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CA-MRSA and HA-MRSA coexist in community and hospital settings in Uganda

CA-MRSA and HA-MRSA coexist in community and hospital settings in Uganda Background: Methicillin resistant Staphylococcus aureus (MRSA) strains were once confined to hospitals however, in the last 20 years MRSA infections have emerged in the community in people with no prior exposure to hospitals. Strains causing such infections were novel and referred to as community-associated MRSA (CA-MRSA). The aim of this study was to determine the MRSA carriage rate in children in eastern Uganda, and to investigate coexistence between CA-MRSA and hospital-associated (HA-MRSA). Methods: Between February and October 2011, nasopharyngeal samples (one per child) from 742 healthy children under 5 years in rural eastern Uganda were processed for isolation of MRSA, which was identified based on inhibition zone diameter of ≤19 mm on 30 μg cefoxitin disk. SCCmec and spa typing were performed for MRSA isolates. Results: A total of 140 S. aureus isolates (18.9%, 140/742) were recovered from the children of which 5.7% (42/742) were MRSA. Almost all (95.2%, 40/42) MRSA isolates were multidrug resistant (MDR). The most prevalent SCCmec elements were types IV (40.5%, 17/42) and I (38.1%, 16/42). The overall frequency of SCCmec types IV and V combined, hence CA-MRSA, was 50% (21/42). Likewise, the overall frequency of SCCmec types I, II and III combined, hence HA-MRSA, was 50% (21/42). Spa types t002, t037, t064, t4353 and t12939 were detected and the most frequent were t064 (19%, 8/42) and t037 (12%, 5/42). Conclusion: The MRSA carriage rate in children in eastern Uganda is high (5.7%) and comparable to estimates for Mulago Hospital in Kampala city. Importantly, HA-MRSA (mainly of spa type t037) and CA-MRSA (mainly of spa type t064) coexist in children in the community in eastern Uganda, and due to high proportion of MDR detected, outpatient treatment of MRSA infection in eastern Uganda might be difficult. Keywords: Eastern Uganda, Iganga/Mayuge districts, Coexistence, Hospital-associated MRSA, Community-associated MRSA, mecA, SCCmec types, spa types Background aureus is a common pathogen in healthy adults and im- Staphylococcus aureus is a recognized cause of mild to munosuppressed individuals [3–12], and persons with severe infections worldwide [1, 2]. However, the burden genetic predispositions [10]. As well, S. aureus is second due to staphylococcal infections in Africa is apparently only to the pneumococcus among the frequent causes of overshadowed by the ‘big three’ diseases –HIV/AIDS, pneumonia in children in Africa [13]. tuberculosis and malaria [3, 4]. Indeed, surveillance Methicillin resistant S. aureus (MRSA) strains, now studies on bacterial infections in Africa show that S. widespread globally, have complicated treatment and control of staphylococcal infections. Once confined to * Correspondence: dkateete@chs.mak.ac.ug hospitals and/or health care environments, MRSA strains Department of Immunology and Molecular Biology, Makerere University are now frequent causes of infection in the community. College of Health Sciences, Kampala, Uganda Nevertheless, surveillance studies have revealed differ- Department of Medical Microbiology, Makerere University College of Health Sciences, Kampala, Uganda ences in MRSA strains causing infections in hospitalized Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 2 of 9 patients and healthcare workers in hospitals vis-à-vis The children screened for MRSA carriage were from a MRSA isolates causing infection in the community (i.e. total of 742 households (one child per household). They community-associated MRSA) [1, 2, 14]. While such de- were selected from the IMHDSS population register marcation of MRSA as “hospital/health care-associated using simple random sampling. Each household was vis- MRSA” (HA-MRSA) or “community-associated MRSA” ited and a child aged between 2 months and 59 months (CA-MRSA) can be confusing [1, 14–16], there are clear was selected using the lottery method of sampling. Using differences in phenotypes and genetic background of a pretested questionnaire, the primary caretaker of the MRSA strains associated with infection in either setting, child in each household was interviewed for information community or hospital [1, 2, 14, 17, 18]. Genotypically, on demographic characteristics, history of illnesses and CA-MRSA are newer and more virulent strains, which antibiotic treatment. Following caretaker consent, a emerged in the late 1990s as major causes of skin and soft nasopharyngeal sample from each child was collected by tissue infections in healthy and relatively young people a study nurse using pre-packed sterile calcium alginate with no prior exposure to hospitals [1, 2, 19, 20]. CA- swabs on flexible aluminum shafts (Becton, Dickson and MRSA strains typically carry SCCmec types IV or V and Company, New Jersey). Swabs were placed in Amies they are generally susceptible to non-β-lactam antimicro- transport medium in a tube and transported to the Clin- bials [1, 2, 14]. Additionally, CA-MRSA carry (but not ical Microbiology laboratory at Makerere University always) Panton Valentine Leukocidin (PVL) encoding College of Health Sciences where they were processed genes LukS-PV and LukF-PV [1, 2] that are associated with for culturing and isolation/identification of S. aureus increased virulence. On the other hand, HA-MRSA according to standard microbiological procedures pub- strains carry SCCmec types I, II, or III and seldom pos- lished previously [25]. sess PVL-encoding genes [1, 2]. HA-MRSA are associ- Susceptibility of S. aureus to antibiotics was deter- ated with nosocomial infections e.g. endocarditis and mined by the disc diffusion antibiotic sensitivity testing they are often resistant to non-β-lactam antimicrobial method as recommended by the Clinical and Laboratory agents especially aminoglycosides, macrolides, lincosa- Standards Institute, (CLSI, 2011) [26]. Briefly, colonies of mides and fluoroquinolones [1, 2]. pure bacterial isolates were suspended in sterile normal Although CA-MRSA has been predicted to replace saline to a turbidity of McFarland standard 0.5, and uni- HA-MRSA in hospitals [19], mathematical models pre- formly spread on Muller Hinton agar (MHA) plates (Bio- dict coexistence between the two strains given the high labs®, Hungary) with antibiotic disks (Biolabs®, Hungary): rates of discharge and hospitalization which bolster penicillin G (10 U), cefoxitin (30 μg), clindamycin (2 μg), hospital-community interactions [21]. Relatedly, we erythromycin (15 μg), vancomycin (30 μg), tetracycline previously detected MRSA strains carrying SCCmec types (30 μg), linezolid (30 μg), trimethoprim/sulphameth- IV or V at Mulago Hospital in Kampala city [22, 23], point- oxazole (1.25/23.5 μg), chloramphenicol (5 μg), cipro- ing to coexistence between CA-MRSA and HA-MRSA in floxacin (5 μg), and gentamicin (10 μg). Plates were thehospital. Theaim of this studywas to determine incubated at 37 °C for 24 h. Inhibition zones were the MRSA carriage rate in children in eastern Uganda, measured in millimeters and interpreted as susceptible and to investigate coexistence between CA-MRSA and (S), intermediate (I) or resistant (R). S. aureus with in- HA-MRSA. hibition zone diameters of ≤19 mm on 30 μg cefoxitin disk were considered to be MRSA, and confirmed for mecA gene carriage by PCR [1, 22]. Methods Study setting, susceptibility testing and MRSA Classification of isolates as CA-MRSA or HA-MRSA identification Because CA-MRSA and HA-MRSA can be recovered from This cross-sectional study was nested in a study that in- either setting (i.e. community or hospital), to classify iso- vestigated pneumococcal carriage in children under 5 lates as CA-MRSA or HA-MRSA we used isolate genotypic years age in the Iganga/Mayuge Health & Demographic characteristics and not clinical/epidemiological features. Surveillance Site (IMHDSS) [13], located in Iganga and Thus, given that SCCmec types I, II & III are typically re- Mayuge districts in eastern Uganda 120 km from Kampala stricted to HA-MRSA and not found widely in healthy pop- city, Uganda’s capital. The IMHDSS is a rural community ulations while SCCmec types IV & V are predominantly covering a contiguous area of ~ 155 km comprising of associated with CA-MRSA [1, 2, 18, 19, 21, 27], MRSA iso- 65 villages and approx. 85,000 people living in 15,652 lates that carried SCCmec types I, II, or III were classified households. It is characterized with significant inter- as HA-MRSA while isolates with SCCmec types IV or V action between healthcare workers and community were classified as CA-MRSA [28]. SCCmec genotyping to members, and 13% of its population are children under delineate HA-MRSA and CA-MRSA was performed as de- 5 years of age [24]. scribed by Boye, et al., (2007) [29]. Also, we compared Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 3 of 9 SCCmec types for MRSA isolates from the IMHDSS in per cent (42/140) of S. aureus were cefoxitin resistant and eastern Uganda to previously described SCCmec types for these were confirmed to be MRSA upon mecA gene PCR MRSA isolates from Mulago Hospital in Kampala [22, 23] (all 42 isolates were mecA positive). Thus, MRSA preva- and pastoral communities in rural western Uganda [30, 31]. lence in S. aureus isolates was 30% and its carriage rate in Coexistence between HA-MRSA and CA-MRSA in the children was 5.7% (42/742). Almost all MRSA isolates i.e. community or hospital was based on occurrence of MRSA 95.2% (40/42) were multidrug resistant (MDR, resistance strains with genetic background of both HA-MRSA (i.e. to three or more classes of antimicrobials) and MDR rates SCCmec types I, II or III) and CA-MRSA (i.e. SCCmec for CA-MRSA and HA-MRSA isolates were similar, types IV or V) in either setting. Table 1. All MRSA isolates were susceptible to rifampicin and anti-MRSA agents (vancomycin & linezolid) and gen- Spa typing erally to clindamycin but they were significantly resistant For spa typing, the x-region (200–400 bp) of S. aureus to non-β-lactam antimicrobial agents commonly used to spa gene was amplified from MRSA with primers and treat staphylococcal infections (SXT, erythromycin, genta- PCR conditions described by Harmsen et al., 2003 [32]. micin, chloramphenicol). Purified PCR products were sequenced at MBN Labora- tories (Kampala, Uganda) or ACGT Inc. (Wheeling, IL, USA) using forward and reverse primers used in PCRs. Spa types and SCCmec elements To obtain spa types, sequences were submitted to an on- The most predominant SCCmec elements were SCCmec line spaTyper server (http://spatyper.fortinbras.us/) and type IV (40.5%, 17/42) and SCCmec type I (38.1%, 16/42). confirmed by cross-checking with Ridom Spa Server SCCmec types II and V accounted for 4 isolates each (http://spaserver2.ridom.de/spatypes.shtml). For quality (9.5%, 4/42) while SCCmec type III accounted for one iso- control, standard reference S. aureus strains ATCC- late. The overall frequency of SCCmec types IV and V 43300 -mecA+, PVL- (MRSA) and ATCC-29213 -mecA-, combined, which define the genetic background of MRSA PVL- (MSSA) & ATCC-25923 -mecA-, PVL+ (MSSA) isolates associated with the community, was 50% (21/42) were used as positive or negative controls. Furthermore, implying the prevalence of CA-MRSA in children was to detect PVL genes, isolates were subjected to PCR- 50% (21/42). This is relatively low compared to reported detection of a 433 bp fragment overlapping the lukS-PV rates of CA-MRSA in the community. Furthermore, the and lukF-PV genes using previously published protocols overall frequency of SCCmec types I, II and III combined, [22, 23]. Apart from spa typing in which all PCR products which define the genetic trait of MRSA isolates associated were sequenced, DNA sequencing of amplified segments with healthcare environments, was 50% (21/42) hence of mecA and PVL genes for randomly selected isolates was similar to SCCmec types IV and IV combined. The PVL performed and sequences confirmed by BLAST searching gene prevalence was low (i.e. 21.4%, 9/42) and distributed at the National Center for Biotechnology Information equally in CA-MRSA and HA-MRSA, Table 1. Taken to- (NCBI) https://blast.ncbi.nlm.nih.gov/Blast.cgi gether, these data show that CA-MRSA and HA-MRSA coexist in children in the community in eastern Uganda, Results Table 1 &Fig. 1. Demographics The observed coexistence between CA-MRSA and MRSA isolates were recovered from 42 of the 742 chil- HA-MRSA in Uganda was first reported at Mulago dren sampled. The characteristics of study population Hospital in Kampala [22, 23] but not explored further. were described previously [13] however, we will highlight Therefore, we compared previously reported SCCmec a few statistics pertinent to this study. The mean age of types for isolates at Mulago Hospital [22, 23] and pas- the children was 30 months and 52% were girls. All chil- toral communities in western Uganda [30, 31] with dren were healthy at the time of screening i.e. none had SCCmec types for isolates from IMHDSS. Due to fre- observable clinical symptoms however, based on reports quent interactions between healthcare personnel from of caretakers (mothers), majority (≥90%) were sick 2 the Mulago Hospital setting and community members in weeks prior to screening and the most common symp- IMHDSS, we hypothesized that the SCCmec types’ dis- toms were fever, running nose and cough. Approx. 30% tribution in the two settings would be similar. Indeed, of the previously sick children were given antibiotics, there was no statistical significance (P = 0.1014) in the mostly ampicillin and co-trimoxazole. distribution of SCCmec types between the IMHSS and Mulago Hospital (Fig. 1) hence, CA-MRSA and HA- MRSA prevalence and drug resistance patterns MRSA coexist in IMHDSS (community) and Mulago The processed nasopharyngeal samples yielded 600 Gram Hospital. Conversely, MRSA from pastoral communi- positive and catalase positive isolates (one per sample/ ties in rural western Uganda carried only SCCmec types child) of which 140 were confirmed to be S. aureus. Thirty IV and V, Fig. 1. Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 4 of 9 Table 1 Genotypes and antibiotic susceptibility patterns of CA- & HA-MRSA from children ≤5 years in eastern Uganda Isolate # PVL mecA SCCmec FOX PEN TET ERY SXT CHL GEN CIP CLI RIF VAN LZD MDR Spa type phenotype HA-MRSA (n = 21) 52–1 + + I R R R RRRR S S S S S Yes 1320–1 – + I R R R RRRR RS S S S Yes 244C-1 – + I R R R RRRR S S S S S Yes K1057–1 – + I R R R SSR R SS S S S Yes t037 K264–1 + + I R R R SSR R SS S S S Yes K284–1 – + I R R R RRRR S S S S S Yes K36–1 – + I R R R RRRS S S S S S Yes t037 K370–1 – + I R R R RRRR S S S S S Yes K39–1 – + I R R R RRRR RS S S S Yes K4834–1 – + I R R R SSR R SS S S S Yes t037 K970–1 – + I R R R SI SS I S S S S No t037 R030–1 – + I R R R RRRR RS S S S Yes R10–1 – + I R R R R R R S R S S S S Yes t12939 R110–1 + + I R R R R R S S S S S S S Yes Unknown R19–1 – + I R R R RRRR S S S S S Yes R220–1 – + I R R R R R S R S S S S S Yes Unknown 1322–1 + + II R R R RRRR I I S S S Yes 306C-1 – + II RRR R R I R S S S S S Yes K911–1 – + II R R R RS RR RS S S S Yes R160–1 – + II R R R R R S S S S S S S Yes t002 R17–1 – + III R R R SR SI SS S S S Yes t037 4 (19) 21 21 21 (100) 21 (100) 21 (100) 16 (76.2) 16 (76.2) 15 (71.4) 15 (71.4) 5 (23.8) 0 (0) 0 (0) 0 (0) 0 (0) 20 (95.2) Total +/R HA-MRSA (%) (100) (100) CA-MRSA (n =21) 1325–1 – + IV R R R R R R I S S S S S Yes Unknown 1326–1 + + IV R R R RS S S RS S S S Yes K2240–1 – + IV R R S S S S S R I S S S No t4353 K2810–1 – + IV R R R RRS S RS S S S Yes R31B-1 – + IV R R R RRS R RS S S S Yes t064 R310–1 – + IV R R R RRRR S S S S S Yes t064 R33–1 + + IV R R R RRRR S S S S S Yes t064 Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 5 of 9 Table 1 Genotypes and antibiotic susceptibility patterns of CA- & HA-MRSA from children ≤5 years in eastern Uganda (Continued) Isolate # PVL mecA SCCmec FOX PEN TET ERY SXT CHL GEN CIP CLI RIF VAN LZD MDR Spa type phenotype K3700–1 – + IV R R R SSR R SS S S S Yes R0100–1 – + IV R R R R R SS SS S S S Yes t064 R02–1 – + IV R R R R R R S R S S S S Yes Unknown R020–1 – + IV R R S SR R R SS S S S Yes R0300–1 – + IV R R R RRRS S S S S S Yes R06–1 – + IV R R R R R SR SS S S S Yes t064 R08–1 + + IV R R R RRRR S S S S S Yes t064 R18–1 – + IV R R R RS RS RS S S S Yes R20–1 – + IV R R I RRRR S S S S S Yes t064 R26A-1 – + IV R R R RRS S RS S S S Yes t064 R040–1 – + V R R R RRRR RS S S S Yes K60–1 + + V R R R RRS S RS S S S Yes K38–1 – + V R R R RRRR I S S S S Yes K350C-1 + + V R R R S S S S R S S S S Yes Unknown Total +/R CA-MRSA (%) 5 (24) 21 21 21 (100) 21 (100) 18 (85.7) 17 (81) 16 (76.2) 12 (57.1) 10 (47.6) 10 (47.6) 0 (0) 0 (0) 0 (0) 0 (0) 20 (95.2) (100) (100) Grand Total +/R (%) 9 42 42 42 42 39 33 32 27 25 15 0 0 0 0 40/42 (95.2) (21.4) (100) (100) (100) (100) (92.9) (78.6) (76.2) (64.3) (59.5) (35.7) (0) (0) (0) (0) The most prevalent Spa types are presented in boldface font FOX cefoxitin, PEN penicillin, TET tetracycline, SXT, ERY erythromycin, CHL chloramphenicol, GEN gentamycin, CIP ciprofloxacin, CLI clindamycin, RIF rifampicin, VAN vancomycin, LZD linezolid, MDR multidrug resistant – resistance to three or more classes of antimicrobials; + Positive, − Negative Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 6 of 9 Fig. 1 SCCmec types for MRSA isolates depicting coexistence between CA-MRSA and HA-MRSA in children under 5 years in rural eastern Uganda. Note that the categorization of MRSA isolates as CA-MRSA or HA-MRSA is based on their genetic background (i.e. SCCmec types) and not clinical/ epidemiological associations. MH denotes Mulago National Referral Hospital; IMHDSS, Health & Demographic Surveillance Site; RWU, Rural Western Uganda A total of five genotypes (t002, t037, t064, t4353 and clinical features of MRSA e.g. the CDC case definition t12939) were detected among MRSA and the most pre- for CA-MRSA infection “Any MRSA infection diagnosed dominant were t064 (19%, 8/42) and t037 (12%, 5/42). for an outpatient or within 48 h of hospitalization if the Thus, t064 and t037 are the prevalent spa types among patient lacks the following health care-associated MRSA CA-MRSA and HA-MRSA isolates respectively, Table 1 risk factors: hemodialysis, surgery, residence in a long- & Additional file 1: Figure S1. When we compared spa term care facility or hospitalization during the previous types with MRSA isolates from Mulago Hospital [22, 23] year, the presence of an indwelling catheter or a percutan- and pastoral communities in rural western Uganda [30, 31], eous device at the time of culture” [1], but such epidemio- we found that with the exception of t002 and t12939, spa logical/clinical definitions are also misleading [1, 14, 21]. types for MRSA isolates from IMHDSS were previously While there is no consensus on interpretation of ‘HA- reported, Additional file 1:Figure S1. Thereweresubtle dif- MRSA vs. CA-MRSA’, MRSA strains are genotypically dis- ferences in distribution of spa types with respect to setting tinguishable through a simple PCR assay, SCCmec typing. e.g. spa types restricted to pastoral communities in rural Currently there are nine SCCmec types –I, II, III, IVa, IVb, western Uganda (circled in Additional file 1:FigureS1). V, VI, VII, VIII and V [1]; types I, II and III are large and occur in HA-MRSA strains while types IV and V are Discussion smaller and occur in CA-MRSA strains [1, 2, 21]. In this study, we found the MRSA carriage rate (5.7%) in There are several factors that could be fuelling coex- children in eastern Uganda to be high and comparable istence between CA-MRSA and HA-MRSA in the com- to reported estimates for MRSA prevalence in adult pop- munity in eastern Uganda. First, previous exposure to ulations in Uganda [7, 9, 23] and generally East Africa antibiotics and/or health care facilities as the children [33, 34]. Furthermore, we have shown that CA-MRSA were reported to be previously sick. The mothers re- and HA-MRSA strains coexist in the community in east- ported that about one third of the children had been ern Uganda and at Mulago hospital in Kampala city. Co- given ampicillin and co-trimoxazole and this could explain existence between CA-MRSA and HA-MRSA has been the high prevalence of MRSA and SXT resistance de- reported extensively in developed countries [16, 35–38] tected. It is important to note that over-treatment of chil- and beyond [35, 39–42] but few studies in Africa have dren with antibiotics is common in Uganda as children explored it. Note, the terms ‘CA-MRSA’ and ‘HA-MRSA’ suffer from 0.3 episodes of pneumonia every year [13]. have also been used to describe the epidemiological and Also, Uganda adopted the World Health Organization’s Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 7 of 9 (WHO) integrated case management of childhood ill- to non-β-lactam antimicrobial agents, perhaps their preva- nesses under which community health workers provide lence contributed to the observed high resistance to non- prompt treatment of malaria and bacterial infections for β-lactam antimicrobials. On the other hand, CA-MRSA children less than 5 years of age. The WHO’s integrated strains are usually susceptible to non-β-lactam antimi- case management guidelines are based on simple clinical crobials [1, 2] but in this study they were not. One ex- signs to help health workers identify and manage malaria, planation for the MDR phenotype and high resistance pneumonia and other childhood illnesses in the commu- to non-β-lactam antimicrobials among CA-MRSA could nity. Although they have been found to increase rational be acquisition of drug resistance genes [27]. A similar prescription of medicines, the WHO guidelines do not trend of CA-MRSA being MDR has been observed distinguish between