Proportion of extended-spectrum b-lactamase (ESBL)-producing isolates among Enterobacteriaceae in Africa: evaluation of the evidence systematic review

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1 J Antimicrob Chemother 2014; 69: doi: /jac/dkt500 Advance Access publication 6 January 2014 Proportion of extended-spectrum b-lactamase (ESBL)-producing isolates among Enterobacteriaceae in Africa: evaluation of the evidence systematic review Giannoula S. Tansarli 1, Panagiotis Poulikakos 1,2, Anastasios Kapaskelis 1,2 and Matthew E. Falagas 1 3 * 1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece; 2 Department of Internal Medicine Infectious Diseases, Mitera Hospital, Hygeia Group, Athens, Greece; 3 Department of Medicine, Tufts University School of Medicine, Boston, MA, USA *Corresponding author. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, Marousi, Athens, Greece. Tel: ; Fax: ; m.falagas@aibs.gr Received 7 June 2013; returned 12 August 2013; revised 21 November 2013; accepted 29 November 2013 Objectives: Extended-spectrum b-lactamases (ESBLs) have become widespread around the world. We sought to evaluate the proportion of ESBL-producing isolates among Enterobacteriaceae in Africa. Methods: A systematic search in the PubMed and Scopus databases was performed in order to identify studies providing the proportion of ESBL-producing isolates among patients either infected or colonized with Enterobacteriaceae. In an effort to incorporate contemporary data, only studies published from 2005 onwards and, among them, only those including isolates that were recovered from 2000 onwards were eligible. Results: Twenty-six studies ( isolates) from 13 African countries met the inclusion criteria. The proportion of ESBL-producing isolates among 13 studies reporting on isolates from a urinary source varied from 1.5% to 22.8%. Four other studies evaluated various clinical samples from different hospitals, showing that the proportion varied from 12.8% to 21.1%. Last, the proportions were 0.7%, 14%, 15.2% and 75.8%, respectively, in four studies evaluating patients with bloodstream infection. In particular, the proportion was 0.7% in a study from Malawi where ceftriaxone was the only available cephalosporin and was 75.8% in a study from Egypt that included only patients from intensive care units. In total, the proportion of ESBL-producing isolates was,15% in 16 out of 26 studies. Conclusions: Data originating from a small number of African countries suggest that the proportion of ESBL-producing isolates among Enterobacteriaceae may not be high in Africa, but is certainly not negligible. Further studies are needed from countries where no or limited relevant data are available. Keywords: Escherichia coli, E. coli, Klebsiella, K. pneumoniae, Proteus, Enterobacter, Salmonella, Shigella, Providencia, Serratia, Citrobacter, Morganella, percentage, resistance Introduction Extended-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae were first detected in Europe and are widespread around the world. Considerable proportions of this type of Enterobacteriaceae have been observed in certain countries of South-East Europe (.30%), while lower proportions have been recorded in Northern Europe. 1 ESBL-producing organisms are commonly implicated both in nosocomial 2 4 and community-acquired infections. 5 7 Since they are by definition resistant to extendedspectrum cephalosporins and most of them co-transfer enzymes conferring resistance to fluoroquinolones 8,9 as well, carbapenems seem to be the treatment of choice for infections caused by these resistant bacteria. 10 Infections caused by ESBL-producing organisms have been associated with high mortality. 11 Africa is a continent where antimicrobial resistance problems have not been illustrated adequately yet, due to the extremely low financial resources of many countries. Antibiotics, as well as other drugs, are lacking from several regions and thus common infections may be left untreated. The prevention of infections in African countries is, therefore, vital for the healthcare systems in Africa. Knowledge of the proportion of multidrug-resistant (MDR) bacteria in these countries could be helpful both to raise awareness of the need to prevent healthcare-associated infections and to improve clinical practice by guiding empirical antibiotic therapy. # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oup.com 1177

