukocidin (PVL)-positive MRSA in Africa. A search on Edited by: the molecular characterization of MRSA in Africa was conducted by two authors using Miklos Fuzi, predefined terms. We screened for articles published in English and French through to Semmelweis University, Hungary October 2014 from five electronic databases. A total of 57 eligible studies were identified. Reviewed by: Iruka N. Okeke, Thirty-four reports from 15 countries provided adequate genotyping data. CC5 is the Haverford College, USA; predominant clonal complex in the healthcare setting in Africa. The hospital-associated University of Ibadan, Nigeria Dmitri Debabov, MRSA ST239/ST241-III [3A] was identified in nine African countries. This clone was also NovaBay Pharmaceuticals, USA described with SCCmec type IV [2B] in Algeria and Nigeria, and type V [5C] in Niger. *Correspondence: In Africa, the European ST80-IV [2B] clone was limited to Algeria, Egypt and Tunisia. Mamadou Kaba, The clonal types ST22-IV [2B], ST36-II [2A], and ST612-IV [2B] were only reported in Division of Medical Microbiology, Department of Clinical Laboratory South Africa. No clear distinctions were observed between MRSA responsible for hospital Sciences, Faculty of Health Sciences, and community infections. The community clones ST8-IV [2B] and ST88-IV [2B] were University of Cape Town, Anzio Road, Observatory, 7925, reported both in the hospital and community settings in Angola, Cameroon, Gabon, Cape Town, South Africa Ghana, Madagascar, Nigeria, and São Tomé and Príncipe. The proportion of PVL-positive mamadou.kaba@hotmail.com MRSA carriage and/or infections ranged from 0.3 to 100% in humans. A number of Specialty section: pandemic clones were identified in Africa. Moreover, some MRSA clones are limited This article was submitted to to specific countries or regions. We strongly advocate for more surveillance studies on Antimicrobials, Resistance and MRSA in Africa. Chemotherapy, a section of the journal Keywords: Staphylococcus aureus, MRSA, molecular epidemiology, Africa, systematic review Frontiers in Microbiology Received: 28 February 2015 Accepted: 08 April 2015 Introduction Published: 30 April 2015 Citation: Methicillin-resistant Staphylococcus aureus (MRSA) is a major public health concern and is respon- Abdulgader SM, Shittu AO, Nicol MP sible for both hospital- and community-associated infections worldwide (De Kraker et al., 2011; and Kaba M (2015) Molecular CDC, 2013; Falagas et al., 2013; Garza-González and Dowzicky, 2013; Lee et al., 2013; Chen and epidemiology of Methicillin-resistant Huang, 2014). It is estimated that MRSA infections within the health care setting alone affected Staphylococcus aureus in Africa: a more than 150,000 patients annually in the European Union, with an additional cost of 380 million systematic review. Euros (Köck et al., 2010). In the United States of America, 80,461 invasive MRSA infections and Front. Microbiol. 6:348. doi: 10.3389/fmicb.2015.00348 11,285 related deaths occurred in 2011, and an estimated annual burden of between $1.4 billion and Frontiers in Microbiology | www.frontiersin.org 1 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa 13.8 billion was attributed to community-acquired MRSA (CDC, et al., 2013; Lim et al., 2013; Nimmo et al., 2013) but information 2013; Lee et al., 2013). Besides, MRSA has been established on this trend is lacking in Africa. The occurrence and changes as a pathogen for domestic animals and linked with livestock- in clonal identities, and their geographic spread is important to associated infections (Verkade and Kluytmans, 2013). understand the spread and evolution of MRSA. Methicillin resistance is usually due to the mecA gene, borne The Panton-Valentine Leukocidin (PVL) is a two-component on the staphylococcal cassette chromosome mec (SCCmec)that pore-forming toxin with cytolytic activity on defined cells of codes for a 78-kDa penicillin binding protein (PBP2a), with the immune system (neutrophils, macrophages and monocytes) decreased affinity to methicillin and all beta-lactam antibiotics (Löffler et al., 2010; Yoong and Torres, 2013). It is encoded (Chambers, 1997). To date, eleven SCCmec types have been iden- by the lukS-PV and lukF-PV genes (Boakes et al., 2011), and tified (IWG-SCC, 2009). Some cassettes, for example, SCCmec PVL-producing S. aureus exhibit a propensity for causing mainly II (53 kb) and SCCmec III (67 kb), are large and possess mobile severe and often recurrent skin and soft tissue infections (Shall- genetic elements (MGE), such as integrated plasmids (pUB110, cross et al., 2013). In addition, PVL-positive MRSA are associated pI258, and pT181) and transposons (e.g., Tn554) (Ito et al., 2001), with community onset-pneumonia (Vandenesch et al., 2003). and are frequently associated with hospital-acquired MRSA (Ma Although the PVL genes are mainly carried by community- et al., 2002; Ito et al., 2004). In contrast, SCCmec IV (21–24 kb) associated MRSA (CA-MRSA) (Vandenesch et al., 2003), data and V (27 kb) are shorter elements, generally susceptible to from West and Central Africa showed that at least 40% of clinical non-beta-lactam antibiotics, and linked with community MRSA methicillin-susceptible S. aureus (MSSA) isolates in this region (Chambers and Deleo, 2010). However, the spread of various are PVL-positive (Breurec et al., 2011a; Schaumburg et al., 2011; MRSA clones between the hospital and community settings has Shittu et al., 2011; Egyir et al., 2014a). Therefore, the acquisi- made the dichotomous ranking difficult (Deurenberg and Sto- tion of the mecA gene by PVL-positive MSSA and the possible bberingh, 2008). Recently, a variant mecA gene (named mecC) dissemination of PVL-positive CA-MRSA could present a signif- which is situated on an SCCmec XI element has been described icant challenge in disease management and infection control in (Shore et al., 2011). It has a higher relative affinity for oxacillin as resource-limited countries in Africa. compared with cefoxitin (Kim et al., 2012), and exhibits only 69% This systematic review examined published literature on the sequence similarity at the nucleotide level and 63% amino-acid molecular epidemiology of MRSA in Africa. By summarizing identity to mecA/PBP2a (Paterson et al., 2014b). Furthermore, currently available data on the continent, our objective was to describe the distribution of MRSA clones, the prevalence of PVL- based on whole genome sequencing, mutations of the endoge- nous penicillin-binding proteins (PBP) 1, 2, and 3 in mecA and positive MRSA, and to highlight the need to develop more com- mecC negative strains have been postulated as a possible alter- prehensive surveillance and reporting systems for multidrug- native mechanism for beta-lactam resistance in MRSA (Ba et al., resistant organisms such as MRSA in Africa. 2014). There is great interest in tracking, identifying and understand- Methods ing the diversity of MRSA in various settings. Currently, the most widely used molecular techniques include Staphylococcus pro- This systematic review was conducted in accordance with tein A gene typing (spa) and multilocus sequence typing (MLST). the preferred reporting items for systematic reviews and Studies (particularly using MLST) have provided evidence that a meta-analyses (PRISMA) guidelines (Moher et al., 2009). small set of lineages, clonal complex (CC)5, CC8, CC22, CC30, and CC45, are associated with most of the MRSA infections in Literature Search Strategy hospitals (Stefani et al., 2012). Besides, a number of different geo- The relevant English and French articles available in five elec- graphically distinct lineages, CC1, CC8, CC30, and CC80, have tronic databases (MEDLINE, EBSCOhost, ISI Web of knowl- also been associated with community MRSA infections (Chatter- edge, Scopus, and African Journals Online) were retrieved by two jee and Otto, 2013), while CC8 and CC30 have been identified authors using predefined search terms (Table S1). The literature as pandemic lineages both in the hospital and community setting search was conducted until 31 October 2014. (Chatterjee and Otto, 2013). Furthermore, regional clones have been described in Australia (sequence type [ST] 93) (Coombs et al., 2009), India (ST772) (D’Souza et al., 2010; Shambat et al., Eligible Article Identification 2012), South Korea (ST72) (Kim et al., 2007), Taiwan and China Figure 1 summarizes the study selection process. All duplicate (ST59) (Chen and Huang, 2014). articles were removed and data on MSSA as well as in-vitro stud- The distribution of MRSA clones in Africa is not well- ies were also excluded. The eligibility of published reports in described. Understanding the molecular epidemiology of MRSA this review was based primarily on polymerase chain reaction in Africa is important as a recent review indicated that since (PCR) detection of the mecA gene, and the use of at least one the year 2000, the prevalence of MRSA appears to be increas- molecular tool for genotyping of MRSA strains (Table 1). In addi- ing in many African countries and pose a visible threat to the tion, worldwide surveys that covered African countries were also continent (Falagas et al., 2013). Furthermore, there is evidence included. An MRSA clone was defined based on the combina- of the replacement of existing MRSA clones with different and tion of MLST sequence type (ST) and SCCmec typing data as new clonal types in a number of countries (Conceição et al., previously reported (Okuma et al., 2002). The nomenclature of 2007; Aires-de-Sousa et al., 2008; Albrecht et al., 2011; Espadinha the SCCmec types was as proposed by the International Working Frontiers in Microbiology | www.frontiersin.org 2 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa FIGURE 1 | Preferred reporting item for systematic reviews. CONS, coagulase negative staphylococci; MSSA, methicillin susceptible S. aureus; MRSA, methicillin resistant S. aureus. Group on the Classification of Staphylococcal Cassette Chromo- Results some Elements (IWG-SCC, 2009). SCCmec elements that could Literature Search not be classified were indicated as non-typeable (SCCmec-NT). The systematic search of the five electronic databases yielded In this study, we categorized MRSA into various CCs according 1775 articles (Figure 1). No additional studies were identified to the current eBURST scheme, Version 3 (accessed 30 October from AJOL. After the removal of duplicate studies and assess- 2014) (eBURST, www.mlst.net, V3) . ment of titles and abstracts, 110 full-text articles were screened, of which 57 studies were considered eligible for the qualitative Data Extraction and Synthesis The relevant data were extracted from each of the articles as analysis according to our inclusion criteria. stated in Table 1. Separate articles that analyzed the same S. Characteristics of the Studies Included in the aureus isolates but answered different questions were considered Systematic Review as a single study. Most of the data analyzed were obtained from single center stud- ies conducted mainly in five countries; Tunisia (n = 13), Nigeria eBURST Analysis (n = 9), South Africa (n = 7), Algeria (n = 5),and Egypt(n = 3) The relationship between the MRSA STs described in this review (Table 1). Multicenter studies were only reported in two articles and other lineages reported world-wide was analyzed using the (Goering et al., 2008; Breurec et al., 2011b), including a survey eBURST scheme. The allelic profiles were downloaded from which comprised five African countries, Cameroon, Madagas- the MLST website (http://saureus.mlst.net/) which included the car, Morocco, Niger and Senegal (Breurec et al., 2011b), and African MRSA STs as well as 223 representative and randomly an inter-continental multicenter study, which included South selected STs (from each CC) based on the differences in their Africa (Goering et al., 2008). Only three studies investigated the allelic profiles. The minimum spanning tree was constructed by detection of MRSA in animals (Table 1). the goeBURST algorithm using the Phyloviz software v1.1 (http:// In most of the reports included in this study, S. aureus was www.phyloviz.net/). identified by phenotypic and culture characteristics, while molec- eBURST [Online]. Available online at: http://www.mlst.net version 3. ular identification (16S rRNA, detection of the thermonuclease Frontiers in Microbiology | www.frontiersin.org 3 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 4 April 2015 | Volume 6 | Article 348 TABLE 1 | Characteristics of eligible articles that studied Methicillin resistant Staphylococcus aureus. Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence STUDIES CONDUCTED IN HUMANS Algeria 2003–2004 Clinical samples from 614 – 204 HA (40)/  –  –   –– Ramdani- hospitals and community CA (21) bouguessa et al., 2004–2007 Human infections (in- 65 – 23 NR  – –  –  –– Bekkhoucha et al., and-out patients) 2009 2005–2007 From military hospital (Pus, NR – 64 HA (50)/  –– – – –  –  Ouchenane et al., venous catheter, tracheal CA (14) 2011, 2013 aspirates, lumbar puncture fluid, blood culture and urine) α α β 2006–2007 Healthy and hospitalized 221 gyrA PCR 99 23 HA (65)/  –   NR  –  Antri et al., 2011 individuals 52 CA (84) 2010–2011 Children and neonates 129 – 25 HA (15)/  –– –   –– Djoudi et al., 2013 (SSTI, bacteraemia, otitis CA (10) and bone/joint infections) Angola 2012 Nasal swabs from inpatients 117 – 68 NR  –     –  Conceição et al., and HCW 2014 Egypt 2007–2008 Pus, sputum, wounds, NR – 21 CA (4)     NR  –  Enany et al., 2010 abscess, blood, urine, and discharge NR SSTI and nasal swabs 38 – 18 CA (18)  – –– – –  –– Sobhy et al., 2012 NR Septic wounds, UTI and RTI 10 – 7 – –  –  –– – – – El-Jakee et al., (nasal swabs) 2011* Gabon 2008–2010 asymptomatic carriers 217 nuc and 12 HA (6)/  –   –  –  Schaumburg (nares, axillae, inguinal 16S rRNA PCR CA (6) et al., 2011; Ateba swabs) and patients Ngoa et al., 2012 (abscess, wound, blood and others) 2010–2013 swabs from S. aureus 460 – 9 NR  ––  –  –  Schaumburg carrier mothers (nasal and et al., 2014 mammillary) and their infants (Nasal and pharyngeal) NR Blood culture of one patient 1 – 1 NR – – –  –  –  Huson et al., 2014 (Continued) Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 5 April 2015 | Volume 6 | Article 348 TABLE 1 | Continued Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence Ghana 2011–2012 In-patients and hospital staff 105 spa gene PCR 6 NR  ––  –  –– Egyir et al., 2013 2010–2012 SSTI and blood samples 308 – 9 NR  ––  –  –– Egyir et al., 2014a from six hospitals 2011–2012 Nasal swabs from 124 – 2 HA (2)  ––  –  –– Egyir et al., 2014b apparently healthy carriers Kenya 2005–2007 In and out-patients with 84 – 69 NR  –– – – –  –– Maina et al., 2013 SSTI boil, abscess, cellulitis and ulcer 2011 Nasal and axillary skin 85 – 6 NR  ––  –   Aiken et al., 2014 swabs from hospitalized patients Libya 2009–2010 Nasal swabs from in-patient 758 – 70 HA (12) –– – – –  –– Al-haddad et al., children, their mothers, CA (6) 2014 out-patient children and HCW Mali 2005 Asymptomatic nasal carriers 88 – 1 CA (1) – – – –  –– – – Ruimy et al., 2008 Mozambique 2010–2011 Post-operative, burn wound 99 – 9 HA (8), –– –  ––  – Van der Meeren infections, skin and soft CA (1) et al., 2014 tissue abscesses Nigeria 1998–2002 Wounds, aspirate, amniotic 276 – 4 NR  –– –  –– – Adesida et al., fluid 2005 2002–2004 Wound samples, blood 200 – 3NR  –– – –  –– – Shittu and Lin, cultures, urine, otitis media 2006b and ocular related infections 2007–2012 Clinical specimen 150 – 12 NR  – ––  –  –  Okon et al., 2009, 2007 Surgical and pediatric 346 – 70 HA (42),  –   –  –  Ghebremedhin patients wound samples, CA (28) et al., 2009 corneal, conjunctival, auricular, genital and nasal swabs 2008–2010 HIV-positive and healthy 202 – 26 NR –  –  –  –– Olalekan et al., individuals (nasal swabs) 2012 (Continued) Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 6 April 2015 | Volume 6 | Article 348 TABLE 1 | Continued Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence 2009 Wound infections, semen, 68 – 11 NR  ––  –  – Shittu et al., 2011 UTI, chronic ulcer, conjunctivitis, throat infections 2009–2011 Patients and carriers 62 – 22 NR  –– –  –  –– Raji et al., 2013 2010 Clinical samples from 51 tuf gene PCR 15 NR  ––  –  – Shittu et al., 2012 patients with burns, septicaemia, wound infections, osteomyelitis, bronchitis and GIT NR Urine, blood and aspirates, 116 – 48 HA (40),  –– – – –  –  Terry Alli et al., wound, eye and ear, urethral CA (8) 2012 and endocervical swab South Africa 2001–2003 Wound samples, sputum, 227 nuc gene PCR 61 NR  –– –  –  – Shittu and Lin, otitis media and blood 2006a; Shittu culture et al., 2007 2001–2003 Isolates from 16 laboratories 241 – 24 NR  –– –  –– – – Essa et al., 2009 in KZN 2001–2003 Wounds, sputum, otitis NR – 61 NR  – –    –– Shittu et al., 2009 media, urine and blood culture 2005–2006 Bacteraemia, SSTI, urine, NR – 320 HA  – –    –  Moodley et al., catheter tip, cerebrospinal 2010 and drainage fluids 2006–2007 Clinical samples NR – 97 HA (79),  – –  ––  –– Makgotlho et al., CA (4) 2009 2007–2008 Pus and pus swabs, urine, NR – 100 CA (10)  – –    –  Jansen van 2007–2011 blood, RTS and CVCT Rensburg et al., 2011, 2012 2009–2010 A wide range of clinical 367 – 56 NR  –     –– Oosthuysen et al., specimens mostly SSTI 2014 São Tome 2010–2012 Patients and healthy carriers 52 – 14 NR  –     –  Conceição et al., and Príncipe 2013 (Continued) Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 7 April 2015 | Volume 6 | Article 348 TABLE 1 | Continued Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence Tanzania 2008 Wound, nasal swab and pus 160 – 24 HA – – –  –  –– Moremi et al., 2010 Apparently healthy children 114 nuc gene PCR 12 CA – – – – –  –– – Moyo et al., 2014 under 5 years (nasal swabs) Tunisia 1998–2007 Clinical specimens from 72 nuc gene PCR 13 HA (13)  –– – –  – –– Bouchami et al., neutropenic patients 2009 2002 Patients who developed NR – 6 HA (6) – –– – –  – –– Ben Ayed et al., MRSA infections 2010 2003–2004 Pus, blood, pleural fluid, NR – 72 NR  –  – ––  –  Ben Nejma et al., venous catheter 2006 2003–2004 Pathological samples from 147 – 19 NR – –– – –  – –– Ben Saida et al., different wards 2005 2003–2005 Pus and associated with NR – 64 CA (64)  –     –  Ben Nejma et al., cutaneous infections 2013 2004 Cutaneous pus, blood NR – 34 HA (32),  –– – –– – –– Ben Jomaa-Jemili cultures, urine and puncture CA (2) et al., 2006 fluids 2004–2005 Cutaneous pus, RTS, urine, 475 – 57 NR – –  – –– – –– Ben Ayed et al., blood culture, 2006 2004–2008 Samples from hospitals and NR – 69 HA (41),  –   –  –– Ben Jomàa-Jemili community CA (28) et al., 2013 2006–2008 Children with CA invasive 36 – 8 CA (8)  –     –– Kechrid et al., infections bacteraemia and 2011 osteomyelitis 2007 Pus and skin infections NR – 11 CA (11)  –     –– Ben Nejma et al., 2008 Pus and blood culture (case 2– 2 NR  –   –  –  Zribi et al., 2011 report) 2008–2009 Humans in contact with 55 – 1 CA (1)  –   –   Ben Slama et al., animals 2011 (Continued) Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 8 April 2015 | Volume 6 | Article 348 TABLE 1 | Continued Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence Uganda 2009–2010 Swabs from patients, HCW 41 – 41 NR  –– – – –   Kateete et al., and from hospital 2011 environment (sinks, door handles, surgical trays, bed and table surfaces) 2011–2012 SSI 64 nuc gene PCR 24 NR  ––  ––  –– Seni et al., 2013 Multicenter 2007–2008 SSTI, NR – 86 CA (9),  –   –  –  Breurec et al., bacteraemia/septicaemia, HA (77) 2011b urine, wounds osteomyelitis and myositis Multicentre 2004–2005 Uncomplicated skin 292 – 105 HA (3)  –– –   –– Goering et al., infections 2008 STUDIES CONDUCTED IN ANIMALS Egypt NR Cows and buffaloes milk, 9– 5 NR –  –  –– – –– El-Jakee et al., cattle septic wounds 2011* Senegal 2009–2011 Pigs (nasal swabs) 73 – 6 NR  ––  –  –  Fall et al., 2012 Tunisia 2010 Healthy sheep (nasal swabs) 73 – 5 CA (6)  –    ––  Gharsa et al., agr, Accessory gene regulator; CA, Community-acquired methicillin-resistant S. aureus; coa, Coagulase gene; CVCT, Central venous catheter tips; GIT, Genital tract infections; gyrA, DNA gyrase gene; HA, Hospital-acquired methicillin resistant S. aureus; HCW, Health care workers; HIV, Human immunodeficiency virus; KZN, KwaZulu-Natal province; MLST, Multilocus locus sequence typing; MRSA, Methicillin-resistant Staphylococcus aureus; No., Number of isolates; NR, Not reported; nuc, Thermonuclease gene; PCR, Polymerase chain reaction; PFGE, Pulsed-field gel electrophoresis; PVL, Panton-Valentine-Leukocidin genes; SCCmec, Staphylococcal chromosomal cassette mec element; RTI, Respiratory tract infections; rRNA, Ribosomal ribonucleic acid; RTS, Respiratory tract specimens; spa, Staphylococcus aureus protein A gene; SSTI, Skin and soft tissue infections; SSI, Surgical site infections; tuf, Elongation factor tu; UTI, Urinary tract infections. ¶ α β # MRSA as confirmed by mecA PCR; , Test was conducted; −, Test was not conducted; Hospitalized individuals; Nasal carrier study; African multicenter study which included Cameroon, Madagascar, Morocco, Niger and Senegal; An international multicenter study which included only South Africa; *Study was conducted in both animal and human host. Abdulgader et al. A systematic review on MRSA in Africa and the elongation factor tu - nuc, tuf - genes) was performed PVL-positive ST1-V [5C] isolated from patients in a tertiary hos- in only 12.3% (7/57). The screening for antibiotic resistance and pital in Nigeria (Raji et al., 2013), and the PVL-negative ST1 with toxin/virulence genes were carried out in seven and 22 studies, a non-typeable SCCmec element (spa type t035 and agr type III) respectively (Table 1). Furthermore, all the eligible studies ana- identified in Tunisia (Ben Jomàa-Jemili et al., 2013). In addition, lyzed MRSA using at least one genotyping technique, and 59.6% an ST1 related sequence type (ST772-V [5C]), “the Bengal-Bay (34/57) provided adequate genotyping data on MRSA clones clone” has been described in Nigeria (Raji et al., 2013). from 15 African countries (Tables 1, 2). Studies included in this systematic review did not investigate on the mecC gene. MRSA CC5 with Sequence Type 5 This clone was documented in 14 studies and consisted of diverse Community- and Hospital- Acquired MRSA SCCmec elements (Table 2). The ST5-I [1B]/III [3A] were iden- Overall, 51% (29/57) of the eligible studies provided the potential tified from clinical samples in health care institutions in South source (hospital- or community-associated) of the MRSA strains. Africa (Shittu et al., 2009; Moodley et al., 2010; Jansen van Rens- Only 17.5% (10/57) reported MRSA from community settings burg et al., 2011; Oosthuysen et al., 2014). ST5-II [2A] has been (Table 1). USA300 (ST8-IV [2B]) and other related sequence described in Nigeria (Raji et al., 2013), and Senegal (Breurec et al., types were noted both in health care and community settings in 2011b). ST5-IV [2B]-PVL-positive was the dominant clone in nine African countries (Tables 1, 2). The “Brazilian/Hungarian hospitalized patients with skin and soft tissue infections in Dakar, clone” (ST239-III [3A]) was associated with hospital-acquired Senegal (Breurec et al., 2011b). In addition, ST5-IV [2B] was infections in nine countries (Tables 1, 2). Furthermore, the “West detected from nasal samples of pigs in the same geographical area Australia MRSA-2” (ST88-IV [2B]) was reported in community- (Fall et al., 2012). ST5-IV [2B] has also been identified in Alge- and hospital-acquired infections in several African countries ria (Ramdani-bouguessa et al., 2006), Gabon (Schaumburg et al., (Table 2). 2011; Ateba Ngoa et al., 2012), Morocco (Breurec et al., 2011b), and South Africa (Essa et al., 2009), while the SCCmec IVa Detection of Panton-Valentine Leukocidin (PVL) [2B] variant was recovered from hospitalized patients in Alge- Genes ria (Ramdani-bouguessa et al., 2006; Bekkhoucha et al., 2009), The screening for PVL-associated genes (lukF-PV and lukS-PV) Angola (Conceição et al., 2014), and São Tomé and Príncipe was carried out in 44 studies, and the detection of PVL genes (Conceição et al., 2013). Moreover, ST5-IVa [2B] was reported was only reported in 32 studies (Table 1). In animals, PVL- from nasal samples of apparently healthy-hospital workers in positive MRSA (ST5) was described in nasal samples of pigs from Angola (Conceição et al., 2014). Other ST5 and related clones identified are ST5-V [5C] in Angola (Conceição et al., 2014), Senegal (Fall et al., 2012). In humans, the proportion of PVL- positive MRSA carriage and/or infections ranged from 0.3 to Cameroon (Breurec et al., 2011b), and Nigeria (Shittu et al., 2011), ST72-SCCmec-NT in South Africa (Jansen van Rensburg 100%. Studies from Algeria and Tunisia reported higher PVL prevalence while investigations from South Africa reported the et al., 2011), ST72-V [5C] in Angola and Ghana (Egyir et al., lowest prevalence (Table 3). Overall, PVL-positive MRSA were 2013, 2014b; Conceição et al., 2014), and ST105-II [2A] from a more frequently reported with skin and soft tissue infections, and patient in São Tomé and Príncipe (Conceição et al., 2013). Fur- community-associated clones (Tables 1, 2). There was no report thermore, ST650-IV [2B] was detected from clinical samples in on the role of PVL in necrotizing pneumonia caused by MRSA in health care institutions in South Africa (Jansen van Rensburg Africa. et al., 2011). Finally, ST2629-V [5C] was described in Angola (Conceição et al., 2014). MRSA Clones Reported in Africa Using the MRSA CC5 with Sequence Type 8 Current eBURST Scheme MRSA assigned to this clone are widespread and diverse across Figures 2, 3 summarize the MRSA clones identified in Africa Africa as evidenced in 27 studies (Table 2). The first known based on MLST CCs. By the current eBURST scheme, six main early or ancestral clone, ST250-I [1B], was mainly associated CCs were identified: CC5, CC22, CC30, CC45, CC80, and CC88. with hospital-acquired infections in Ibadan, South-West Nige- In addition, a number of diverse spa types were identified among ria (Ghebremedhin et al., 2009), and recently observed in Ghana the MRSA clones in Africa (Table 2), but the distribution of spa (Egyir et al., 2014b). ST8-II [2A] was only described in the types t042 and t044 (associated with CC80-IV [2B]) appear to be limited to three North African (Algeria, Egypt and Tunisia) KwaZulu-Natal region of South Africa (Essa et al., 2009), while a number of investigations reported ST8-IV [2B] in Angola countries (Table 2). (Conceição et al., 2014), Cameroon (Breurec et al., 2011b), Clonal Complex 5 Gabon (Schaumburg et al., 2011; Ateba Ngoa et al., 2012), Ghana (Egyir et al., 2014b), Madagascar (Breurec et al., 2011b), Nige- This clonal complex is considered the largest group based on the eBURST scheme (Figure 3). It was subdivided into three main ria (Adesida et al., 2005; Shittu et al., 2012), São Tomé and Príncipe (Conceição et al., 2013) and South Africa (Essa et al., clusters and designated as CC5-ST1, ST5, and ST8. 