viral, parasitic (excluding plasmo- elsewhere especially in Europe, Asia and the Americas dium) and bacterial infections implying that a signifi- [43–46]. Case in point is a study from a large veterin- cant number of children in the community receive ary teaching hospital in Costa Rica where nearly all antibiotics [13]. Thus, some MRSA strains in IMHDSS CA-MRSA isolates investigated were MDR and car- were indeed HA-MRSA perhaps arising from circula- ried SCCmec type IV [44]. tion of “escaped”/“feral” HA-MRSA strains in the com- Lastly, this study had a few limitations. First, the small munity as a consequence of management of childhood number of MRSA isolates investigated implies that differ- infections at home [1]. ences observed could be due to low frequencies of geno- The second factor underlying coexistence of CA-MRSA types recorded. However, we sampled a larger population and HA-MRSA in children in eastern Uganda and gener- for recovery of MRSA compared to previous studies in ally at Mulago Hospital could be the interaction between Uganda [7, 9, 22, 23]. Second, for reasons already ex- healthcare workers and community members. Mathemat- plained, we used isolate genotypic characteristics to clas- ical models of MRSA transmission have predicted that sify MRSA isolates as our interest was in unambiguously Hospital-Community interactions foster coexistence be- identifying CA-MRSA and HA-MRSA. While important, tween CA-MRSA and HA-MRSA strains as the high clinical/epidemiological features were not considered as discharge and hospitalization rates continuously cycle both CA-MRSA and HA-MRSA may occur in either individuals between hospitals and the community [21]. setting i.e. community or hospital [14, 21]. Besides, other investigators have implicated frequent interaction between healthcare workers and community Conclusions members in increasing the risk of colonization with The MRSA carriage rate in children in rural eastern MRSA in the community [17]. In Uganda, medical stu- Uganda is high (5.7%) and comparable to estimates for a dents, faculty, health care workers and researchers from large urban teaching facility, Mulago National Referral the Mulago Hospital setting which includes Makerere Hospital, located in Uganda’s capital, Kampala. Import- University medical school use the IMHDSS as a site for antly, HA-MRSA (mainly of spa type t037) and CA-MRSA disease surveillance, research and community-based med- (mainly of spa type t064) coexist in community and hos- ical education. The IMHDSS community members could pital settings in Uganda with no statistical significance for also be colonized by HA-MRSA from nearby healthcare observed differences in rates. Because interaction between facilities as the IMHDSS is served by a government hos- healthcare workers and community members contributes pital, nine public health centers, three non-governmental to presence of HA-MRSA in the community, standard organization hospitals, 122 drug shops and private clinics hygiene measures should be reinforced to prevent cross- [24]. Furthermore, studies by Asiimwe et al. [30, 31]on transmission at the IMHDSS. As well, due to the high pro- MRSA carriage in pastoral communities in rural western portion of MDR-MRSA detected, outpatient treatment of Uganda provided additional support for coexistence be- MRSA infections in eastern Uganda might be difficult. tween CA-MRSA and HA-MRSA in the IMHDSS and Mulago Hospital. MRSA isolates from pastoral communi- Additional file ties in rural western Uganda carried only SCCmec types IV and V that are typical of CA-MRSA and SCCmec types Additional file 1: Figure S1. Spa types for MRSA isolates from children under 5 years in rural eastern Uganda. MH denotes Mulago National I, II and III were not detected [30, 31] hence, CA-MRSA Referral Hospital; IMHDSS, Health & Demographic Surveillance Site; RWU, and HA-MRSA do not coexist in pastoral communities in Rural Western Uganda. The circle signifies spa types that appear restricted rural western Uganda. In context of health service delivery to rural western Uganda. (TIFF 3173 kb) in Uganda, this is understandable as pastoral communities are remote and often characterized with inadequate health Abbreviations CTAB: Cetrimonium bromide; IMHDSS: Iganga-Mayuge Health & service delivery. Demographic Surveillance Site; mecA: Gene encoding the penicillin binding Almost all MRSA isolates in this study were MDR. As protein 2a (PBP2a); MIC: Minimum inhibitory concentration; MRSA: Methicillin HA-MRSA strains are associated with multiple resistance resistant Staphylococcus aureus; MSSA: Methicillin Susceptible Staphylococcus Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 8 of 9 aureus; PCR: Polymerase chain reaction; PVL: Panton Valentine leukocidin; 4. Schaumburg F, Alabi AS, Peters G, Becker K. New epidemiology of SCCmec: Staphylococcal cassette chromosome mec; Spa: Staphylococcal Staphylococcus aureus infection in Africa. Clin Microbiol Infect. 2014; protein A; SXT: Trimethoprim/sulfamethoxazole 20(7):589–96. 5. Jacob ST, Moore CC, Banura P, Pinkerton R, Meya D, Opendi P, Reynolds SJ, Kenya-Mugisha N, Mayanja-Kizza H, Scheld WM, et al. Severe Sepsis in two Acknowledgements Ugandan hospitals: a prospective observational study of management and We thank the healthy volunteers, children and guardians for accepting to outcomes in a predominantly HIV-1 infected population. PLoS One. 2009; participate in the study. We also thank the staff and management of the 4(11):e7782. Clinical Microbiology and Molecular Biology Laboratories of Makerere 6. Mugalu J, Nakakeeto MK, Kiguli S, Kaddu-Mulindwa DH. Aetiology, risk University College of Health Sciences for technical assistance. factors and immediate outcome of bacteriologically confirmed neonatal septicaemia in Mulago hospital, Uganda. Afr Health Sci. 2006;6(2):120–6. Authors’ contributions 7. Ojulong J, Mwambu T, Joloba M, Bwanga F, Kaddu-Mulindwa D. Relative DPK conceived the study, analyzed and interpreted the data, and wrote the prevalence of methicilline resistant Staphylococcus aureus and its first draft of the manuscript. ER, KK, and JS recruited the study participants susceptibility pattern in mulago hospital, Kampala, Uganda. Tanzan J Health and provided samples from which staphylococci were isolated. BBA, DPK, FB, Res. 2009;11(3):149–53. BM, EK, RM, HB and FKA performed the microbiological procedures and 8. Seni J, Najjuka CF, Kateete DP, Makobore P, Joloba ML, Kajumbula H, molecular assays. DPK, CFN, and MLJ supervised the study protocol. All Kapesa A, Bwanga F. Antimicrobial resistance in hospitalized surgical authors read and approved the final manuscript. patients: a silently emerging public health concern in Uganda. BMC Res Notes. 2013;6:298. Funding 9. Anguzu JR, Olila D. Drug sensitivity patterns of bacterial isolates from septic This work was supported through funding from GlaxoSmithKline (gsk)‘s Trust post-operative wounds in a regional referral hospital in Uganda. Afr Health in Science scheme, and through postdoctoral research support (to DPK) from Sci. 2007;7(3):148–54. 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CA-MRSA and HA-MRSA coexist in community and hospital settings in Uganda

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Copyright © 2019 by The Author(s).