2 In this context, we sought to systematically review and evaluate the available evidence regarding the proportion of ESBL-producing isolates among Enterobacteriaceae in Africa. Methods Literature search A systematic search was conducted in the PubMed and Scopus databases in April The search term that was applied to articles published in both databases from 2005 onwards was the following: (ESBL OR extended spectrum beta lactamase) AND (africa). Additionally, the bibliographies of all relevant studies were hand searched in order to identify further potentially eligible studies. Articles published in languages other than English, German, French, Spanish, Italian or Greek were not evaluated. Study selection criteria Studies reporting the proportion of ESBL-producing isolates among the total Enterobacteriaceae isolates recovered from clinical samples from patients with suspected infections were considered eligible for inclusion in the review. The eligible studies should describe in detail the specific laboratory methods used for the determination of the antimicrobial susceptibility pattern of the pathogens and present the specific breakpoints according to which the MIC of the antibiotics tested was interpreted. Screening studies were excluded from the review. Both adult and paediatric patient populations were eligible, but studies reporting mostly on pregnant women were excluded. When studies included the same or part of the same patient population, the study with the largest population was included. Studies testing,100 isolates of Enterobacteriaceae for ESBL production were excluded. In an effort to incorporate contemporary data, only studies published from 2005 onwards and, among them, only those including isolates that were recovered from 2000 onwards were eligible. Data extraction The extracted data comprised the characteristics of each study (first author name, year of publication, country, study period and design), the type of infection or clinical sample of isolation, the total and individual number of the species of Enterobacteriaceae that were screened for ESBL production and the percentage of ESBL-producing isolates among Enterobacteriaceae. Definitions and outcomes Infection was considered to be present in a study when the investigators of the respective study stated accordingly. The endpoint of the review was the proportion of ESBL-producing isolates among Enterobacteriaceae recovered from clinical samples from patients with suspected infections. Results Two hundred and fifty-six articles were retrieved during the search process (171 from PubMed, 74 from Scopus and 11 from hand searching), out of which 174 were excluded based on the abstract. The full text of the 82 remaining articles was further evaluated, but 56 of them were excluded for various reasons that are presented in detail in Figure 1. Finally, 26 studies from 13 African countries met the criteria and were included in the review. Seven out of the 26 included studies were also included in one of our previous studies, which focused on the antimicrobial susceptibility pattern of uropathogens in Africa. 38 The detailed search process and study selection are presented in Figure 1. In particular, nine studies reported on urinary tract infections (UTIs), 15 18,20,23,31,36,37 among which four were communityacquired, 15,16,23,36 four studies reported on bloodstream infections (BSIs), 19,26,30,35 one on intra-abdominal infections (IAIs), 22 one on invasive shigellosis, 29 two on miscellaneous infections, 25,34 one mostly on UTIs 12 and one mostly on surgical site infections (SSIs). 32 Additionally, studies reporting on samples without clinical information and recovered from the microbiological laboratories of different hospitals or from in- and outpatient settings were also included. Four of them included various samples, 13,21,28,33 one study included exclusively urine samples 27 and one included mainly urine samples. 24 Escherichia coli and Klebsiella spp. were the predominant Enterobacteriaceae among the included studies. The characteristics of the included studies are presented in Table 1. The proportion of ESBL-producing Enterobacteriaceae is presented below, according to the human development index (HDI) of the countries from the 2013 Human Development Report based on data from Countries with high HDI Four of the included studies originated from countries with high HDI, namely Algeria and Tunisia, accounting for 1118 isolates of Enterobacteriaceae that were recovered from patients with infections and screened for ESBL production. 17,20,28,32 The proportion of ESBL-producing isolates varied from 4.3% to 20.2% for UTIs, was 31.4% for SSIs and was 16.4% for the study examining various clinical samples. Countries with medium HDI Ten studies ( isolates) reported on countries with medium HDI, namely Morocco, Egypt and South Africa ,21,22,24,27,29,35,37 The proportion varied from 1.5% to 7.5% for UTIs and was 75.8%, 13.6% and 1.5% for BSI, IAI and invasive shigellosis, respectively. Among samples collected exclusively or in the majority from urine, the proportion varied from 8.1% to 16%. Countries with low HDI Twelve studies (4360 isolates) provided relevant data for countries with low HDI, namely Rwanda, Kenya, Nigeria, Central African Republic, Benin, Senegal, Malawi and Tanzania. 