2009). The MRSA isolates from Angola possessed the SCCmec MRSA CC5 with Sequence Type 1 type IVd element (Conceição et al., 2014). ST612-IV [2B], a This group was reported in Nigeria (Raji et al., 2013) and Tunisia double locus variant (dlv) of ST8-IV [2B], and only recently (Ben Jomàa-Jemili et al., 2013). The clonal type included the reported as PVL-positive (Oosthuysen et al., 2014), is widespread Frontiers in Microbiology | www.frontiersin.org 9 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa TABLE 2 | Methicillin resistant Staphylococcus aureus clones reported in 34 eligible studies. Country Clonal type ST-SCCmec Clonal complex spa type PVL status agr References Algeria ST80-IV [2B] 80 ND + III Ramdani-bouguessa et al., 2006 ST37-IVa [2B] 30 ND + III ST239-III [3A] 5 ND − I ST239-IVa [2B] 5 ND − I ST241-III [3A] 5 ND − I ST637-III [3A] 5 ND − I ST5-IV, IVa [2B] 5 ND +, − II ST635-IV [2B] 80 ND − III ST636-NT 22 ND − I ST80-IV [2B] 80 t044 + ND Bekkhoucha et al., 2009 ST239-III [3A] 5 t037 − ND ST5-IVa [2B] 5 t311, t450 − ND ST88-NT 88 t188, t267 − ND ST80-IV [2B] 80 t044, t4143 + III Antri et al., 2011 ST241-III [3A] 5 ND − III ST8-V [5C] 5 ND − I ST80-IVc [2B] 80 ND +, − ND Djoudi et al., 2013 ST39-II [2A] 30 ND − ND Angola ST5-IVa [2B] 5 t105, t311, t11657 − II Conceição et al., 2014 ST8-IVd, V [2B] 5 t104, t1774 − I ST72-V [5C] 5 t3092 − I ST88-IVa [2B] 88 t186, t325, t786, − III t1951, t3869 ST5-V [5C] 5 t6065 − II ST2629-V [5C] 5 t6065 − II ST789-V [5C] 7 t091 − II Cameroon ST5-V [5C] 5 t311 + II Breurec et al., 2011b ST88-IV [2B] 88 t186 − III ST8-IV [2B] 5 t024, t121, t451 + I ST1289-V [5C] 88 t1339 + III Egypt ST80-IVc [2B] 80 t042, t044, t070, t983 + III Enany et al., 2010 ST30-IVa [2B] 30 t251, t318 + III ST1010-X 121 t159, t312 + IV Gabon ST8-IV [2B] 5 t121 + I Schaumburg et al., 2011; Ateba Ngoa et al., 2012 ST88-IV [2B] 88 t186 − III ST5-IV [2B] 5 t653 − II ST5-IV [2B] 5 t653 − ND Schaumburg et al., 2014 ST8-NT 5 t112, t121 + ND ST45-V [5C] 45 t437, t8860 − ND ST88-IV [2B] 88 t4195 − ND Ghana ST72-V [5C] 5 t537 − ND Egyir et al., 2013 ST8-V [5C] 5 t064 − ND ST88-IV [2B] 88 t325, t1951, t2649 − ND ST72-V [5C] 5 t537 − ND Egyir et al., 2014b ST8-IV [2B] 5 t121 + ND ST239-III [3A] 5 t037 − ND ST250-I [1B] 5 t928 − ND ST2021-V [5C] 5 t024 − ND (Continued) Frontiers in Microbiology | www.frontiersin.org 10 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa TABLE 2 | Continued Country Clonal type ST-SCCmec Clonal complex spa type PVL status agr References ST88-IV [2B] 88 t186 − ND ST789-IV [2B] 7 t547 + ND ST508-V [5C] 45 t5132 − ND Egyir et al., 2014a Kenya ST239-III [3A] 5 t037 − ND Aiken et al., 2014 Madagascar ST8-IV [2B] 5 t121 + I Breurec et al., 2011b ST30-V [5C] 30 t4686 − III ST88-IV [2B] 88 t186 − III Morocco ST239, ST241-III [3A] 5 t037, t138 − I ST5-IV [2B] 5 t311 + II Niger ST239, ST241-III [3A] 5 t138 − I ST239, ST241-V [5C] 5 t037 − I ST88-IV [2B] 88 t186 − III Nigeria ST8-IV [2B] 5 ND − ND Adesida et al., 2005 ST88-IV [2B] 88 t186 + III Ghebremedhin et al., 2009 ST241-IV [2B] 5 t037 − I ST250-I [1B] 5 t194, t292 − I ST241-III [3A] 5 t037 − ND Shittu et al., 2011 ST8-V [5C] 5 t064 − ND ST8-V [5C] 5 t451 − ND ST94-IV [2B] 5 t008 − ND ST5-V [5C] 5 t002 − ND ST241-III [3A] 5 t037 − ND Shittu et al., 2012 ST88-IV [2B] 88 t729, t1603 − ND ST37-III [3A] 30 t074 − ND ST39-II [2A] 30 t007 − ND ST8-V [5C],IV [2B], ST8-NT 5 t064 − ND ST152-NT 152 t4690 + ND ST1-V [5C] 5 ND + ND Raji et al., 2013 ST239-III[3A] 5ND − ND mercury ST5-II [2A] 5 ND − ND ST8-V [5C] 5 ND − ND ST247-I [1B] 5 ND − ND ST772-V [5C] 5 ND + ND ST88-IV [2B] 88 ND − ND ST241-III [3A] 5 ND − ND Okon et al., 2009 Senegal ST5-IV [2B]* 5 t311 + ND Fall et al., 2012 ST88-IV [2B]* 88 t3489 − ND ST239, ST241-III [3A] 5 t037, t138 − I Breurec et al., 2011b ST5-II [2A] 5 t311 + II ST5-IV [2B] 5 t311 + II ST88-IV [2B] 88 t168 − III South Africa ST5-IV [2B] 5 ND ND ND Essa et al., 2009 ST8-IV [2B] 5 ND ND ND ST8-II [2A] 5 ND ND ND (Continued) Frontiers in Microbiology | www.frontiersin.org 11 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa TABLE 2 | Continued Country Clonal type ST-SCCmec Clonal complex spa type PVL status agr References ST239-III [3A] 5 ND ND ND ST45-IV [2B] 45 ND ND ND ST612-IV [2B] 5 ND − ND Goering et al., 2008 ST36-II [2A] 30 ND − ND ST1173-IV [2B] 5 t064 − ND Shittu et al., 2009 ST1338-IV [2B] 5 t064 − ND ST239-III [3A] 5 t037 − ND ST5-III [3A] 5 t045 − ND ST239-III [3A] 5 t037 − ND Moodley et al., 2010 ST612-IV [2B] 5 t064 − ND ST5-I [1B] 5 t045 − ND ST22-IV [2B] 22 t032 − ND ST22-IV [2B] 22 t891 + ND ST36-II [2A] 30 t012 − ND ST239-III [3A] 5 t037 − ND Jansen van Rensburg et al., 2011 ST5-I [1B] 5 t045 ND ND ST650-IV [2B] 5 t002 ND ND ST612-IV [2B] 5 t064, t1443, t2196 ND ND ST72-NT 5 t3092 ND ND ST22-IV [2B] 22 t032 ND ND ST36-II [2A] 30 t012, t021 ND ND ST5-I [1B] 5 t002 − II Oosthuysen et al., 2014 ST8-V [5C] 5 t064 − I ST612-IV [2B] 5 t064 + I ST239-III [3A] 5 t021 − I ST22-V [5C] 22 t891 + I ST22-IV [2B] 22 t891 − I ST36-II [2A] 30 t021 − III São Tome ST5-IVa [2B] 5 t105 − II Conceição et al., 2013 and Príncipe ST105-II [2A] 5 t002 − II ST8-V [5C] 5 t451 − I ST8-IV [2B] 5 t451 − I ST88-IVa [2B] 88 t186, t786 − III Tunisia ST80-IV [2B] 80 t044 + III Ben Nejma et al., 2009 ST80-IV [2B] 80 t044 + III Ben Nejma et al., 2013 ST728-IVc [2B] 80 t042, t044 + III Kechrid et al., 2011 ST8-IVc [2B] 5 t062 + II ST80-IVc [2B] 80 t203 + III Ben Slama et al., 2011 ST1-NT 5 t035 − III Ben Jomàa-Jemili et al., 2013 ST247-I [1B] 5 t040 − I ST239-III [3A] 5 t003 − I ST241-III [3A] 5 t125 − I ST97-NT 5 t003 − I ST1819-I [1B] 5 NS − I ST80-IVc [2B] 80 t070 + III ST2563-IVc [2B] 80 t070 + III (Continued) Frontiers in Microbiology | www.frontiersin.org 12 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa TABLE 2 | Continued Country Clonal type ST-SCCmec Clonal complex spa type PVL status agr References ST1440-IVc [2B] 80 t070 + III ST80-IVc [2B] 80 t1021 − II ST80-IVc [2B] 80 ND − III ST22-NT 22 t998 − II ST45-NT 45 ND − I ST153-NT 80 NST + III ST153-NT 80 t044 ND III Gharsa et al., 2012 agr, Accessory gene regulator; CC, Clonal complex; NT, Non typeable; ND, Not determined; NST, New spa type; PVL, Panton-Valentine Leukocidin genes; SCCmec, Staphylococcal chromosomal cassette mec element; ST, Sequence type; spa, Staphylococcus aureus protein A gene; X , Unknown SCCmec type other than I, II, III, IV or V; *Clones isolated from pigs; +, PVL positive; −, PVL negative. TABLE 3 | Panton-Valentine Leukocidin prevalence as reported by the eligible studies with sample size of 30 or above. Country PVL positive (no. Prevalence References positive/total tested) (%) Algeria 46/61 75 Ramdani-bouguessa et al., 19/64 30 Ouchenane et al., 2011 94/122 77 Antri et al., 2011 Kenya 14/69 20 Maina et al., 2013 Libya 10/35 29 Al-haddad et al., 2014 Nigeria 33/70 47 Ghebremedhin et al., 2009 South Africa 1/320 0.3 Moodley et al., 2010 4/97 4 Makgotlho et al., 2009 5/56 9 Oosthuysen et al., 2014 Tunisia 68/72 94 Ben Nejma et al., 2006 64/64 100 Ben Nejma et al., 2013 43/69 62 Ben Jomàa-Jemili et al., Uganda 30/41 73 Kateete et al., 2011 Multicenter* 20/86 23 Breurec et al., 2011b *Multicenter study which included Cameroon, Madagascar, Morocco, Niger and Senegal. FIGURE 2 | MRSA clones reported in Africa. Each clonal complex is PVL, Panton-Valentine Leukocidin; no., Number. annotated with a colored circle. The number of studies conducted in each country is also indicated. across South Africa (Goering et al., 2008; Moodley et al., 2010; Jansen van Rensburg et al., 2011; Oosthuysen et al., 2014), alongside other variants such as ST1173/ST1338-IV [2B] (Shittu et al., 2011), Angola (Conceição et al., 2014), Ghana (Egyir et al., et al., 2009). The ST8-IV [2B] clone in South Africa was iden- 2013), Nigeria (Shittu et al., 2011, 2012; Raji et al., 2013), São tified from a variety of clinical infections, in particular, bacter- Tomé and Príncipe (Conceição et al., 2013), and South Africa aemia, skin and soft tissue and wound infections (Shittu et al., (Oosthuysen et al., 2014). Other STs observed within the CC5- 2009; Moodley et al., 2010; Jansen van Rensburg et al., 2011; ST8 cluster include ST8-SCCmec-NT in Gabon (Schaumburg Oosthuysen et al., 2014). An ST8-IVc [2B] strain (PVL-positive; et al., 2014) and Nigeria (Shittu et al., 2012), ST94-IV [2B] spa type t062) was identified from a 4 day old male child with described in Nigeria (Shittu et al., 2011) and ST97-SCCmec-NT community-acquired invasive infection in Tunisia (Kechrid et al., in Tunisia (Ben Jomàa-Jemili et al., 2013). In addition, ST247-I 2011). Furthermore, ST8-V [5C] was described in Algeria (Antri [1B] was reported only in Tunisia (Ben Jomàa-Jemili et al., 2013) Frontiers in Microbiology | www.frontiersin.org 13 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa FIGURE 3 | The minimum spanning tree was constructed by the randomly selected STs (from each CC) based on the differences in goeBURST algorithm using the Phyloviz software v1.1 their allelic profiles. The Group founder is colored in green and the (http://www.phyloviz.net/). The allelic profiles were downloaded from related STs are in blue. The six main CCs described in this review the MLST website (http://saureus.mlst.net/) which included the MRSA are indicated by the dotted lines and the STs reported in Africa are sequence types (STs) described in this review as well as 223 indicated by the red color. and Nigeria (Raji et al., 2013), ST637-III [3A] in Algeria SCCmec variants, ST239-IVa [2B], ST239/ST241-V [5C], and (Ramdani-bouguessa et al., 2006), ST1819-I [1B] in Tunisia ST241-IV [2B], and associated with hospital-acquired infec- (Ben Jomàa-Jemili et al., 2013), and ST2021-V [5C] in Ghana tions were reported in Algeria (Ramdani-bouguessa et al., 2006), (Egyir et al., 2014b). Niger (Breurec et al., 2011b), and Nigeria (Ghebremedhin et al., The “Brazilian/Hungarian clone” (ST239-III [3A]) is an 2009). hybrid of CC30 and CC8 based on a single large chromoso- mal replacement (Robinson and Enright, 2004), and ST241-III Clonal Complex 22 [3A] is a single locus variant (slv) of ST239-III [3A]. These two In Africa, ST22 was identified only in Algeria (Ramdani- STs were identified concurrently in Algeria (Ramdani-bouguessa bouguessa et al., 2006), South Africa (Moodley et al., 2010; et al., 2006), Morocco, Niger and Senegal (Breurec et al., 2011b), Jansen van Rensburg et al., 2011; Oosthuysen et al., 2014), and and Tunisia (Ben Jomàa-Jemili et al., 2013). ST239-III [3A] has Tunisia (Ben Jomàa-Jemili et al., 2013). ST22-IV [2B] was related also been described in Ghana (Egyir et al., 2014b) and Kenya with hospital-associated infections in the Western Cape and (Aiken et al., 2014), and consistently since 2001 in South Africa KwaZulu-Natal provinces of South Africa. A variant of ST22 (Essa et al., 2009; Shittu et al., 2009; Moodley et al., 2010; Jansen (ST22-V [5C]-PVL-positive) was also reported in an hospital in van Rensburg et al., 2011; Oosthuysen et al., 2014). A recent study Western Cape, South Africa (Oosthuysen et al., 2014). The ST22 detected ST239 with the SCCmec type III [3A] in a ter- identified in Tunisia possessed a non-typeable SCCmec element mercury tiary health care facility in South-West Nigeria (Raji et al., 2013). (Ben Jomàa-Jemili et al., 2013). Besides, an ST636-SCCmec-NT ST241-III [3A] is the dominant clone in North-East Nigeria isolate has also been reported in Algeria (Ramdani-bouguessa (Okon et al., 2009; Shittu et al., 2011, 2012). Interestingly, three et al., 2006). Frontiers in Microbiology | www.frontiersin.org 14 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa Clonal Complex 30 2013) and Senegal (Breurec et al., 2011b). The MRSA isolates ST30-IVa [2B]-PVL-positive, also known as “South-West Pacific from Angola possessed an SCCmec IVa [2B] element (Conceição clone,” has been reported in Egypt (Enany et al., 2010), and et al., 2014). PVL-positive ST88-IV [2B] were detected in Nigeria a multicenter African study identified ST30-V [5C] only in (Ghebremedhin et al., 2009), andanSCCmec subtype ST88-IVa [2B] was identified among three health care workers and a patient Antananarivo, Madagascar (Breurec et al., 2011b). The hospital associated ST36-II [2A] (UK-EMRSA-16), was described only in in São Tomé and Príncipe (Conceição et al., 2013). The ST88-IV South Africa (Goering et al., 2008; Moodley et al., 2010; Jansen [2B] with spa type t3489 was also recovered from nasal samples van Rensburg et al., 2011; Oosthuysen et al., 2014), while ST39- of swine in Senegal (Fall et al., 2012). In addition, an SCCmec II [2A] a dlv was identified in an hospital in Algiers, Algeria non-typeable ST88 was described from an out-patient in Algeria (Djoudi et al., 2013), and Ile-Ife, South-West Nigeria (Shittu (Bekkhoucha et al., 2009), and a strain related to WA-MRSA-2 et al., 2012). MRSA assigned with these groups (ST36-II [2A] and (ST1289-IV [2B]) was identified in Yaoundé, Cameroon (Breurec ST39-II [2A]) were PVL-negative. Furthermore, two SCCmec et al., 2011b). variants, ST37-IVa [2B] and ST37-III [3A], were reported in Other Clonal Complexes Algeria (Ramdani-bouguessa et al., 2006) and Nigeria (Shittu CC7, CC121, and CC152 have been reported in Africa. The PVL- et al., 2012), respectively. negative ST789 (assigned with CC7) was identified in Angola (with SCCmec IV [2B]) (Conceição et al., 2014). However, in Clonal Complex 45 Ghana, ST789 was PVL-positive and carried an SCCmec IV ST45-IV [2B], the “Berlin clone,” was detected in an hospi- element [2B] (Egyir et al., 2014b). An ST1010-PVL-positive tal in the KwaZulu-Natal (South Africa) during a multicen- (CC121) with non-typeable SCCmec element has only been ter surveillance study (Essa et al., 2009) and ST45-V [5C] was described in Egypt (Enany et al., 2010). Furthermore, PVL- reported in mother-infant pairs in Gabon (Schaumburg et al., positive MRSA assigned to CC152 (ST152-SCCmec-NT) was 2014). An MRSA with a non-typeable SCCmec associated with reported in Nigeria (Shittu et al., 2012). community-acquired infections has been identified in Tunisia (Ben Jomàa-Jemili et al., 2013). Finally, ST508-V [5C], a slv to ST45, and also associated with community-acquired infections Discussion was described in Ghana (Egyir et al., 2014a). MRSA has been reported in Africa, at least since 1978 (Scragg Clonal Complex 80 et al., 1978). This systematic review showed that adequate data on The CC80 was limited to three North African countries: Alge- the molecular epidemiology of MRSA are limited, with reports ria, Egypt, and Tunisia (Table 2). The European clone, ST80-IV from only 15 of the 54 African countries. No spa type was [2B]-PVL-positive, was first described in Algeria from both hos- dominant, however, t042 and t044 were the major spa types pitalized and outpatients (Ramdani-bouguessa et al., 2006), and identified in three North African countries (Table 2). Moreover, has