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Biomedicine; Medical Microbiology; Drug Resistance; Infectious Diseases
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Abstract

Background: Methicillin resistant Staphylococcus aureus (MRSA) strains were once confined to hospitals however, in the last 20 years MRSA infections have emerged in the community in people with no prior exposure to hospitals. Strains causing such infections were novel and referred to as community-associated MRSA (CA-MRSA). The aim of this study was to determine the MRSA carriage rate in children in eastern Uganda, and to investigate coexistence between CA-MRSA and hospital-associated (HA-MRSA). Methods: Between February and October 2011, nasopharyngeal samples (one per child) from 742 healthy children under 5 years in rural eastern Uganda were processed for isolation of MRSA, which was identified based on inhibition zone diameter of ≤19 mm on 30 μg cefoxitin disk. SCCmec and spa typing were performed for MRSA isolates. Results: A total of 140 S. aureus isolates (18.9%, 140/742) were recovered from the children of which 5.7% (42/742) were MRSA. Almost all (95.2%, 40/42) MRSA isolates were multidrug resistant (MDR). The most prevalent SCCmec elements were types IV (40.5%, 17/42) and I (38.1%, 16/42). The overall frequency of SCCmec types IV and V combined, hence CA-MRSA, was 50% (21/42). Likewise, the overall frequency of SCCmec types I, II and III combined, hence HA-MRSA, was 50% (21/42). Spa types t002, t037, t064, t4353 and t12939 were detected and the most frequent were t064 (19%, 8/42) and t037 (12%, 5/42). Conclusion: The MRSA carriage rate in children in eastern Uganda is high (5.7%) and comparable to estimates for Mulago Hospital in Kampala city. Importantly, HA-MRSA (mainly of spa type t037) and CA-MRSA (mainly of spa type t064) coexist in children in the community in eastern Uganda, and due to high proportion of MDR detected, outpatient treatment of MRSA infection in eastern Uganda might be difficult. Keywords: Eastern Uganda, Iganga/Mayuge districts, Coexistence, Hospital-associated MRSA, Community-associated MRSA, mecA, SCCmec types, spa types Background aureus is a common pathogen in healthy adults and im- Staphylococcus aureus is a recognized cause of mild to munosuppressed individuals [3–12], and persons with severe infections worldwide [1, 2]. However, the burden genetic predispositions [10]. As well, S. aureus is second due to staphylococcal infections in Africa is apparently only to the pneumococcus among the frequent causes of overshadowed by the ‘big three’ diseases –HIV/AIDS, pneumonia in children in Africa [13]. tuberculosis and malaria [3, 4]. Indeed, surveillance Methicillin resistant S. aureus (MRSA) strains, now studies on bacterial infections in Africa show that S. widespread globally, have complicated treatment and control of staphylococcal infections. Once confined to * Correspondence: dkateete@chs.mak.ac.ug hospitals and/or health care environments, MRSA strains Department of Immunology and Molecular Biology, Makerere University are now frequent causes of infection in the community. College of Health Sciences, Kampala, Uganda Nevertheless, surveillance studies have revealed differ- Department of Medical Microbiology, Makerere University College of Health Sciences, Kampala, Uganda ences in MRSA strains causing infections in hospitalized Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 2 of 9 patients and healthcare workers in hospitals vis-à-vis The children screened for MRSA carriage were from a MRSA isolates causing infection in the community (i.e. total of 742 households (one child per household). They community-associated MRSA) [1, 2, 14]. While such de- were selected from the IMHDSS population register marcation of MRSA as “hospital/health care-associated using simple random sampling. Each household was vis- MRSA” (HA-MRSA) or “community-associated MRSA” ited and a child aged between 2 months and 59 months (CA-MRSA) can be confusing [1, 14–16], there are clear was selected using the lottery method of sampling. Using differences in phenotypes and genetic background of a pretested questionnaire, the primary caretaker of the MRSA strains associated with infection in either setting, child in each household was interviewed for information community or hospital [1, 2, 14, 17, 18]. Genotypically, on demographic characteristics, history of illnesses and CA-MRSA are newer and more virulent strains, which antibiotic treatment. Following caretaker consent, a emerged in the late 1990s as major causes of skin and soft nasopharyngeal sample from each child was collected by tissue infections in healthy and relatively young people a study nurse using pre-packed sterile calcium alginate with no prior exposure to hospitals [1, 2, 19, 20]. CA- swabs on flexible aluminum shafts (Becton, Dickson and MRSA strains typically carry SCCmec types IV or V and Company, New Jersey). Swabs were placed in Amies they are generally susceptible to non-β-lactam antimicro- transport medium in a tube and transported to the Clin- bials [1, 2, 14]. Additionally, CA-MRSA carry (but not ical Microbiology laboratory at Makerere University always) Panton Valentine Leukocidin (PVL) encoding College of Health Sciences where they were processed genes LukS-PV and LukF-PV [1, 2] that are associated with for culturing and isolation/identification of S. aureus increased virulence. On the other hand, HA-MRSA according to standard microbiological procedures pub- strains carry SCCmec types I, II, or III and seldom pos- lished previously [25]. sess PVL-encoding genes [1, 2]. HA-MRSA are associ- Susceptibility of S. aureus to antibiotics was deter- ated with nosocomial infections e.g. endocarditis and mined by the disc diffusion antibiotic sensitivity testing they are often resistant to non-β-lactam antimicrobial method as recommended by the Clinical and Laboratory agents especially aminoglycosides, macrolides, lincosa- Standards Institute, (CLSI, 2011) [26]. Briefly, colonies of mides and fluoroquinolones [1, 2]. pure bacterial isolates were suspended in sterile normal Although CA-MRSA has been predicted to replace saline to a turbidity of McFarland standard 0.5, and uni- HA-MRSA in hospitals [19], mathematical models pre- formly spread on Muller Hinton agar (MHA) plates (Bio- dict coexistence between the two strains given the high labs®, Hungary) with antibiotic disks (Biolabs®, Hungary): rates of discharge and hospitalization which bolster penicillin G (10 U), cefoxitin (30 μg), clindamycin (2 μg), hospital-community interactions [21]. Relatedly, we erythromycin (15 μg), vancomycin (30 μg), tetracycline previously detected MRSA strains carrying SCCmec types (30 μg), linezolid (30 μg), trimethoprim/sulphameth- IV or V at Mulago Hospital in Kampala city [22, 23], point- oxazole (1.25/23.5 μg), chloramphenicol (5 μg), cipro- ing to coexistence between CA-MRSA and HA-MRSA in floxacin (5 μg), and gentamicin (10 μg). Plates were thehospital. Theaim of this studywas to determine incubated at 37 °C for 24 h. Inhibition zones were the MRSA carriage rate in children in eastern Uganda, measured in millimeters and interpreted as susceptible and to investigate coexistence between CA-MRSA and (S), intermediate (I) or resistant (R). S. aureus with in- HA-MRSA. hibition zone diameters of ≤19 mm on 30 μg cefoxitin disk were considered to be MRSA, and confirmed for mecA gene carriage by PCR [1, 22]. Methods Study setting, susceptibility testing and MRSA Classification of isolates as CA-MRSA or HA-MRSA identification Because CA-MRSA and HA-MRSA can be recovered from This cross-sectional study was nested in a study that in- either setting (i.e. community or hospital), to classify iso- vestigated pneumococcal carriage in children under 5 lates as CA-MRSA or HA-MRSA we used isolate genotypic years age in the Iganga/Mayuge Health & Demographic characteristics and not clinical/epidemiological features. Surveillance Site (IMHDSS) [13], located in Iganga and Thus, given that SCCmec types I, II & III are typically re- Mayuge districts in eastern Uganda 120 km from Kampala stricted to HA-MRSA and not found widely in healthy pop- city, Uganda’s capital. The IMHDSS is a rural community ulations while SCCmec types IV & V are predominantly covering a contiguous area of ~ 155 km comprising of associated with CA-MRSA [1, 2, 18, 19, 21, 27], MRSA iso- 65 villages and approx. 85,000 people living in 15,652 lates that carried SCCmec types I, II, or III were classified households. It is characterized with significant inter- as HA-MRSA while isolates with SCCmec types IV or V action between healthcare workers and community were classified as CA-MRSA [28]. SCCmec genotyping to members, and 13% of its population are children under delineate HA-MRSA and CA-MRSA was performed as de- 5 years of age [24]. scribed by Boye, et al., (2007) [29]. Also, we compared Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 3 of 9 SCCmec types for MRSA isolates from the IMHDSS in per cent (42/140) of S. aureus were cefoxitin resistant and eastern Uganda to previously described SCCmec types for these were confirmed to be MRSA upon mecA gene PCR MRSA isolates from Mulago Hospital in Kampala [22, 23] (all 42 isolates were mecA positive). Thus, MRSA preva- and pastoral communities in rural western Uganda [30, 31]. lence in S. aureus isolates was 30% and its carriage rate in Coexistence between HA-MRSA and CA-MRSA in the children was 5.7% (42/742). Almost all MRSA isolates i.e. community or hospital was based on occurrence of MRSA 95.2% (40/42) were multidrug resistant (MDR, resistance strains with genetic background of both HA-MRSA (i.e. to three or more classes of antimicrobials) and MDR rates SCCmec types I, II or III) and CA-MRSA (i.e. SCCmec for CA-MRSA and HA-MRSA isolates were similar, types IV or V) in either setting. Table 1. All MRSA isolates were susceptible to rifampicin and anti-MRSA agents (vancomycin & linezolid) and gen- Spa typing erally to clindamycin but they were significantly resistant For spa typing, the x-region (200–400 bp) of S. aureus to non-β-lactam antimicrobial agents commonly used to spa gene was amplified from MRSA with primers and treat staphylococcal infections (SXT, erythromycin, genta- PCR conditions described by Harmsen et al., 2003 [32]. micin, chloramphenicol). Purified PCR products were sequenced at MBN Labora- tories (Kampala, Uganda) or ACGT Inc. (Wheeling, IL, USA) using forward and reverse primers used in PCRs. Spa types and SCCmec elements To obtain spa types, sequences were submitted to an on- The most predominant SCCmec elements were SCCmec line spaTyper server (http://spatyper.fortinbras.us/) and type IV (40.5%, 17/42) and SCCmec type I (38.1%, 16/42). confirmed by cross-checking with Ridom Spa Server SCCmec types II and V accounted for 4 isolates each (http://spaserver2.ridom.de/spatypes.shtml). For quality (9.5%, 4/42) while SCCmec type III accounted for one iso- control, standard reference S. aureus strains ATCC- late. The overall frequency of SCCmec types IV and V 43300 -mecA+, PVL- (MRSA) and ATCC-29213 -mecA-, combined, which define the genetic background of MRSA PVL- (MSSA) & ATCC-25923 -mecA-, PVL+ (MSSA) isolates associated with the community, was 50% (21/42) were used as positive or negative controls. Furthermore, implying the prevalence of CA-MRSA in children was to detect PVL genes, isolates were subjected to PCR- 50% (21/42). This is relatively low compared to reported detection of a 433 bp fragment overlapping the lukS-PV rates of CA-MRSA in the community. Furthermore, the and lukF-PV genes using previously published protocols overall frequency of SCCmec types I, II and III combined, [22, 23]. Apart from spa typing in which all PCR products which define the genetic trait of MRSA isolates associated were sequenced, DNA sequencing of amplified segments with healthcare environments, was 50% (21/42) hence of mecA and PVL genes for randomly selected isolates was similar to SCCmec types IV and IV combined. The PVL performed and sequences confirmed by BLAST searching gene prevalence was low (i.e. 21.4%, 9/42) and distributed at the National Center for Biotechnology Information equally in CA-MRSA and HA-MRSA, Table 1. Taken to- (NCBI) https://blast.ncbi.nlm.nih.gov/Blast.cgi gether, these data show that CA-MRSA and HA-MRSA coexist in children in the community in eastern Uganda, Results Table 1 &Fig. 1. Demographics The observed coexistence between CA-MRSA and MRSA isolates were recovered from 42 of the 742 chil- HA-MRSA in Uganda was first reported at Mulago dren sampled. The characteristics of study population Hospital in Kampala [22, 23] but not explored further. were described previously [13] however, we will highlight Therefore, we compared previously reported SCCmec a few statistics pertinent to this study. The mean age of types for isolates at Mulago Hospital [22, 23] and pas- the children was 30 months and 52% were girls. All chil- toral communities in western Uganda [30, 31] with dren were healthy at the time of screening i.e. none had SCCmec types for isolates from IMHDSS. Due to fre- observable clinical symptoms however, based on reports quent interactions between healthcare personnel from of caretakers (mothers), majority (≥90%) were sick 2 the Mulago Hospital setting and community members in weeks prior to screening and the most common symp- IMHDSS, we hypothesized that the SCCmec types’ dis- toms were fever, running nose and cough. Approx. 30% tribution in the two settings would be similar. Indeed, of the previously sick children were given antibiotics, there was no statistical significance (P = 0.1014) in the mostly ampicillin and co-trimoxazole. distribution of SCCmec types between the IMHSS and Mulago Hospital (Fig. 1) hence, CA-MRSA and HA- MRSA prevalence and drug resistance patterns MRSA coexist in IMHDSS (community) and Mulago The processed nasopharyngeal samples yielded 600 Gram Hospital. Conversely, MRSA from pastoral communi- positive and catalase positive isolates (one per sample/ ties in rural western Uganda carried only SCCmec types child) of which 140 were confirmed to be S. aureus. Thirty IV and V, Fig. 1. Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 4 of 9 Table 1 Genotypes and antibiotic susceptibility patterns of CA- & HA-MRSA from children ≤5 years in eastern Uganda Isolate # PVL mecA SCCmec FOX PEN TET ERY SXT CHL GEN CIP CLI RIF VAN LZD MDR Spa type phenotype HA-MRSA (n = 21) 52–1 + + I R R R RRRR S S S S S Yes 1320–1 – + I R R R RRRR RS S S S Yes 244C-1 – + I R R R RRRR S S S S S Yes K1057–1 – + I R R R SSR R SS S S S Yes t037 K264–1 + + I R R R SSR R SS S S S Yes K284–1 – + I R R R RRRR S S S S S Yes K36–1 – + I R R R RRRS S S S S S Yes t037 K370–1 – + I R R R RRRR S S S S S Yes K39–1 – + I R R R RRRR RS S S S Yes K4834–1 – + I R R R SSR R SS S S S Yes t037 K970–1 – + I R R R SI SS I S S S S No t037 R030–1 – + I R R R RRRR RS S S S Yes R10–1 – + I R R R R R R S R S S S S Yes t12939 R110–1 + + I R R R R R S S S S S S S Yes Unknown R19–1 – + I R R R RRRR S S S S S Yes R220–1 – + I R R R R R S R S S S S S Yes Unknown 1322–1 + + II R R R RRRR I I S S S Yes 306C-1 – + II RRR R R I R S S S S S Yes K911–1 – + II R R R RS RR RS S S S Yes R160–1 – + II R R R R R S S S S S S S Yes t002 R17–1 – + III R R R SR SI SS S S S Yes t037 4 (19) 21 21 21 (100) 21 (100) 21 (100) 16 (76.2) 16 (76.2) 15 (71.4) 15 (71.4) 5 (23.8) 0 (0) 0 (0) 0 (0) 0 (0) 20 (95.2) Total +/R HA-MRSA (%) (100) (100) CA-MRSA (n =21) 1325–1 – + IV R R R R R R I S S S S S Yes Unknown 1326–1 + + IV R R R RS S S RS S S S Yes K2240–1 – + IV R R S S S S S R I S S S No t4353 K2810–1 – + IV R R R RRS S RS S S S Yes R31B-1 – + IV R R R RRS R RS S S S Yes t064 R310–1 – + IV R R R RRRR S S S S S Yes t064 R33–1 + + IV R R R RRRR S S S S S Yes t064 Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 5 of 9 Table 1 Genotypes and antibiotic susceptibility patterns of CA- & HA-MRSA from children ≤5 years in eastern Uganda (Continued) Isolate # PVL mecA SCCmec FOX PEN TET ERY SXT CHL GEN CIP CLI RIF VAN LZD MDR Spa type phenotype K3700–1 – + IV R R R SSR R SS S S S Yes R0100–1 – + IV R R R R R SS SS S S S Yes t064 R02–1 – + IV R R R R R R S R S S S S Yes Unknown R020–1 – + IV R R S SR R R SS S S S Yes R0300–1 – + IV R R R RRRS S S S S S Yes R06–1 – + IV R R R R R SR SS S S S Yes t064 R08–1 + + IV R R R RRRR S S S S S Yes t064 R18–1 – + IV R R R RS RS RS S S S Yes R20–1 – + IV R R I RRRR S S S S S Yes t064 R26A-1 – + IV R R R RRS S RS S S S Yes t064 R040–1 – + V R R R RRRR RS S S S Yes K60–1 + + V R R R RRS S RS S S S Yes K38–1 – + V R R R RRRR I S S S S Yes K350C-1 + + V R R R S S S S R S S S S Yes Unknown Total +/R CA-MRSA (%) 5 (24) 21 21 21 (100) 21 (100) 18 (85.7) 17 (81) 16 (76.2) 12 (57.1) 10 (47.6) 10 (47.6) 0 (0) 0 (0) 0 (0) 0 (0) 20 (95.2) (100) (100) Grand Total +/R (%) 9 42 42 42 42 39 33 32 27 25 15 0 0 0 0 40/42 (95.2) (21.4) (100) (100) (100) (100) (92.9) (78.6) (76.2) (64.3) (59.5) (35.7) (0) (0) (0) (0) The most prevalent Spa types are presented in boldface font FOX cefoxitin, PEN penicillin, TET tetracycline, SXT, ERY erythromycin, CHL chloramphenicol, GEN gentamycin, CIP ciprofloxacin, CLI clindamycin, RIF rifampicin, VAN vancomycin, LZD linezolid, MDR multidrug resistant – resistance to three or more classes of antimicrobials; + Positive, − Negative Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 6 of 9 Fig. 1 SCCmec types for MRSA isolates depicting coexistence between CA-MRSA and HA-MRSA in children under 5 years in rural eastern Uganda. Note that the categorization of MRSA isolates as CA-MRSA or HA-MRSA is based on their genetic background (i.e. SCCmec types) and not clinical/ epidemiological associations. MH denotes Mulago National Referral Hospital; IMHDSS, Health & Demographic Surveillance Site; RWU, Rural Western Uganda A total of five genotypes (t002, t037, t064, t4353 and clinical features of MRSA e.g. the CDC case definition t12939) were detected among MRSA and the most pre- for CA-MRSA infection “Any MRSA infection diagnosed dominant were t064 (19%, 8/42) and t037 (12%, 5/42). for an outpatient or within 48 h of hospitalization if the Thus, t064 and t037 are the prevalent spa types among patient lacks the following health care-associated MRSA CA-MRSA and HA-MRSA isolates respectively, Table 1 risk factors: hemodialysis, surgery, residence in a long- & Additional file 1: Figure S1. When we compared spa term care facility or hospitalization during the previous types with MRSA isolates from Mulago Hospital [22, 23] year, the presence of an indwelling catheter or a percutan- and pastoral communities in rural western Uganda [30, 31], eous device at the time of culture” [1], but such epidemio- we found that with the exception of t002 and t12939, spa logical/clinical definitions are also misleading [1, 14, 21]. types for MRSA isolates from IMHDSS were previously While there is no consensus on interpretation of ‘HA- reported, Additional file 1:Figure S1. Thereweresubtle dif- MRSA vs. CA-MRSA’, MRSA strains are genotypically dis- ferences in distribution of spa types with respect to setting tinguishable through a simple PCR assay, SCCmec typing. e.g. spa types restricted to pastoral communities in rural Currently there are nine SCCmec types –I, II, III, IVa, IVb, western Uganda (circled in Additional file 1:FigureS1). V, VI, VII, VIII and V [1]; types I, II and III are large and occur in HA-MRSA strains while types IV and V are Discussion smaller and occur in CA-MRSA strains [1, 2, 21]. In this study, we found the MRSA carriage rate (5.7%) in There are several factors that could be fuelling coex- children in eastern Uganda to be high and comparable istence between CA-MRSA and HA-MRSA in the com- to reported estimates for MRSA prevalence in adult pop- munity in eastern Uganda. First, previous exposure to ulations in Uganda [7, 9, 23] and generally East Africa antibiotics and/or health care facilities as the children [33, 34]. Furthermore, we have shown that CA-MRSA were reported to be previously sick. The mothers re- and HA-MRSA strains coexist in the community in east- ported that about one third of the children had been ern Uganda and at Mulago hospital in Kampala city. Co- given ampicillin and co-trimoxazole and this could explain existence between CA-MRSA and HA-MRSA has been the high prevalence of MRSA and SXT resistance de- reported extensively in developed countries [16, 35–38] tected. It is important to note that over-treatment of chil- and beyond [35, 39–42] but few studies in Africa have dren with antibiotics is common in Uganda as children explored it. Note, the terms ‘CA-MRSA’ and ‘HA-MRSA’ suffer from 0.3 episodes of pneumonia every year [13]. have also been used to describe the epidemiological and Also, Uganda adopted the World Health Organization’s Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 7 of 9 (WHO) integrated case management of childhood ill- to non-β-lactam antimicrobial agents, perhaps their preva- nesses under which community health workers provide lence contributed to the observed high resistance to non- prompt treatment of malaria and bacterial infections for β-lactam antimicrobials. On the other hand, CA-MRSA children less than 5 years of age. The WHO’s integrated strains are usually susceptible to non-β-lactam antimi- case management guidelines are based on simple clinical crobials [1, 2] but in this study they were not. One ex- signs to help health workers identify and manage malaria, planation for the MDR phenotype and high resistance pneumonia and other childhood illnesses in the commu- to non-β-lactam antimicrobials among CA-MRSA could nity. Although they have been found to increase rational be acquisition of drug resistance genes [27]. A similar prescription of