12,13,18,19,23,25,26,30,31,33,34,36 The proportion varied from 3.8% to 22.8% among studies reporting exclusively or mostly on UTIs, was 22% and 10.3% in the two studies including miscellaneous infections and was 15.2%, 14% and 0.7% in the three studies reporting on BSIs. Finally, the proportion was 12.8% and 21.1% in the two studies reporting on various samples. Discussion This study showed that the proportion of ESBL-producing isolates among Enterobacteriaceae may not be high in Africa, but certainly is not negligible. In 16 out of 26 studies, the proportion of ESBL-producing isolates was,15%. 1178

3 JAC Articles identified and screened in PubMed database (N = 171) Articles identified and screened during handsearching (N = 11) Articles identified and screened in Scopus database (N = 74) Full-text articles assessed (N = 58) Full-text articles assessed (N = 7) Full-text articles assessed (N = 17) Articles excluded (N = 56) Studies including <100 isolates of Enterobacteriaceae (n = 22) Duplicates (n = 11) Data on Africa were presented along with those on other continents (n = 5) Studies including part of same population (n = 5) Infections and colonization were presented simultaneously (n = 3) The prevalence of ESBL-producing Enterobacteriaceae could not be extracted (n = 5) Studies including isolates recovered before 2000 (n = 2) No testing for ESBL production was performed (n = 2) Not found (n = 1) Studies included in the systematic review (N = 26) Figure 1. Flow diagram of the systematic search and study selection process. Nevertheless, there were few studies in which the percentage was extremely high or low. In a study from Egypt, which included only BSIs in patients in intensive care units (ICUs), the proportion of ESBL-producing isolates exceeded 75%. 35 This percentage is high and might represent the high proportion of ESBLs in Egypt. However, it should be noted that blood cultures were from patients with nosocomial BSIs (3 days after ICU admission); infections due to MDR pathogens may occur more commonly in patients with high severity of disease while in the ICU and acquisition is more likely to occur in a hospital environment. On the other hand, the proportion of ESBLs was extremely low (0.7%) in a study from Malawi, which is a low-resource country. 26 The authors of the study reported that ceftriaxone was the only available cephalosporin in Malawi and its use was limited. Yet, the proportion of ESBLs was.30% in a study from Algeria reporting mainly on SSIs. 32 Finally, a number of pregnant women were also included in a study showing a very low (3.8%) proportion of ESBL-producing isolates among patients with communityacquired infections. 36 The most common site of reported infections by ESBLproducing isolates was the urinary tract, where the proportion of these isolates was overall rather low, reaching up to 23%. Predictably, the proportion was low for community-acquired infections (1.5% 7.5%) and much higher among urine samples collected from hospitals (15% 16%). Furthermore, ESBLs were more commonly identified among Klebsiella spp. than E. coli isolates, which is consistent with data from Europe. 1 Notably, there was no evident difference in the percentages among African countries with different HDIs. In an effort to compare our findings with the respective findings of studies reporting on data from Europe, some interesting conclusions are drawn. First, the proportion of ESBL-producing Enterobacteriaceae among patients with IAIs according to data from the Study Monitoring Antimicrobial Resistance Trends 40 was lower in Europe (5.3%) compared with the findings in Africa ( 14%). Data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) refer to the percentage of E. coli and Klebsiella pneumoniae strains resistant to thirdgeneration cephalosporins in blood and CSF infections in Europe and estimate the fraction of ESBL-producing strains within. Four of our studies reported on ESBL-producing Enterobacteriaceae in BSIs that ranged from 0.7% 26 to 76%. 35 Comparing the results of our study with the data from EARS-Net, it seems that in Malawi, ESBL production is in the lowest range found in European countries. The percentage reported in the study from Egypt 35 is comparable to countries with very high rates of resistance both with regard to E. coli (40.9%) as well as to Klebsiella spp. (80.9%). However, this study carried many limitations as mentioned 1179