continued to be the leading clone in the country (Ramdani- we did not observe a clear distinction between hospital- and bouguessa et al., 2006; Bekkhoucha et al., 2009; Antri et al., community-associated MRSA clones in Africa which is in agree- 2011; Djoudi et al., 2013). ST80-IVc [2B] has been identified ment with other investigations worldwide (Fossum Moen et al., in Egypt (Enany et al., 2010), and Tunisia (Ben Slama et al., 2013; Pasquale et al., 2013; Sherwood et al., 2013; Tavares et al., 2011; Ben Jomàa-Jemili et al., 2013). In addition, sequence types 2013). In this systematic review, the use of the current eBURST related to ST80 have been recovered from human clinical sam- scheme grouped several African MRSA CCs (CC1, CC5, CC8, ples (ST153-SCCmec-NT, ST728-IVc [2B], ST1440-IVc [2B], and and CC7) into a single cluster, (CC5). This raises some con- ST2563-IVc [2B]) (Kechrid et al., 2011; Ben Jomàa-Jemili et al., cern on a suitable method for discrimination and grouping of S. 2013), and nasal specimen of healthy sheep (ST153-SCCmec-NT) aureus isolates. To overcome the above mentioned issue, whole (Gharsa et al., 2012) in Tunisia. The afore-mentioned sequence genome sequencing approach might be the alternative (Dabul types, ST728, ST1440 and ST2563 belonged to accessory gene and Camargo, 2014). regulator (agr) type III and were PVL-positive. Moreover, a Although a combination of factors could be responsible for PVL-negative ST80-IVc [2B] with agr type II has also been the dissemination of clones between continents, increased move- detected in Tunisia (Ben Jomàa-Jemili et al., 2013), and a PVL- ment of human population within or between countries might negative ST635-IV [2B] in Algeria (Ramdani-bouguessa et al., be one of the potential factors (Rogers et al., 2011). International 2006). travel could play a significant role in the transmission of MRSA, particularly the replacement of existing MRSA with fitter and Clonal Complex 88 more transmissible clones (Zhou et al., 2014). We observed that The “West Australia MRSA-2 clone” (WA-MRSA-2), ST88-IV the predominant hospital-associated epidemic clones, EMRSA- [2B], was reported in both hospital and community settings 15 [ST22-IV [2B]) and (EMRSA-16 [ST36-II [2A]), in the United in eight African countries; Angola (Conceição et al., 2014), Kingdom (UK) (Johnson et al., 2005) were reported only in South Cameroon (Breurec et al., 2011b), Gabon (Schaumburg et al., Africa (Goering et al., 2008; Moodley et al., 2010; Jansen van 2011; Ateba Ngoa et al., 2012), Ghana (Egyir et al., 2013, 2014b), Rensburg et al., 2011; Oosthuysen et al., 2014). Moreover, ST80- Madagascar (Breurec et al., 2011b), Niger (Breurec et al., 2011b), IV [2B] (the European clone) has consistently been recognized Nigeria (Ghebremedhin et al., 2009; Shittu et al., 2012; Raji et al., as the predominant PVL-positive MRSA clone in North Africa Frontiers in Microbiology | www.frontiersin.org 15 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa (Ramdani-bouguessa et al., 2006; Bekkhoucha et al., 2009; Ben either rare or limited to people with direct contact with MRSA Nejma et al., 2009, 2013; Enany et al., 2010; Antri et al., 2011; infected/carrier animals (Verkade and Kluytmans, 2013). Using Ben Slama et al., 2011; Ben Jomàa-Jemili et al., 2013; Djoudi whole genome sequencing, evidence of zoonotic transmission et al., 2013). A recent report based on whole genome analy- of MRSA harboring mecC was reported in Denmark (Harri- sis provided strong evidence that the European ST80-IV [2B] son et al., 2013). The mecC-positive MRSA, initially known as was derived from a PVL-positive MSSA ancestor in sub-Saharan a livestock MRSA belonging to the CC130, is recognized in Africa that acquired the SCCmec IV element, and clonal spread both animals and humans in Europe (Paterson et al., 2014a). In was enhanced by increased transnational movement (Stegger addition, this clone has been implicated in severe infections in et al, 2014). However, the factors responsible for the limited humans (Paterson et al., 2014b), resulting in one death (García- spread of the ST80-IV [2B] only in North Africa observed so far Garrote et al., 2014). The clinical importance of mecC-positive are unclear. MRSA is not yet clear in Africa as data is unavailable. Therefore, The SCCmec IV (and its subtypes) and SCCmec V were iden- we suggest that surveillance for MRSA should include detec- tified in several MRSA clones, and ST5 and ST8 clearly showed tion of the mecC gene where mecA is not detected in resistant more diversity in terms of SCCmec types compared with other isolates. STs in Africa. The success of these SCCmec types (IV and V) This systematic review did not seek to provide comprehen- could be due to their small sizes and low fitness costs (Enright sive information on the burden of PVL-positive MRSA in Africa. et al., 2002; Okuma et al., 2002; Monecke et al., 2011). It is However, it provided some interesting observations on their epi- also noteworthy that the SCCmec types IVa and IVc were iden- demiology in Africa such as the identification of PVL-positive tified in genetically unrelated clones, e.g., ST5-IVa [2B] (CC5) isolates assigned with CC7 (originally classified with CC152) in Algeria (Ramdani-bouguessa et al., 2006; Bekkhoucha et al., in Ghana (Egyir et al., 2014a), CC88-IV [2B] in Cameroon 2009), São Tomé and Príncipe (Conceição et al., 2013), ST8- (Breurec et al., 2011b) and Nigeria (Ghebremedhin et al., 2009), IVc [2B] in Tunisia (CC5) (Kechrid et al., 2011), and ST37-IVa ST612-IV [2B] in South Africa (Oosthuysen et al., 2014), and [2B] (CC30) in Algeria (Ramdani-bouguessa et al., 2006). This CC152 in Nigeria (Shittu et al., 2012). Until now, CC152 was might suggest horizontal gene transfer or independent acquisi- only described in the Balkan region (Francois et al., 2008). tion (Mašlaòová et al., 2013). Another interesting observation The mode of acquisition of the mecA gene by ST152 is still was the detection of the SCCmec type IVa and V in the hospital- unknown, but it might be explained by either its introduction through international travel or the acquisition of the methi- associated ST239/ST241-III [3A] in Algeria (Ramdani-bouguessa et al., 2006), Nigeria (Ghebremedhin et al., 2009), and Niger cillin resistance gene by PVL-positive MSSA, which is prevalent (Breurec et al., 2011b). Since ancient MSSA strains for this ST in West and Central Africa (Ruimy et al., 2008; Okon et al., have not been reported (Enright et al., 2002), our observation 2009; Breurec et al., 2011a; Schaumburg et al., 2011; Shittu et al., suggests that acquisition of these SCCmec types by MSSA is less 2011, 2012; Egyir et al., 2014a). These observations highlight likely, and points to the possible replacement of SCCmec type III the need for further surveillance data (including information on with IV and V on the ST239/241 genome (Li et al., 2013). community-acquired necrotizing pneumonia) to understand the Data on the epidemiology of MRSA in animals are limited epidemiology of PVL-associated S. aureus in both hospital and in Africa (EL Seedy et al., 2012; Fall et al., 2012; Gharsa et al., community settings on the African continent. 2012). Moreover, the genetic relatedness between human and animal MRSA has not been investigated (Table 2). It should be Conclusion noted, however, that human-associated ST5-IV [2B], ST88-IV [2B], and ST153-SCCmec-NT have been reported from animals A number of pandemic MRSA clones were identified in Africa. in Tunisia (Gharsa et al., 2012) and Senegal (Fall et al., 2012). In contrast, some MRSA clones are limited to specific countries Recently, human-associated S. aureus lineages were described or regions. Although the eBURST snapshot provided a descrip- in captive Chimpanzees in Gabon, Madagascar, Uganda and tion of the relationship between the MRSA clones reported in Zambia (Schaumburg et al., 2012, 2013; Nagel et al., 2013). Africa and other lineages submitted into the MLST database Notably, a likely case of S. aureus transmission from a veterinar- from other continents, the objective of this review was not to ian to a chimpanzee from the same sanctuary was demonstrated understand the origin of MRSA clones in Africa, as this will (Schaumburg et al., 2012). Zoonotic transmission may consti- require in depth analysis like whole genome sequencing. How- tute a major concern in Africa, where there is often substan- ever, it did show that CC5 is the largest group and predominant tial exposure to domesticated animals (Fall et al., 2012; Gharsa in Africa. Nevertheless, the limited data available on MRSA in et al., 2012). Furthermore, animal-adapted clones might undergo Africa draw attention to the need for increased surveillance of further host-adaptive evolutionary changes, which could result MRSA and molecular epidemiological studies. We strongly rec- in an epidemic spread of new and more virulent strains in the ommend improved co-operation between clinicians and micro- human population (Spoor et al., 2013). Other risk factors for biologists in Africa. This synergy could provide an understanding animal to human MRSA transmission, which include contam- on the local epidemiology of MRSA. In addition, we strongly inated environment (Verkade and Kluytmans, 2013) and meat advocate the establishment of effective diagnostic microbiology products (Hamid and Youssef, 2013), have not been investi- facilities that will incorporate high-throughput technologies for gated in Africa. Livestock-associated MRSA are widespread in monitoring the clonal expansion and dissemination of MRSA. In Europe, but the transmission of these strains to humans is the meantime, increased networking through collaboration with Frontiers in Microbiology | www.frontiersin.org 16 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa S. aureus reference centers could provide support for genotyp- (OPP107641), United States of America; Deutscher Akademis- ing services to African countries with limited resources. Finally, cher Austausch Dienst, Germany; Carnegie Corporation of New population-based surveillances for MRSA are needed to evaluate York, United States of America. Any opinions, findings and con- the situation of community associated MRSA as well as studies on clusions, or recommendations expressed in this review are those MRSA from animal hosts. To understand the origin of the newly of the authors, and therefore do not represent the official position emerged clones, MSSA genotyping needs to be incorporated with of the funders. MRSA surveillance studies. Acknowledgments Author Contributions SMA is supported by the Organization for Women in Science for the developing World (OWSD) and the Drakenstein Child MK, AS, and SMA initiated the project. SMA extracted the data Health Study, Cape Town, South Africa; AS was supported by and reviewed the articles with MK. SMA, AS, MN, and MK wrote Deutscher Akademischer Austausch Dienst (DAAD award) Staff the manuscript. All the authors reviewed the final version of the Exchange Programme (2013); MK was a recipient of Carnegie manuscript prior to submission for publication Corporation of New York (USA) fellowship and is currently a Wellcome Trust (UK) Fellow. 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USA300 ins on the host: cell lysis and beyond. Curr. Opin. Microbiol. 16, 63–69. doi: methicillin-resistant Staphylococcus aureus emerging as a cause of bloodstream 10.1016/j.mib.2013.01.012 Frontiers in Microbiology | www.frontiersin.org 20 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa Zhou, Y. P., Wilder-Smith, A., and Hsu, L.-Y. (2014). The role of international The first and corresponding authors had full access to the study data. All authors travel in the spread of methicillin-resistant Staphylococcus aureus. J. Trav. Med. had final responsibility for the decision to submit the article for publication. The 21, 272–281. doi: 10.1111/jtm.12133 authors declare that the research was conducted in the absence of any commercial Zribi, M., Etienne, J., El Euch, D., Zribi, H., Bes, M., Meugnier, H., et al. (2011). or financial relationships that could be construed as a potential conflict of interest. Detection of the first strain of glycopeptide intermediary Staphylococcus aureus in Tunis Rabta hospital. Path. Biol. 59, 334–335. doi: 10.1016/j.patbio.2009. Copyright © 2015 Abdulgader, Shittu, Nicol and Kaba. This is an open-access arti- 10.002 cle distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this Conflict of Interest Statement: The authors have no conflict of interest to declare related to the content of this paper. The funders had no role in the study design, journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. data collection and analysis, decision to publish, or preparation of the manuscript. 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Molecular epidemiology of Methicillin-resistant Staphylococcus aureus in Africa: a systematic review

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Abstract