medicines, the WHO guidelines do not trend of CA-MRSA being MDR has been observed distinguish between viral, parasitic (excluding plasmo- elsewhere especially in Europe, Asia and the Americas dium) and bacterial infections implying that a signifi- [43–46]. Case in point is a study from a large veterin- cant number of children in the community receive ary teaching hospital in Costa Rica where nearly all antibiotics [13]. Thus, some MRSA strains in IMHDSS CA-MRSA isolates investigated were MDR and car- were indeed HA-MRSA perhaps arising from circula- ried SCCmec type IV [44]. tion of “escaped”/“feral” HA-MRSA strains in the com- Lastly, this study had a few limitations. First, the small munity as a consequence of management of childhood number of MRSA isolates investigated implies that differ- infections at home [1]. ences observed could be due to low frequencies of geno- The second factor underlying coexistence of CA-MRSA types recorded. However, we sampled a larger population and HA-MRSA in children in eastern Uganda and gener- for recovery of MRSA compared to previous studies in ally at Mulago Hospital could be the interaction between Uganda [7, 9, 22, 23]. Second, for reasons already ex- healthcare workers and community members. Mathemat- plained, we used isolate genotypic characteristics to clas- ical models of MRSA transmission have predicted that sify MRSA isolates as our interest was in unambiguously Hospital-Community interactions foster coexistence be- identifying CA-MRSA and HA-MRSA. While important, tween CA-MRSA and HA-MRSA strains as the high clinical/epidemiological features were not considered as discharge and hospitalization rates continuously cycle both CA-MRSA and HA-MRSA may occur in either individuals between hospitals and the community [21]. setting i.e. community or hospital [14, 21]. Besides, other investigators have implicated frequent interaction between healthcare workers and community Conclusions members in increasing the risk of colonization with The MRSA carriage rate in children in rural eastern MRSA in the community [17]. In Uganda, medical stu- Uganda is high (5.7%) and comparable to estimates for a dents, faculty, health care workers and researchers from large urban teaching facility, Mulago National Referral the Mulago Hospital setting which includes Makerere Hospital, located in Uganda’s capital, Kampala. Import- University medical school use the IMHDSS as a site for antly, HA-MRSA (mainly of spa type t037) and CA-MRSA disease surveillance, research and community-based med- (mainly of spa type t064) coexist in community and hos- ical education. The IMHDSS community members could pital settings in Uganda with no statistical significance for also be colonized by HA-MRSA from nearby healthcare observed differences in rates. Because interaction between facilities as the IMHDSS is served by a government hos- healthcare workers and community members contributes pital, nine public health centers, three non-governmental to presence of HA-MRSA in the community, standard organization hospitals, 122 drug shops and private clinics hygiene measures should be reinforced to prevent cross- [24]. Furthermore, studies by Asiimwe et al. [30, 31]on transmission at the IMHDSS. As well, due to the high pro- MRSA carriage in pastoral communities in rural western portion of MDR-MRSA detected, outpatient treatment of Uganda provided additional support for coexistence be- MRSA infections in eastern Uganda might be difficult. tween CA-MRSA and HA-MRSA in the IMHDSS and Mulago Hospital. MRSA isolates from pastoral communi- Additional file ties in rural western Uganda carried only SCCmec types IV and V that are typical of CA-MRSA and SCCmec types Additional file 1: Figure S1. Spa types for MRSA isolates from children under 5 years in rural eastern Uganda. MH denotes Mulago National I, II and III were not detected [30, 31] hence, CA-MRSA Referral Hospital; IMHDSS, Health & Demographic Surveillance Site; RWU, and HA-MRSA do not coexist in pastoral communities in Rural Western Uganda. The circle signifies spa types that appear restricted rural western Uganda. In context of health service delivery to rural western Uganda. (TIFF 3173 kb) in Uganda, this is understandable as pastoral communities are remote and often characterized with inadequate health Abbreviations CTAB: Cetrimonium bromide; IMHDSS: Iganga-Mayuge Health & service delivery. Demographic Surveillance Site; mecA: Gene encoding the penicillin binding Almost all MRSA isolates in this study were MDR. As protein 2a (PBP2a); MIC: Minimum inhibitory concentration; MRSA: Methicillin HA-MRSA strains are associated with multiple resistance resistant Staphylococcus aureus; MSSA: Methicillin Susceptible Staphylococcus Kateete et al. Antimicrobial Resistance and Infection Control (2019) 8:94 Page 8 of 9 aureus; PCR: Polymerase chain reaction; PVL: Panton Valentine leukocidin; 4. Schaumburg F, Alabi AS, Peters G, Becker K. New epidemiology of SCCmec: Staphylococcal cassette chromosome mec; Spa: Staphylococcal Staphylococcus aureus infection in Africa. Clin Microbiol Infect. 2014; protein A; SXT: Trimethoprim/sulfamethoxazole 20(7):589–96. 5. Jacob ST, Moore CC, Banura P, Pinkerton R, Meya D, Opendi P, Reynolds SJ, Kenya-Mugisha N, Mayanja-Kizza H, Scheld WM, et al. Severe Sepsis in two Acknowledgements Ugandan hospitals: a prospective observational study of management and We thank the healthy volunteers, children and guardians for accepting to outcomes in a predominantly HIV-1 infected population. PLoS One. 2009; participate in the study. We also thank the staff and management of the 4(11):e7782. Clinical Microbiology and Molecular Biology Laboratories of Makerere 6. Mugalu J, Nakakeeto MK, Kiguli S, Kaddu-Mulindwa DH. Aetiology, risk University College of Health Sciences for technical assistance. factors and immediate outcome of bacteriologically confirmed neonatal septicaemia in Mulago hospital, Uganda. Afr Health Sci. 2006;6(2):120–6. Authors’ contributions 7. Ojulong J, Mwambu T, Joloba M, Bwanga F, Kaddu-Mulindwa D. Relative DPK conceived the study, analyzed and interpreted the data, and wrote the prevalence of methicilline resistant Staphylococcus aureus and its first draft of the manuscript. ER, KK, and JS recruited the study participants susceptibility pattern in mulago hospital, Kampala, Uganda. Tanzan J Health and provided samples from which staphylococci were isolated. BBA, DPK, FB, Res. 2009;11(3):149–53. BM, EK, RM, HB and FKA performed the microbiological procedures and 8. Seni J, Najjuka CF, Kateete DP, Makobore P, Joloba ML, Kajumbula H, molecular assays. DPK, CFN, and MLJ supervised the study protocol. All Kapesa A, Bwanga F. Antimicrobial resistance in hospitalized surgical authors read and approved the final manuscript. patients: a silently emerging public health concern in Uganda. BMC Res Notes. 2013;6:298. Funding 9. Anguzu JR, Olila D. Drug sensitivity patterns of bacterial isolates from septic This work was supported through funding from GlaxoSmithKline (gsk)‘s Trust post-operative wounds in a regional referral hospital in Uganda. Afr Health in Science scheme, and through postdoctoral research support (to DPK) from Sci. 2007;7(3):148–54. 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