REVIEW published: 30 April 2015 doi: 10.3389/fmicb.2015.00348 Molecular epidemiology of Methicillin-resistant Staphylococcus aureus in Africa: a systematic review 1 2 1, 3, 4 1, 3 Shima M. Abdulgader , Adebayo O. Shittu ,Mark P. Nicol and Mamadou Kaba * Division of Medical Microbiology, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of 2 3 Cape Town, Cape Town, South Africa, Department of Microbiology, Obafemi Awolowo University, Ile-Ife, Nigeria, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa, National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious global problem, with considerable impact on patients and substantial health care costs. This systematic review provides an overview on the clonal diversity of MRSA, as well as the prevalence of Panton-Valentine leukocidin (PVL)-positive MRSA in Africa. A search on Edited by: the molecular characterization of MRSA in Africa was conducted by two authors using Miklos Fuzi, predefined terms. We screened for articles published in English and French through to Semmelweis University, Hungary October 2014 from five electronic databases. A total of 57 eligible studies were identified. Reviewed by: Iruka N. Okeke, Thirty-four reports from 15 countries provided adequate genotyping data. CC5 is the Haverford College, USA; predominant clonal complex in the healthcare setting in Africa. The hospital-associated University of Ibadan, Nigeria Dmitri Debabov, MRSA ST239/ST241-III [3A] was identified in nine African countries. This clone was also NovaBay Pharmaceuticals, USA described with SCCmec type IV [2B] in Algeria and Nigeria, and type V [5C] in Niger. *Correspondence: In Africa, the European ST80-IV [2B] clone was limited to Algeria, Egypt and Tunisia. Mamadou Kaba, The clonal types ST22-IV [2B], ST36-II [2A], and ST612-IV [2B] were only reported in Division of Medical Microbiology, Department of Clinical Laboratory South Africa. No clear distinctions were observed between MRSA responsible for hospital Sciences, Faculty of Health Sciences, and community infections. The community clones ST8-IV [2B] and ST88-IV [2B] were University of Cape Town, Anzio Road, Observatory, 7925, reported both in the hospital and community settings in Angola, Cameroon, Gabon, Cape Town, South Africa Ghana, Madagascar, Nigeria, and São Tomé and Príncipe. The proportion of PVL-positive mamadou.kaba@hotmail.com MRSA carriage and/or infections ranged from 0.3 to 100% in humans. A number of Specialty section: pandemic clones were identified in Africa. Moreover, some MRSA clones are limited This article was submitted to to specific countries or regions. We strongly advocate for more surveillance studies on Antimicrobials, Resistance and MRSA in Africa. Chemotherapy, a section of the journal Keywords: Staphylococcus aureus, MRSA, molecular epidemiology, Africa, systematic review Frontiers in Microbiology Received: 28 February 2015 Accepted: 08 April 2015 Introduction Published: 30 April 2015 Citation: Methicillin-resistant Staphylococcus aureus (MRSA) is a major public health concern and is respon- Abdulgader SM, Shittu AO, Nicol MP sible for both hospital- and community-associated infections worldwide (De Kraker et al., 2011; and Kaba M (2015) Molecular CDC, 2013; Falagas et al., 2013; Garza-González and Dowzicky, 2013; Lee et al., 2013; Chen and epidemiology of Methicillin-resistant Huang, 2014). It is estimated that MRSA infections within the health care setting alone affected Staphylococcus aureus in Africa: a more than 150,000 patients annually in the European Union, with an additional cost of 380 million systematic review. Euros (Köck et al., 2010). In the United States of America, 80,461 invasive MRSA infections and Front. Microbiol. 6:348. doi: 10.3389/fmicb.2015.00348 11,285 related deaths occurred in 2011, and an estimated annual burden of between $1.4 billion and Frontiers in Microbiology | www.frontiersin.org 1 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa 13.8 billion was attributed to community-acquired MRSA (CDC, et al., 2013; Lim et al., 2013; Nimmo et al., 2013) but information 2013; Lee et al., 2013). Besides, MRSA has been established on this trend is lacking in Africa. The occurrence and changes as a pathogen for domestic animals and linked with livestock- in clonal identities, and their geographic spread is important to associated infections (Verkade and Kluytmans, 2013). understand the spread and evolution of MRSA. Methicillin resistance is usually due to the mecA gene, borne The Panton-Valentine Leukocidin (PVL) is a two-component on the staphylococcal cassette chromosome mec (SCCmec)that pore-forming toxin with cytolytic activity on defined cells of codes for a 78-kDa penicillin binding protein (PBP2a), with the immune system (neutrophils, macrophages and monocytes) decreased affinity to methicillin and all beta-lactam antibiotics (Löffler et al., 2010; Yoong and Torres, 2013). It is encoded (Chambers, 1997). To date, eleven SCCmec types have been iden- by the lukS-PV and lukF-PV genes (Boakes et al., 2011), and tified (IWG-SCC, 2009). Some cassettes, for example, SCCmec PVL-producing S. aureus exhibit a propensity for causing mainly II (53 kb) and SCCmec III (67 kb), are large and possess mobile severe and often recurrent skin and soft tissue infections (Shall- genetic elements (MGE), such as integrated plasmids (pUB110, cross et al., 2013). In addition, PVL-positive MRSA are associated pI258, and pT181) and transposons (e.g., Tn554) (Ito et al., 2001), with community onset-pneumonia (Vandenesch et al., 2003). and are frequently associated with hospital-acquired MRSA (Ma Although the PVL genes are mainly carried by community- et al., 2002; Ito et al., 2004). In contrast, SCCmec IV (21–24 kb) associated MRSA (CA-MRSA) (Vandenesch et al., 2003), data and V (27 kb) are shorter elements, generally susceptible to from West and Central Africa showed that at least 40% of clinical non-beta-lactam antibiotics, and linked with community MRSA methicillin-susceptible S. aureus (MSSA) isolates in this region (Chambers and Deleo, 2010). However, the spread of various are PVL-positive (Breurec et al., 2011a; Schaumburg et al., 2011; MRSA clones between the hospital and community settings has Shittu et al., 2011; Egyir et al., 2014a). Therefore, the acquisi- made the dichotomous ranking difficult (Deurenberg and Sto- tion of the mecA gene by PVL-positive MSSA and the possible bberingh, 2008). Recently, a variant mecA gene (named mecC) dissemination of PVL-positive CA-MRSA could present a signif- which is situated on an SCCmec XI element has been described icant challenge in disease management and infection control in (Shore et al., 2011). It has a higher relative affinity for oxacillin as resource-limited countries in Africa. compared with cefoxitin (Kim et al., 2012), and exhibits only 69% This systematic review examined published literature on the sequence similarity at the nucleotide level and 63% amino-acid molecular epidemiology of MRSA in Africa. By summarizing identity to mecA/PBP2a (Paterson et al., 2014b). Furthermore, currently available data on the continent, our objective was to describe the distribution of MRSA clones, the prevalence of PVL- based on whole genome sequencing, mutations of the endoge- nous penicillin-binding proteins (PBP) 1, 2, and 3 in mecA and positive MRSA, and to highlight the need to develop more com- mecC negative strains have been postulated as a possible alter- prehensive surveillance and reporting systems for multidrug- native mechanism for beta-lactam resistance in MRSA (Ba et al., resistant organisms such as MRSA in Africa. 2014). There is great interest in tracking, identifying and understand- Methods ing the diversity of MRSA in various settings. Currently, the most widely used molecular techniques include Staphylococcus pro- This systematic review was conducted in accordance with tein A gene typing (spa) and multilocus sequence typing (MLST). the preferred reporting items for systematic reviews and Studies (particularly using MLST) have provided evidence that a meta-analyses (PRISMA) guidelines (Moher et al., 2009). small set of lineages, clonal complex (CC)5, CC8, CC22, CC30, and CC45, are associated with most of the MRSA infections in Literature Search Strategy hospitals (Stefani et al., 2012). Besides, a number of different geo- The relevant English and French articles available in five elec- graphically distinct lineages, CC1, CC8, CC30, and CC80, have tronic databases (MEDLINE, EBSCOhost, ISI Web of knowl- also been associated with community MRSA infections (Chatter- edge, Scopus, and African Journals Online) were retrieved by two jee and Otto, 2013), while CC8 and CC30 have been identified authors using predefined search terms (Table S1). The literature as pandemic lineages both in the hospital and community setting search was conducted until 31 October 2014. (Chatterjee and Otto, 2013). Furthermore, regional clones have been described in Australia (sequence type [ST] 93) (Coombs et al., 2009), India (ST772) (D’Souza et al., 2010; Shambat et al., Eligible Article Identification 2012), South Korea (ST72) (Kim et al., 2007), Taiwan and China Figure 1 summarizes the study selection process. All duplicate (ST59) (Chen and Huang, 2014). articles were removed and data on MSSA as well as in-vitro stud- The distribution of MRSA clones in Africa is not well- ies were also excluded. The eligibility of published reports in described. Understanding the molecular epidemiology of MRSA this review was based primarily on polymerase chain reaction in Africa is important as a recent review indicated that since (PCR) detection of the mecA gene, and the use of at least one the year 2000, the prevalence of MRSA appears to be increas- molecular tool for genotyping of MRSA strains (Table 1). In addi- ing in many African countries and pose a visible threat to the tion, worldwide surveys that covered African countries were also continent (Falagas et al., 2013). Furthermore, there is evidence included. An MRSA clone was defined based on the combina- of the replacement of existing MRSA clones with different and tion of MLST sequence type (ST) and SCCmec typing data as new clonal types in a number of countries (Conceição et al., previously reported (Okuma et al., 2002). The nomenclature of 2007; Aires-de-Sousa et al., 2008; Albrecht et al., 2011; Espadinha the SCCmec types was as proposed by the International Working Frontiers in Microbiology | www.frontiersin.org 2 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa FIGURE 1 | Preferred reporting item for systematic reviews. CONS, coagulase negative staphylococci; MSSA, methicillin susceptible S. aureus; MRSA, methicillin resistant S. aureus. Group on the Classification of Staphylococcal Cassette Chromo- Results some Elements (IWG-SCC, 2009). SCCmec elements that could Literature Search not be classified were indicated as non-typeable (SCCmec-NT). The systematic search of the five electronic databases yielded In this study, we categorized MRSA into various CCs according 1775 articles (Figure 1). No additional studies were identified to the current eBURST scheme, Version 3 (accessed 30 October from AJOL. After the removal of duplicate studies and assess- 2014) (eBURST, www.mlst.net, V3) . ment of titles and abstracts, 110 full-text articles were screened, of which 57 studies were considered eligible for the qualitative Data Extraction and Synthesis The relevant data were extracted from each of the articles as analysis according to our inclusion criteria. stated in Table 1. Separate articles that analyzed the same S. Characteristics of the Studies Included in the aureus isolates but answered different questions were considered Systematic Review as a single study. Most of the data analyzed were obtained from single center stud- ies conducted mainly in five countries; Tunisia (n = 13), Nigeria eBURST Analysis (n = 9), South Africa (n = 7), Algeria (n = 5),and Egypt(n = 3) The relationship between the MRSA STs described in this review (Table 1). Multicenter studies were only reported in two articles and other lineages reported world-wide was analyzed using the (Goering et al., 2008; Breurec et al., 2011b), including a survey eBURST scheme. The allelic profiles were downloaded from which comprised five African countries, Cameroon, Madagas- the MLST website (http://saureus.mlst.net/) which included the car, Morocco, Niger and Senegal (Breurec et al., 2011b), and African MRSA STs as well as 223 representative and randomly an inter-continental multicenter study, which included South selected STs (from each CC) based on the differences in their Africa (Goering et al., 2008). Only three studies investigated the allelic profiles. The minimum spanning tree was constructed by detection of MRSA in animals (Table 1). the goeBURST algorithm using the Phyloviz software v1.1 (http:// In most of the reports included in this study, S. aureus was www.phyloviz.net/). identified by phenotypic and culture characteristics, while molec- eBURST [Online]. Available online at: http://www.mlst.net version 3. ular identification (16S rRNA, detection of the thermonuclease Frontiers in Microbiology | www.frontiersin.org 3 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 4 April 2015 | Volume 6 | Article 348 TABLE 1 | Characteristics of eligible articles that studied Methicillin resistant Staphylococcus aureus. Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence STUDIES CONDUCTED IN HUMANS Algeria 2003–2004 Clinical samples from 614 – 204 HA (40)/  –  –   –– Ramdani- hospitals and community CA (21) bouguessa et al., 2004–2007 Human infections (in- 65 – 23 NR  – –  –  –– Bekkhoucha et al., and-out patients) 2009 2005–2007 From military hospital (Pus, NR – 64 HA (50)/  –– – – –  –  Ouchenane et al., venous catheter, tracheal CA (14) 2011, 2013 aspirates, lumbar puncture fluid, blood culture and urine) α α β 2006–2007 Healthy and hospitalized 221 gyrA PCR 99 23 HA (65)/  –   NR  –  Antri et al., 2011 individuals 52 CA (84) 2010–2011 Children and neonates 129 – 25 HA (15)/  –– –   –– Djoudi et al., 2013 (SSTI, bacteraemia, otitis CA (10) and bone/joint infections) Angola 2012 Nasal swabs from inpatients 117 – 68 NR  –     –  Conceição et al., and HCW 2014 Egypt 2007–2008 Pus, sputum, wounds, NR – 21 CA (4)     NR  –  Enany et al., 2010 abscess, blood, urine, and discharge NR SSTI and nasal swabs 38 – 18 CA (18)  – –– – –  –– Sobhy et al., 2012 NR Septic wounds, UTI and RTI 10 – 7 – –  –  –– – – – El-Jakee et al., (nasal swabs) 2011* Gabon 2008–2010 asymptomatic carriers 217 nuc and 12 HA (6)/  –   –  –  Schaumburg (nares, axillae, inguinal 16S rRNA PCR CA (6) et al., 2011; Ateba swabs) and patients Ngoa et al., 2012 (abscess, wound, blood and others) 2010–2013 swabs from S. aureus 460 – 9 NR  ––  –  –  Schaumburg carrier mothers (nasal and et al., 2014 mammillary) and their infants (Nasal and pharyngeal) NR Blood culture of one patient 1 – 1 NR – – –  –  –  Huson et al., 2014 (Continued) Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 5 April 2015 | Volume 6 | Article 348 TABLE 1 | Continued Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence Ghana 2011–2012 In-patients and hospital staff 105 spa gene PCR 6 NR  ––  –  –– Egyir et al., 2013 2010–2012 SSTI and blood samples 308 – 9 NR  ––  –  –– Egyir et al., 2014a from six hospitals 2011–2012 Nasal swabs from 124 – 2 HA (2)  ––  –  –– Egyir et al., 2014b apparently healthy carriers Kenya 2005–2007 In and out-patients with 84 – 69 NR  –– – – –  –– Maina et al., 2013 SSTI boil, abscess, cellulitis and ulcer 2011 Nasal and axillary skin 85 – 6 NR  ––  –   Aiken et al., 2014 swabs from hospitalized patients Libya 2009–2010 Nasal swabs from in-patient 758 – 70 HA (12) –– – – –  –– Al-haddad et al., children, their mothers, CA (6) 2014 out-patient children and HCW Mali 2005 Asymptomatic nasal carriers 88 – 1 CA (1) – – – –  –– – – Ruimy et al., 2008 Mozambique 2010–2011 Post-operative, burn wound 99 – 9 HA (8), –– –  ––  – Van der Meeren infections, skin and soft CA (1) et al., 2014 tissue abscesses Nigeria 1998–2002 Wounds, aspirate, amniotic 276 – 4 NR  –– –  –– – Adesida et al., fluid 2005 2002–2004 Wound samples, blood 200 – 3NR  –– – –  –– – Shittu and Lin, cultures, urine, otitis media 2006b and ocular related infections 2007–2012 Clinical specimen 150 – 12 NR  – ––  –  –  Okon et al., 2009, 2007 Surgical and pediatric 346 – 70 HA (42),  –   –  –  Ghebremedhin patients wound samples, CA (28) et al., 2009 corneal, conjunctival, auricular, genital and nasal swabs 2008–2010 HIV-positive and healthy 202 – 26 NR –  –  –  –– Olalekan et al., individuals (nasal swabs) 2012 (Continued) Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 6 April 2015 | Volume 6 | Article 348 TABLE 1 | Continued Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence 2009 Wound infections, semen, 68 – 11 NR  ––  –  – Shittu et al., 2011 UTI, chronic ulcer, conjunctivitis, throat infections 2009–2011 Patients and carriers 62 – 22 NR  –– –  –  –– Raji et al., 2013 2010 Clinical samples from 51 tuf gene PCR 15 NR  ––  –  – Shittu et al., 2012 patients with burns, septicaemia, wound infections, osteomyelitis, bronchitis and GIT NR Urine, blood and aspirates, 116 – 48 HA (40),  –– – – –  –  Terry Alli et al., wound, eye and ear, urethral CA (8) 2012 and endocervical swab South Africa 2001–2003 Wound samples, sputum, 227 nuc gene PCR 61 NR  –– –  –  – Shittu and Lin, otitis media and blood 2006a; Shittu culture et al., 2007 2001–2003 Isolates from 16 laboratories 241 – 24 NR  –– –  –– – – Essa et al., 2009 in KZN 2001–2003 Wounds, sputum, otitis NR – 61 NR  – –    –– Shittu et al., 2009 media, urine and blood culture 2005–2006 Bacteraemia, SSTI, urine, NR – 320 HA  – –    –  Moodley et al., catheter tip, cerebrospinal 2010 and drainage fluids 2006–2007 Clinical samples NR – 97 HA (79),  – –  ––  –– Makgotlho et al., CA (4) 2009 2007–2008 Pus and pus swabs, urine, NR – 100 CA (10)  – –    –  Jansen van 2007–2011 blood, RTS and CVCT Rensburg et al., 2011, 2012 2009–2010 A wide range of clinical 367 – 56 NR  –     –– Oosthuysen et al., specimens mostly SSTI 2014 São Tome 2010–2012 Patients and healthy carriers 52 – 14 NR  –     –  Conceição et al., and Príncipe 2013 (Continued) Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 7 April 2015 | Volume 6 | Article 348 TABLE 1 | Continued Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence Tanzania 2008 Wound, nasal swab and pus 160 – 24 HA – – –  –  –– Moremi et al., 2010 Apparently healthy children 114 nuc gene PCR 12 CA – – – – –  –– – Moyo et al., 2014 under 5 years (nasal swabs) Tunisia 1998–2007 Clinical specimens from 72 nuc gene PCR 13 HA (13)  –– – –  – –– Bouchami et al., neutropenic patients 2009 2002 Patients who developed NR – 6 HA (6) – –– – –  – –– Ben Ayed et al., MRSA infections 2010 2003–2004 Pus, blood, pleural fluid, NR – 72 NR  –  – ––  –  Ben Nejma et al., venous catheter 2006 2003–2004 Pathological samples from 147 – 19 NR – –– – –  – –– Ben Saida et al., different wards 2005 2003–2005 Pus and associated with NR – 64 CA (64)  –     –  Ben Nejma et al., cutaneous infections 2013 2004 Cutaneous pus, blood NR – 34 HA (32),  –– – –– – –– Ben Jomaa-Jemili cultures, urine and puncture CA (2) et al., 2006 fluids 2004–2005 Cutaneous pus, RTS, urine, 475 – 57 NR – –  – –– – –– Ben Ayed et al., blood culture, 2006 2004–2008 Samples from hospitals and NR – 69 HA (41),  –   –  –– Ben Jomàa-Jemili community CA (28) et al., 2013 2006–2008 Children with CA invasive 36 – 8 CA (8)  –     –– Kechrid et al., infections bacteraemia and 2011 osteomyelitis 2007 Pus and skin infections NR – 11 CA (11)  –     –– Ben Nejma et al., 2008 Pus and blood culture (case 2– 2 NR  –   –  –  Zribi et al., 2011 report) 2008–2009 Humans in contact with 55 – 1 CA (1)  –   –   Ben Slama et al., animals 2011 (Continued) Abdulgader et al. A systematic review on MRSA in Africa Frontiers in Microbiology | www.frontiersin.org 8 April 2015 | Volume 6 | Article 348 TABLE 1 | Continued Country Study period Study population (sample No. of S. S. aureus No. of Setting Genotyping tools PVL Detection of genes References type) aureus molecular MRSA (no.) isolates identification SCCmec coa agr spa typing MLST PFGE Antibiotic Toxin/ resistance Virulence Uganda 2009–2010 Swabs from patients, HCW 41 – 41 NR  –– – – –   Kateete et al., and from hospital 2011 environment (sinks, door handles, surgical trays, bed and table surfaces) 2011–2012 SSI 64 nuc gene PCR 24 NR  ––  ––  –– Seni et al., 2013 Multicenter 2007–2008 SSTI, NR – 86 CA (9),  –   –  –  Breurec et al., bacteraemia/septicaemia, HA (77) 2011b urine, wounds osteomyelitis and myositis Multicentre 2004–2005 Uncomplicated skin 292 – 105 HA (3)  –– –   –– Goering et al., infections 2008 STUDIES CONDUCTED IN ANIMALS Egypt NR Cows and buffaloes milk, 9– 5 NR –  –  –– – –– El-Jakee et al., cattle septic wounds 2011* Senegal 2009–2011 Pigs (nasal swabs) 73 – 6 NR  ––  –  –  Fall et al., 2012 Tunisia 2010 Healthy sheep (nasal swabs) 73 – 5 CA (6)  –    ––  Gharsa et al., agr, Accessory gene regulator; CA, Community-acquired methicillin-resistant S. aureus; coa, Coagulase gene; CVCT, Central venous catheter tips; GIT, Genital tract infections; gyrA, DNA gyrase gene; HA, Hospital-acquired methicillin resistant S. aureus; HCW, Health care workers; HIV, Human immunodeficiency virus; KZN, KwaZulu-Natal province; MLST, Multilocus locus sequence typing; MRSA, Methicillin-resistant Staphylococcus aureus; No., Number of isolates; NR, Not reported; nuc, Thermonuclease gene; PCR, Polymerase chain reaction; PFGE, Pulsed-field gel electrophoresis; PVL, Panton-Valentine-Leukocidin genes; SCCmec, Staphylococcal chromosomal cassette mec element; RTI, Respiratory tract infections; rRNA, Ribosomal ribonucleic acid; RTS, Respiratory tract specimens; spa, Staphylococcus aureus protein A gene; SSTI, Skin and soft tissue infections; SSI, Surgical site infections; tuf, Elongation factor tu; UTI, Urinary tract infections. ¶ α β # MRSA as confirmed by mecA PCR; , Test was conducted; −, Test was not conducted; Hospitalized individuals; Nasal carrier study; African multicenter study which included Cameroon, Madagascar, Morocco, Niger and Senegal; An international multicenter study which included only South Africa; *Study was conducted in both animal and human host. Abdulgader et al. A systematic review on MRSA in Africa and the elongation factor tu - nuc, tuf - genes) was performed PVL-positive ST1-V [5C] isolated from patients in a tertiary hos- in only 12.3% (7/57). The screening for antibiotic resistance and pital in Nigeria (Raji et al., 2013), and the PVL-negative ST1 with toxin/virulence genes were carried out in seven and 22 studies, a non-typeable SCCmec element (spa type t035 and agr type III) respectively (Table 1). Furthermore, all the eligible studies ana- identified in Tunisia (Ben Jomàa-Jemili et al., 2013). In addition, lyzed MRSA using at least one genotyping technique, and 59.6% an ST1 related sequence type (ST772-V [5C]), “the Bengal-Bay (34/57) provided adequate genotyping data on MRSA clones clone” has been described in Nigeria (Raji et al., 2013). from 15 African countries (Tables 1, 2). Studies included in this systematic review did not investigate on the mecC gene. MRSA CC5 with Sequence Type 5 This clone was documented in 14 studies and consisted of diverse Community- and Hospital- Acquired MRSA SCCmec elements (Table 2). The ST5-I [1B]/III [3A] were iden- Overall, 51% (29/57) of the eligible studies provided the potential tified from clinical samples in health care institutions in South source (hospital- or community-associated) of the MRSA strains. Africa (Shittu et al., 2009; Moodley et al., 2010; Jansen van Rens- Only 17.5% (10/57) reported MRSA from community settings burg et al., 2011; Oosthuysen et al., 2014). ST5-II [2A] has been (Table 1). USA300 (ST8-IV [2B]) and other related sequence described in Nigeria (Raji et al., 2013), and Senegal (Breurec et al., types were noted both in health care and community settings in 2011b). ST5-IV [2B]-PVL-positive was the dominant clone in nine African countries (Tables 1, 2). The “Brazilian/Hungarian hospitalized patients with skin and soft tissue infections in Dakar, clone” (ST239-III [3A]) was associated with hospital-acquired Senegal (Breurec et al., 2011b). In addition, ST5-IV [2B] was infections in nine countries (Tables 1, 2). Furthermore, the “West detected from nasal samples of pigs in the same geographical area Australia MRSA-2” (ST88-IV [2B]) was reported in community- (Fall et al., 2012). ST5-IV [2B] has also been identified in Alge- and hospital-acquired infections in several African countries ria (Ramdani-bouguessa et al., 2006), Gabon (Schaumburg et al., (Table 2). 2011; Ateba Ngoa et al., 2012), Morocco (Breurec et al., 2011b), and South Africa (Essa et al., 2009), while the SCCmec IVa Detection of Panton-Valentine Leukocidin (PVL) [2B] variant was recovered from hospitalized patients in Alge- Genes ria (Ramdani-bouguessa et al., 2006; Bekkhoucha et al., 2009), The screening for PVL-associated genes (lukF-PV and lukS-PV) Angola (Conceição et al., 2014), and São Tomé and Príncipe was carried out in 44 studies, and the detection of PVL genes (Conceição et al., 2013). Moreover, ST5-IVa [2B] was reported was only reported in 32 studies (Table 1). In animals, PVL- from nasal samples of apparently healthy-hospital workers in positive MRSA (ST5) was described in nasal samples of pigs from Angola (Conceição et al., 2014). Other ST5 and related clones identified are ST5-V [5C] in Angola (Conceição et al., 2014), Senegal (Fall et al., 2012). In humans, the proportion of PVL- positive MRSA carriage and/or infections ranged from 0.3 to Cameroon (Breurec et al., 2011b), and Nigeria (Shittu et al., 2011), ST72-SCCmec-NT in South Africa (Jansen van Rensburg 100%. Studies from Algeria and Tunisia reported higher PVL prevalence while investigations from South Africa reported the et al., 2011), ST72-V [5C] in Angola and Ghana (Egyir et al., lowest prevalence (Table 3). Overall, PVL-positive MRSA were 2013, 2014b; Conceição et al., 2014), and ST105-II [2A] from a more frequently reported with skin and soft tissue infections, and patient in São Tomé and Príncipe (Conceição et al., 2013). Fur- community-associated clones (Tables 1, 2). There was no report thermore, ST650-IV [2B] was detected from clinical samples in on the role of PVL in necrotizing pneumonia caused by MRSA in health care institutions in South Africa (Jansen van Rensburg Africa. et al., 2011). Finally, ST2629-V [5C] was described in Angola (Conceição et al., 2014). MRSA Clones Reported in Africa Using the MRSA CC5 with Sequence Type 8 Current eBURST Scheme MRSA assigned to this clone are widespread and diverse across Figures 2, 3 summarize the MRSA clones identified in Africa Africa as evidenced in 27 studies (Table 2). The first known based on MLST CCs. By the current eBURST scheme, six main early or ancestral clone, ST250-I [1B], was mainly associated CCs were identified: CC5, CC22, CC30, CC45, CC80, and CC88. with hospital-acquired infections in Ibadan, South-West Nige- In addition, a number of diverse spa types were identified among ria (Ghebremedhin et al., 2009), and recently observed in Ghana the MRSA clones in Africa (Table 2), but the distribution of spa (Egyir et al., 2014b). ST8-II [2A] was only described in the types t042 and t044 (associated with CC80-IV [2B]) appear to be limited to three North African (Algeria, Egypt and Tunisia) KwaZulu-Natal region of South Africa (Essa et al., 2009), while a number of investigations reported ST8-IV [2B] in Angola countries (Table 2). (Conceição et al., 2014), Cameroon (Breurec et al., 2011b), Clonal Complex 5 Gabon (Schaumburg et al., 2011; Ateba Ngoa et al., 2012), Ghana (Egyir et al., 2014b), Madagascar (Breurec et al., 2011b), Nige- This clonal complex is considered the largest group based on the eBURST scheme (Figure 3). It was subdivided into three main ria (Adesida et al., 2005; Shittu et al., 2012), São Tomé and Príncipe (Conceição et al., 2013) and South Africa (Essa et al., clusters and designated as CC5-ST1, ST5, and ST8. 2009). The MRSA isolates from Angola possessed the SCCmec MRSA CC5 with Sequence Type 1 type IVd element (Conceição et al., 2014). ST612-IV [2B], a This group was reported in Nigeria (Raji et al., 2013) and Tunisia double locus variant (dlv) of ST8-IV [2B], and only recently (Ben Jomàa-Jemili et al., 2013). The clonal type included the reported as PVL-positive (Oosthuysen et al., 2014), is widespread Frontiers in Microbiology | www.frontiersin.org 9 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa TABLE 2 | Methicillin resistant Staphylococcus aureus clones reported in 34 eligible studies. Country Clonal type ST-SCCmec Clonal complex spa type PVL status agr References Algeria ST80-IV [2B] 80 ND + III Ramdani-bouguessa et al., 2006 ST37-IVa [2B] 30 ND + III ST239-III [3A] 5 ND − I ST239-IVa [2B] 5 ND − I ST241-III [3A] 5 ND − I ST637-III [3A] 5 ND − I ST5-IV, IVa [2B] 5 ND +, − II ST635-IV [2B] 80 ND − III ST636-NT 22 ND − I ST80-IV [2B] 80 t044 + ND Bekkhoucha et al., 2009 ST239-III [3A] 5 t037 − ND ST5-IVa [2B] 5 t311, t450 − ND ST88-NT 88 t188, t267 − ND ST80-IV [2B] 80 t044, t4143 + III Antri et al., 2011 ST241-III [3A] 5 ND − III ST8-V [5C] 5 ND − I ST80-IVc [2B] 80 ND +, − ND Djoudi et al., 2013 ST39-II [2A] 30 ND − ND Angola ST5-IVa [2B] 5 t105, t311, t11657 − II Conceição et al., 2014 ST8-IVd, V [2B] 5 t104, t1774 − I ST72-V [5C] 5 t3092 − I ST88-IVa [2B] 88 t186, t325, t786, − III t1951, t3869 ST5-V [5C] 5 t6065 − II ST2629-V [5C] 5 t6065 − II ST789-V [5C] 7 t091 − II Cameroon ST5-V [5C] 5 t311 + II Breurec et al., 2011b ST88-IV [2B] 88 t186 − III ST8-IV [2B] 5 t024, t121, t451 + I ST1289-V [5C] 88 t1339 + III Egypt ST80-IVc [2B] 80 t042, t044, t070, t983 + III Enany et al., 2010 ST30-IVa [2B] 30 t251, t318 + III ST1010-X 121 t159, t312 + IV Gabon ST8-IV [2B] 5 t121 + I Schaumburg et al., 2011; Ateba Ngoa et al., 2012 ST88-IV [2B] 88 t186 − III ST5-IV [2B] 5 t653 − II ST5-IV [2B] 5 t653 − ND Schaumburg et al., 2014 ST8-NT 5 t112, t121 + ND ST45-V [5C] 45 t437, t8860 − ND ST88-IV [2B] 88 t4195 − ND Ghana ST72-V [5C] 5 t537 − ND Egyir et al., 2013 ST8-V [5C] 5 t064 − ND ST88-IV [2B] 88 t325, t1951, t2649 − ND ST72-V [5C] 5 t537 − ND Egyir et al., 2014b ST8-IV [2B] 5 t121 + ND ST239-III [3A] 5 t037 − ND ST250-I [1B] 5 t928 − ND ST2021-V [5C] 5 t024 − ND (Continued) Frontiers in Microbiology | www.frontiersin.org 10 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa TABLE 2 | Continued Country Clonal type ST-SCCmec Clonal complex spa type PVL status agr References ST88-IV [2B] 88 t186 − ND ST789-IV [2B] 7 t547 + ND ST508-V [5C] 45 t5132 − ND Egyir et al., 2014a Kenya ST239-III [3A] 5 t037 − ND Aiken et al., 2014 Madagascar ST8-IV [2B] 5 t121 + I Breurec et al., 2011b ST30-V [5C] 30 t4686 − III ST88-IV [2B] 88 t186 − III Morocco ST239, ST241-III [3A] 5 t037, t138 − I ST5-IV [2B] 5 t311 + II Niger ST239, ST241-III [3A] 5 t138 − I ST239, ST241-V [5C] 5 t037 − I ST88-IV [2B] 88 t186 − III Nigeria ST8-IV [2B] 5 ND − ND Adesida et al., 2005 ST88-IV [2B] 88 t186 + III Ghebremedhin et al., 2009 ST241-IV [2B] 5 t037 − I ST250-I [1B] 5 t194, t292 − I ST241-III [3A] 5 t037 − ND Shittu et al., 2011 ST8-V [5C] 5 t064 − ND ST8-V [5C] 5 t451 − ND ST94-IV [2B] 5 t008 − ND ST5-V [5C] 5 t002 − ND ST241-III [3A] 5 t037 − ND Shittu et al., 2012 ST88-IV [2B] 88 t729, t1603 − ND ST37-III [3A] 30 t074 − ND ST39-II [2A] 30 t007 − ND ST8-V [5C],IV [2B], ST8-NT 5 t064 − ND ST152-NT 152 t4690 + ND ST1-V [5C] 5 ND + ND Raji et al., 2013 ST239-III[3A] 5ND − ND mercury ST5-II [2A] 5 ND − ND ST8-V [5C] 5 ND − ND ST247-I [1B] 5 ND − ND ST772-V [5C] 5 ND + ND ST88-IV [2B] 88 ND − ND ST241-III [3A] 5 ND − ND Okon et al., 2009 Senegal ST5-IV [2B]* 5 t311 + ND Fall et al., 2012 ST88-IV [2B]* 88 t3489 − ND ST239, ST241-III [3A] 5 t037, t138 − I Breurec et al., 2011b ST5-II [2A] 5 t311 + II ST5-IV [2B] 5 t311 + II ST88-IV [2B] 88 t168 − III South Africa ST5-IV [2B] 5 ND ND ND Essa et al., 2009 ST8-IV [2B] 5 ND ND ND ST8-II [2A] 5 ND ND ND (Continued) Frontiers in Microbiology | www.frontiersin.org 11 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa TABLE 2 | Continued Country Clonal type ST-SCCmec Clonal complex spa type PVL status agr References ST239-III [3A] 5 ND ND ND ST45-IV [2B] 45 ND ND ND ST612-IV [2B] 5 ND − ND Goering et al., 2008 ST36-II [2A] 30 ND − ND ST1173-IV [2B] 5 t064 − ND Shittu et al., 2009 ST1338-IV [2B] 5 t064 − ND ST239-III [3A] 5 t037 − ND ST5-III [3A] 5 t045 − ND ST239-III [3A] 5 t037 − ND Moodley et al., 2010 ST612-IV [2B] 5 t064 − ND ST5-I [1B] 5 t045 − ND ST22-IV [2B] 22 t032 − ND ST22-IV [2B] 22 t891 + ND ST36-II [2A] 30 t012 − ND ST239-III [3A] 5 t037 − ND Jansen van Rensburg et al., 2011 ST5-I [1B] 5 t045 ND ND ST650-IV [2B] 5 t002 ND ND ST612-IV [2B] 5 t064, t1443, t2196 ND ND ST72-NT 5 t3092 ND ND ST22-IV [2B] 22 t032 ND ND ST36-II [2A] 30 t012, t021 ND ND ST5-I [1B] 5 t002 − II Oosthuysen et al., 2014 ST8-V [5C] 5 t064 − I ST612-IV [2B] 5 t064 + I ST239-III [3A] 5 t021 − I ST22-V [5C] 22 t891 + I ST22-IV [2B] 22 t891 − I ST36-II [2A] 30 t021 − III São Tome ST5-IVa [2B] 5 t105 − II Conceição et al., 2013 and Príncipe ST105-II [2A] 5 t002 − II ST8-V [5C] 5 t451 − I ST8-IV [2B] 5 t451 − I ST88-IVa [2B] 88 t186, t786 − III Tunisia ST80-IV [2B] 80 t044 + III Ben Nejma et al., 2009 ST80-IV [2B] 80 t044 + III Ben Nejma et al., 2013 ST728-IVc [2B] 80 t042, t044 + III Kechrid et al., 2011 ST8-IVc [2B] 5 t062 + II ST80-IVc [2B] 80 t203 + III Ben Slama et al., 2011 ST1-NT 5 t035 − III Ben Jomàa-Jemili et al., 2013 ST247-I [1B] 5 t040 − I ST239-III [3A] 5 t003 − I ST241-III [3A] 5 t125 − I ST97-NT 5 t003 − I ST1819-I [1B] 5 NS − I ST80-IVc [2B] 80 t070 + III ST2563-IVc [2B] 80 t070 + III (Continued) Frontiers in Microbiology | www.frontiersin.org 12 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa TABLE 2 | Continued Country Clonal type ST-SCCmec Clonal complex spa type PVL status agr References ST1440-IVc [2B] 80 t070 + III ST80-IVc [2B] 80 t1021 − II ST80-IVc [2B] 80 ND − III ST22-NT 22 t998 − II ST45-NT 45 ND − I ST153-NT 80 NST + III ST153-NT 80 t044 ND III Gharsa et al., 2012 agr, Accessory gene regulator; CC, Clonal complex; NT, Non typeable; ND, Not determined; NST, New spa type; PVL, Panton-Valentine Leukocidin genes; SCCmec, Staphylococcal chromosomal cassette mec element; ST, Sequence type; spa, Staphylococcus aureus protein A gene; X , Unknown SCCmec type other than I, II, III, IV or V; *Clones isolated from pigs; +, PVL positive; −, PVL negative. TABLE 3 | Panton-Valentine Leukocidin prevalence as reported by the eligible studies with sample size of 30 or above. Country PVL positive (no. Prevalence References positive/total tested) (%) Algeria 46/61 75 Ramdani-bouguessa et al., 19/64 30 Ouchenane et al., 2011 94/122 77 Antri et al., 2011 Kenya 14/69 20 Maina et al., 2013 Libya 10/35 29 Al-haddad et al., 2014 Nigeria 33/70 47 Ghebremedhin et al., 2009 South Africa 1/320 0.3 Moodley et al., 2010 4/97 4 Makgotlho et al., 2009 5/56 9 Oosthuysen et al., 2014 Tunisia 68/72 94 Ben Nejma et al., 2006 64/64 100 Ben Nejma et al., 2013 43/69 62 Ben Jomàa-Jemili et al., Uganda 30/41 73 Kateete et al., 2011 Multicenter* 20/86 23 Breurec et al., 2011b *Multicenter study which included Cameroon, Madagascar, Morocco, Niger and Senegal. FIGURE 2 | MRSA clones reported in Africa. Each clonal complex is PVL, Panton-Valentine Leukocidin; no., Number. annotated with a colored circle. The number of studies conducted in each country is also indicated. across South Africa (Goering et al., 2008; Moodley et al., 2010; Jansen van Rensburg et al., 2011; Oosthuysen et al., 2014), alongside other variants such as ST1173/ST1338-IV [2B] (Shittu et al., 2011), Angola (Conceição et al., 2014), Ghana (Egyir et al., et al., 2009). The ST8-IV [2B] clone in South Africa was iden- 2013), Nigeria (Shittu et al., 2011, 2012; Raji et al., 2013), São tified from a variety of clinical infections, in particular, bacter- Tomé and Príncipe (Conceição et al., 2013), and South Africa aemia, skin and soft tissue and wound infections (Shittu et al., (Oosthuysen et al., 2014). Other STs observed within the CC5- 2009; Moodley et al., 2010; Jansen van Rensburg et al., 2011; ST8 cluster include ST8-SCCmec-NT in Gabon (Schaumburg Oosthuysen et al., 2014). An ST8-IVc [2B] strain (PVL-positive; et al., 2014) and Nigeria (Shittu et al., 2012), ST94-IV [2B] spa type t062) was identified from a 4 day old male child with described in Nigeria (Shittu et al., 2011) and ST97-SCCmec-NT community-acquired invasive infection in Tunisia (Kechrid et al., in Tunisia (Ben Jomàa-Jemili et al., 2013). In addition, ST247-I 2011). Furthermore, ST8-V [5C] was described in Algeria (Antri [1B] was reported only in Tunisia (Ben Jomàa-Jemili et al., 2013) Frontiers in Microbiology | www.frontiersin.org 13 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa FIGURE 3 | The minimum spanning tree was constructed by the randomly selected STs (from each CC) based on the differences in goeBURST algorithm using the Phyloviz software v1.1 their allelic profiles. The Group founder is colored in green and the (http://www.phyloviz.net/). The allelic profiles were downloaded from related STs are in blue. The six main CCs described in this review the MLST website (http://saureus.mlst.net/) which included the MRSA are indicated by the dotted lines and the STs reported in Africa are sequence types (STs) described in this review as well as 223 indicated by the red color. and Nigeria (Raji et al., 2013), ST637-III [3A] in Algeria SCCmec variants, ST239-IVa [2B], ST239/ST241-V [5C], and (Ramdani-bouguessa et al., 2006), ST1819-I [1B] in Tunisia ST241-IV [2B], and associated with hospital-acquired infec- (Ben Jomàa-Jemili et al., 2013), and ST2021-V [5C] in Ghana tions were reported in Algeria (Ramdani-bouguessa et al., 2006), (Egyir et al., 2014b). Niger (Breurec et al., 2011b), and Nigeria (Ghebremedhin et al., The “Brazilian/Hungarian clone” (ST239-III [3A]) is an 2009). hybrid of CC30 and CC8 based on a single large chromoso- mal replacement (Robinson and Enright, 2004), and ST241-III Clonal Complex 22 [3A] is a single locus variant (slv) of ST239-III [3A]. These two In Africa, ST22 was identified only in Algeria (Ramdani- STs were identified concurrently in Algeria (Ramdani-bouguessa bouguessa et al., 2006), South Africa (Moodley et al., 2010; et al., 2006), Morocco, Niger and Senegal (Breurec et al., 2011b), Jansen van Rensburg et al., 2011; Oosthuysen et al., 2014), and and Tunisia (Ben Jomàa-Jemili et al., 2013). ST239-III [3A] has Tunisia (Ben Jomàa-Jemili et al., 2013). ST22-IV [2B] was related also been described in Ghana (Egyir et al., 2014b) and Kenya with hospital-associated infections in the Western Cape and (Aiken et al., 2014), and consistently since 2001 in South Africa KwaZulu-Natal provinces of South Africa. A variant of ST22 (Essa et al., 2009; Shittu et al., 2009; Moodley et al., 2010; Jansen (ST22-V [5C]-PVL-positive) was also reported in an hospital in van Rensburg et al., 2011; Oosthuysen et al., 2014). A recent study Western Cape, South Africa (Oosthuysen et al., 2014). The ST22 detected ST239 with the SCCmec type III [3A] in a ter- identified in Tunisia possessed a non-typeable SCCmec element mercury tiary health care facility in South-West Nigeria (Raji et al., 2013). (Ben Jomàa-Jemili et al., 2013). Besides, an ST636-SCCmec-NT ST241-III [3A] is the dominant clone in North-East Nigeria isolate has also been reported in Algeria (Ramdani-bouguessa (Okon et al., 2009; Shittu et al., 2011, 2012). Interestingly, three et al., 2006). Frontiers in Microbiology | www.frontiersin.org 14 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa Clonal Complex 30 2013) and Senegal (Breurec et al., 2011b). The MRSA isolates ST30-IVa [2B]-PVL-positive, also known as “South-West Pacific from Angola possessed an SCCmec IVa [2B] element (Conceição clone,” has been reported in Egypt (Enany et al., 2010), and et al., 2014). PVL-positive ST88-IV [2B] were detected in Nigeria a multicenter African study identified ST30-V [5C] only in (Ghebremedhin et al., 2009), andanSCCmec subtype ST88-IVa [2B] was identified among three health care workers and a patient Antananarivo, Madagascar (Breurec et al., 2011b). The hospital associated ST36-II [2A] (UK-EMRSA-16), was described only in in São Tomé and Príncipe (Conceição et al., 2013). The ST88-IV South Africa (Goering et al., 2008; Moodley et al., 2010; Jansen [2B] with spa type t3489 was also recovered from nasal samples van Rensburg et al., 2011; Oosthuysen et al., 2014), while ST39- of swine in Senegal (Fall et al., 2012). In addition, an SCCmec II [2A] a dlv was identified in an hospital in Algiers, Algeria non-typeable ST88 was described from an out-patient in Algeria (Djoudi et al., 2013), and Ile-Ife, South-West Nigeria (Shittu (Bekkhoucha et al., 2009), and a strain related to WA-MRSA-2 et al., 2012). MRSA assigned with these groups (ST36-II [2A] and (ST1289-IV [2B]) was identified in Yaoundé, Cameroon (Breurec ST39-II [2A]) were PVL-negative. Furthermore, two SCCmec et al., 2011b). variants, ST37-IVa [2B] and ST37-III [3A], were reported in Other Clonal Complexes Algeria (Ramdani-bouguessa et al., 2006) and Nigeria (Shittu CC7, CC121, and CC152 have been reported in Africa. The PVL- et al., 2012), respectively. negative ST789 (assigned with CC7) was identified in Angola (with SCCmec IV [2B]) (Conceição et al., 2014). However, in Clonal Complex 45 Ghana, ST789 was PVL-positive and carried an SCCmec IV ST45-IV [2B], the “Berlin clone,” was detected in an hospi- element [2B] (Egyir et al., 2014b). An ST1010-PVL-positive tal in the KwaZulu-Natal (South Africa) during a multicen- (CC121) with non-typeable SCCmec element has only been ter surveillance study (Essa et al., 2009) and ST45-V [5C] was described in Egypt (Enany et al., 2010). Furthermore, PVL- reported in mother-infant pairs in Gabon (Schaumburg et al., positive MRSA assigned to CC152 (ST152-SCCmec-NT) was 2014). An MRSA with a non-typeable SCCmec associated with reported in Nigeria (Shittu et al., 2012). community-acquired infections has been identified in Tunisia (Ben Jomàa-Jemili et al., 2013). Finally, ST508-V [5C], a slv to ST45, and also associated with community-acquired infections Discussion was described in Ghana (Egyir et al., 2014a). MRSA has been reported in Africa, at least since 1978 (Scragg Clonal Complex 80 et al., 1978). This systematic review showed that adequate data on The CC80 was limited to three North African countries: Alge- the molecular epidemiology of MRSA are limited, with reports ria, Egypt, and Tunisia (Table 2). The European clone, ST80-IV from only 15 of the 54 African countries. No spa type was [2B]-PVL-positive, was first described in Algeria from both hos- dominant, however, t042 and t044 were the major spa types pitalized and outpatients (Ramdani-bouguessa et al., 2006), and identified in three North African countries (Table 2). Moreover, has continued to be the leading clone in the country (Ramdani- we did not observe a clear distinction between hospital- and bouguessa et al., 2006; Bekkhoucha et al., 2009; Antri et al., community-associated MRSA clones in Africa which is in agree- 2011; Djoudi et al., 2013). ST80-IVc [2B] has been identified ment with other investigations worldwide (Fossum Moen et al., in Egypt (Enany et al., 2010), and Tunisia (Ben Slama et al., 2013; Pasquale et al., 2013; Sherwood et al., 2013; Tavares et al., 2011; Ben Jomàa-Jemili et al., 2013). In addition, sequence types 2013). In this systematic review, the use of the current eBURST related to ST80 have been recovered from human clinical sam- scheme grouped several African MRSA CCs (CC1, CC5, CC8, ples (ST153-SCCmec-NT, ST728-IVc [2B], ST1440-IVc [2B], and and CC7) into a single cluster, (CC5). This raises some con- ST2563-IVc [2B]) (Kechrid et al., 2011; Ben Jomàa-Jemili et al., cern on a suitable method for discrimination and grouping of S. 2013), and nasal specimen of healthy sheep (ST153-SCCmec-NT) aureus isolates. To overcome the above mentioned issue, whole (Gharsa et al., 2012) in Tunisia. The afore-mentioned sequence genome sequencing approach might be the alternative (Dabul types, ST728, ST1440 and ST2563 belonged to accessory gene and Camargo, 2014). regulator (agr) type III and were PVL-positive. Moreover, a Although a combination of factors could be responsible for PVL-negative ST80-IVc [2B] with agr type II has also been the dissemination of clones between continents, increased move- detected in Tunisia (Ben Jomàa-Jemili et al., 2013), and a PVL- ment of human population within or between countries might negative ST635-IV [2B] in Algeria (Ramdani-bouguessa et al., be one of the potential factors (Rogers et al., 2011). International 2006). travel could play a significant role in the transmission of MRSA, particularly the replacement of existing MRSA with fitter and Clonal Complex 88 more transmissible clones (Zhou et al., 2014). We observed that The “West Australia MRSA-2 clone” (WA-MRSA-2), ST88-IV the predominant hospital-associated epidemic clones, EMRSA- [2B], was reported in both hospital and community settings 15 [ST22-IV [2B]) and (EMRSA-16 [ST36-II [2A]), in the United in eight African countries; Angola (Conceição et al., 2014), Kingdom (UK) (Johnson et al., 2005) were reported only in South Cameroon (Breurec et al., 2011b), Gabon (Schaumburg et al., Africa (Goering et al., 2008; Moodley et al., 2010; Jansen van 2011; Ateba Ngoa et al., 2012), Ghana (Egyir et al., 2013, 2014b), Rensburg et al., 2011; Oosthuysen et al., 2014). Moreover, ST80- Madagascar (Breurec et al., 2011b), Niger (Breurec et al., 2011b), IV [2B] (the European clone) has consistently been recognized Nigeria (Ghebremedhin et al., 2009; Shittu et al., 2012; Raji et al., as the predominant PVL-positive MRSA clone in North Africa Frontiers in Microbiology | www.frontiersin.org 15 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa (Ramdani-bouguessa et al., 2006; Bekkhoucha et al., 2009; Ben either rare or limited to people with direct contact with MRSA Nejma et al., 2009, 2013; Enany et al., 2010; Antri et al., 2011; infected/carrier animals (Verkade and Kluytmans, 2013). Using Ben Slama et al., 2011; Ben Jomàa-Jemili et al., 2013; Djoudi whole genome sequencing, evidence of zoonotic transmission et al., 2013). A recent report based on whole genome analy- of MRSA harboring mecC was reported in Denmark (Harri- sis provided strong evidence that the European ST80-IV [2B] son et al., 2013). The mecC-positive MRSA, initially known as was derived from a PVL-positive MSSA ancestor in sub-Saharan a livestock MRSA belonging to the CC130, is recognized in Africa that acquired the SCCmec IV element, and clonal spread both animals and humans in Europe (Paterson et al., 2014a). In was enhanced by increased transnational movement (Stegger addition, this clone has been implicated in severe infections in et al, 2014). However, the factors responsible for the limited humans (Paterson et al., 2014b), resulting in one death (García- spread of the ST80-IV [2B] only in North Africa observed so far Garrote et al., 2014). The clinical importance of mecC-positive are unclear. MRSA is not yet clear in Africa as data is unavailable. Therefore, The SCCmec IV (and its subtypes) and SCCmec V were iden- we suggest that surveillance for MRSA should include detec- tified in several MRSA clones, and ST5 and ST8 clearly showed tion of the mecC gene where mecA is not detected in resistant more diversity in terms of SCCmec types compared with other isolates. STs in Africa. The success of these SCCmec types (IV and V) This systematic review did not seek to provide comprehen- could be due to their small sizes and low fitness costs (Enright sive information on the burden of PVL-positive MRSA in Africa. et al., 2002; Okuma et al., 2002; Monecke et al., 2011). It is However, it provided some interesting observations on their epi- also noteworthy that the SCCmec types IVa and IVc were iden- demiology in Africa such as the identification of PVL-positive tified in genetically unrelated clones, e.g., ST5-IVa [2B] (CC5) isolates assigned with CC7 (originally classified with CC152) in Algeria (Ramdani-bouguessa et al., 2006; Bekkhoucha et al., in Ghana (Egyir et al., 2014a), CC88-IV [2B] in Cameroon 2009), São Tomé and Príncipe (Conceição et al., 2013), ST8- (Breurec et al., 2011b) and Nigeria (Ghebremedhin et al., 2009), IVc [2B] in Tunisia (CC5) (Kechrid et al., 2011), and ST37-IVa ST612-IV [2B] in South Africa (Oosthuysen et al., 2014), and [2B] (CC30) in Algeria (Ramdani-bouguessa et al., 2006). This CC152 in Nigeria (Shittu et al., 2012). Until now, CC152 was might suggest horizontal gene transfer or independent acquisi- only described in the Balkan region (Francois et al., 2008). tion (Mašlaòová et al., 2013). Another interesting observation The mode of acquisition of the mecA gene by ST152 is still was the detection of the SCCmec type IVa and V in the hospital- unknown, but it might be explained by either its introduction through international travel or the acquisition of the methi- associated ST239/ST241-III [3A] in Algeria (Ramdani-bouguessa et al., 2006), Nigeria (Ghebremedhin et al., 2009), and Niger cillin resistance gene by PVL-positive MSSA, which is prevalent (Breurec et al., 2011b). Since ancient MSSA strains for this ST in West and Central Africa (Ruimy et al., 2008; Okon et al., have not been reported (Enright et al., 2002), our observation 2009; Breurec et al., 2011a; Schaumburg et al., 2011; Shittu et al., suggests that acquisition of these SCCmec types by MSSA is less 2011, 2012; Egyir et al., 2014a). These observations highlight likely, and points to the possible replacement of SCCmec type III the need for further surveillance data (including information on with IV and V on the ST239/241 genome (Li et al., 2013). community-acquired necrotizing pneumonia) to understand the Data on the epidemiology of MRSA in animals are limited epidemiology of PVL-associated S. aureus in both hospital and in Africa (EL Seedy et al., 2012; Fall et al., 2012; Gharsa et al., community settings on the African continent. 2012). Moreover, the genetic relatedness between human and animal MRSA has not been investigated (Table 2). It should be Conclusion noted, however, that human-associated ST5-IV [2B], ST88-IV [2B], and ST153-SCCmec-NT have been reported from animals A number of pandemic MRSA clones were identified in Africa. in Tunisia (Gharsa et al., 2012) and Senegal (Fall et al., 2012). In contrast, some MRSA clones are limited to specific countries Recently, human-associated S. aureus lineages were described or regions. Although the eBURST snapshot provided a descrip- in captive Chimpanzees in Gabon, Madagascar, Uganda and tion of the relationship between the MRSA clones reported in Zambia (Schaumburg et al., 2012, 2013; Nagel et al., 2013). Africa and other lineages submitted into the MLST database Notably, a likely case of S. aureus transmission from a veterinar- from other continents, the objective of this review was not to ian to a chimpanzee from the same sanctuary was demonstrated understand the origin of MRSA clones in Africa, as this will (Schaumburg et al., 2012). Zoonotic transmission may consti- require in depth analysis like whole genome sequencing. How- tute a major concern in Africa, where there is often substan- ever, it did show that CC5 is the largest group and predominant tial exposure to domesticated animals (Fall et al., 2012; Gharsa in Africa. Nevertheless, the limited data available on MRSA in et al., 2012). Furthermore, animal-adapted clones might undergo Africa draw attention to the need for increased surveillance of further host-adaptive evolutionary changes, which could result MRSA and molecular epidemiological studies. We strongly rec- in an epidemic spread of new and more virulent strains in the ommend improved co-operation between clinicians and micro- human population (Spoor et al., 2013). Other risk factors for biologists in Africa. This synergy could provide an understanding animal to human MRSA transmission, which include contam- on the local epidemiology of MRSA. In addition, we strongly inated environment (Verkade and Kluytmans, 2013) and meat advocate the establishment of effective diagnostic microbiology products (Hamid and Youssef, 2013), have not been investi- facilities that will incorporate high-throughput technologies for gated in Africa. Livestock-associated MRSA are widespread in monitoring the clonal expansion and dissemination of MRSA. In Europe, but the transmission of these strains to humans is the meantime, increased networking through collaboration with Frontiers in Microbiology | www.frontiersin.org 16 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa S. aureus reference centers could provide support for genotyp- (OPP107641), United States of America; Deutscher Akademis- ing services to African countries with limited resources. Finally, cher Austausch Dienst, Germany; Carnegie Corporation of New population-based surveillances for MRSA are needed to evaluate York, United States of America. Any opinions, findings and con- the situation of community associated MRSA as well as studies on clusions, or recommendations expressed in this review are those MRSA from animal hosts. To understand the origin of the newly of the authors, and therefore do not represent the official position emerged clones, MSSA genotyping needs to be incorporated with of the funders. MRSA surveillance studies. Acknowledgments Author Contributions SMA is supported by the Organization for Women in Science for the developing World (OWSD) and the Drakenstein Child MK, AS, and SMA initiated the project. SMA extracted the data Health Study, Cape Town, South Africa; AS was supported by and reviewed the articles with MK. SMA, AS, MN, and MK wrote Deutscher Akademischer Austausch Dienst (DAAD award) Staff the manuscript. All the authors reviewed the final version of the Exchange Programme (2013); MK was a recipient of Carnegie manuscript prior to submission for publication Corporation of New York (USA) fellowship and is currently a Wellcome Trust (UK) Fellow. Financial Support Supplementary Material This systematic review was supported by the Organization for Women in Science for the Developing World; Clinical Infectious The Supplementary Material for this article can be found Diseases Research Initiative, University of Cape Town, South online at: http://journal.frontiersin.org/article/10.3389/fmicb. Africa; Bill and Melinda Gates Foundation Global Health Grant 2015.00348/abstract References Ben Ayed, S., Boutiba-Ben Boubaker, I., Boukadida, J., Hammami, S., and Ben Redjeb, S. (2010). Hospital acquired outbreak of methicillin-resistant Staphy- Adesida, S., Boelens, H., Babajide, B., Kehinde, A., Snijders, S., van Leeuwen, W., lococcus aureus infection initiated by a health care worker. Tunis. Med. 88, et al. (2005). Major epidemic clones of Staphylococcus aureus in Nigeria. Microb. 199–202. Drug. Resist. 11, 115–121. doi: 10.1089/mdr.2005.11.115 Ben Ayed, S., Boutiba-Ben Boubaker, I., Samir, E., and Ben Redjeb, S. (2006). Preva- Aiken, A. 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USA300 ins on the host: cell lysis and beyond. Curr. Opin. Microbiol. 16, 63–69. doi: methicillin-resistant Staphylococcus aureus emerging as a cause of bloodstream 10.1016/j.mib.2013.01.012 Frontiers in Microbiology | www.frontiersin.org 20 April 2015 | Volume 6 | Article 348 Abdulgader et al. A systematic review on MRSA in Africa Zhou, Y. P., Wilder-Smith, A., and Hsu, L.-Y. (2014). The role of international The first and corresponding authors had full access to the study data. All authors travel in the spread of methicillin-resistant Staphylococcus aureus. J. Trav. Med. had final responsibility for the decision to submit the article for publication. The 21, 272–281. doi: 10.1111/jtm.12133 authors declare that the research was conducted in the absence of any commercial Zribi, M., Etienne, J., El Euch, D., Zribi, H., Bes, M., Meugnier, H., et al. (2011). or financial relationships that could be construed as a potential conflict of interest. Detection of the first strain of glycopeptide intermediary Staphylococcus aureus in Tunis Rabta hospital. Path. Biol. 59, 334–335. doi: 10.1016/j.patbio.2009. Copyright © 2015 Abdulgader, Shittu, Nicol and Kaba. This is an open-access arti- 10.002 cle distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this Conflict of Interest Statement: The authors have no conflict of interest to declare related to the content of this paper. The funders had no role in the study design, journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. data collection and analysis, decision to publish, or preparation of the manuscript. Frontiers in Microbiology | www.frontiersin.org 21 April 2015 | Volume 6 | Article 348

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