4 1180 Table 1. Characteristics of the studies reporting on the proportion of ESBL-producing isolates among Enterobacteriaceae First author, year Country Study period Study design Infections or sources of clinical samples a Total number of Enterobacteriaceae isolates screened for ESBLs; pathogens (number of isolates of each pathogen) High HDI Ben Haj Tunisia 2009 SC retrospective UTI 198; Klebsiella spp. b (198) 20.2% Khalifa, 2012 Nedjai, 2012 Algeria 2009 SC prospective mostly SSI 207; Klebsiella spp. (NR), Enterobacter 31.4% spp. (NR), Serratia marcescens (NR) Bouzenoune, Algeria SC retrospective UTI 208; E. coli (147), other (61) 4.3% 2009 Iabadene, 2009 Algeria MC prospective all samples 505; E. coli (223), E. cloacae (149), 16.4% K. pneumoniae (112), S. marcescens (6), Proteus mirabilis (7), Providencia stuartii (8) Medium HDI Barguigua, 2013 Morocco 2010 MC prospective community-acquired UTI 453; K. pneumoniae (453) 7.5% Bamford, 2012 South Africa MC retrospective (surveillance) urine ; E. coli (358843) 8.1% Brink, 2012 South Africa MC prospective IAI 808; E. coli (566), Klebsiella spp. (171), P. mirabilis (71) Proportion of ESBLs among Enterobacteriaceae 13.6%: 7.6% E. coli, 34.5% Klebsiella spp., 11.3% P. mirabilis Keddy, 2012 South Africa MC prospective invasive shigellosis 263; Shigella spp. (263) 1.5% Barguigua, 2011 Morocco MC prospective community-acquired UTI 803; E. coli (767), K. pneumoniae (36) 1.5%: 1.3% E. coli, 5.6% K. pneumoniae Fam, 2011 Egypt SC prospective (surveillance) urine c 520; E. coli (291), K. pneumoniae (165), other (64) 16%: 19% E. coli, 14% K. pneumoniae Saied, 2011 Egypt MC prospective BSI 185; K. pneumoniae (162), E. coli (23) 75.8%: 80.6% K. pneumoniae, 40.9% E. coli Zohoun, 2010 Morocco 2008 SC retrospective UTI 1099; E. coli (NR), Klebsiella spp. (NR), Enterobacter cloacae (NR) 5% Habte, 2009 South Africa MC retrospective urine 806; E. coli (482), Klebsiella spp. (239), Proteus spp. (85) Brink, 2007 South Africa 2006 MC prospective (surveillance) Low HDI Aibinu, 2012 Nigeria two-centre prospective Muvunyi, 2011 Rwanda 2009 two-centre prospective all samples 39957; E. coli (28412), K. pneumoniae (7514), Enterobacter spp. (4031) all samples 109; E. coli (109) 12.8% UTI 184; E. coli (119), Klebsiella spp. (37), Proteus spp. (12), Enterobacter spp. (9), Citrobacter spp. (7) 15.1%: 17.4% E. coli, 12.6% Klebsiella spp., 9.4% Proteus spp. 9.7%: 5% E. coli, 26% K. pneumoniae, 12% Enterobacter spp. 22.8% Systematic review

5 Ogbolu, 2011 Nigeria MC prospective all samples 109; K. pneumoniae (63), E. coli (28), P. mirabilis (11), E. cloacae (2), Morganella morganii (3), Serratia odorifera (1), Citrobacter freundii (1) 21.1%: 12.7% K. pneumoniae, 25% E. coli, 27.3% P. mirabilis, 100% E. cloacae, 66.7% M. morganii, 100% S. odorifera Kohli, 2010 Kenya SC retrospective BSI 107; E. coli (69), Klebsiella spp. (38) 14%; 14% E. coli, 13% Klebsiella spp. Olowe, 2010 Nigeria SC prospective miscellaneous (including 116; E. coli (116) 10.3% UTI, gastrointestinal infection, septicaemia) Bercion, 2009 Central African Republic SC retrospective UTI 418; E. coli (357), K. pneumoniae (57), Enterobacter spp. (3), M. morganii (1) 12%: 8.1% E. coli, 29.8% K. pneumoniae, 100% Enterobacter spp., 100% M. morganii Ahoyo, 2007 Benin 2005 SC prospective miscellaneous (65% 143; E. coli (143) 22% suspected UTI) Sire, 2007 Senegal MC prospective community-acquired UTI 1010; E. coli (1010) 3.8% Frank, 2006 Central African SC prospective UTI, pneumonia, wound 450 4% Republic infection, ear infection d Gray, 2006 Malawi SC prospective BSI 1191 e ; Klebsiella spp. (NR), E. coli (NR), E. cloacae (NR) 0.7% Blomberg, 2005 Tanzania SC prospective septicaemia 125 f ; Klebsiella spp. (52), E. coli (36), Salmonella spp. (37) Dromigny, 2005 Senegal SC prospective community-acquired UTI 398; E. coli (398) 6.3% 15.2%: 17.3% Klebsiella spp., 25% E. coli, 2.7% Salmonella spp. Systematic review SC, single centre; MC, multicentre; NR, not reported. a In the studies reporting only the source of the clinical sample, no clinical information was available regarding the presence or absence of infection. b In this study, 94.9% of the Klebsiella spp. isolates were K. pneumoniae. c The majority of the isolates were collected from urine specimens in this study. d Vaginal or intestinal colonization was also included in this study. e Out of 1191 isolates, 649 originated from adult patients and 542 from paediatric patients. f In this study, all isolates were recovered from paediatric patients. JAC 1181

6 above and comparisons are arbitrary. One study from a country with low HDI 30 found 14% ESBL-producing E. coli, which is comparable to most countries of Southern Europe. The remaining study showed 25% ESBL-producing E. coli, 19 while in most countries of Southern Europe the percentages were between 10% and 25%; only in Slovakia (31%) and Cyprus (36.2%) was the percentage higher. Among K. pneumoniae isolates, the percentages varied from 13% 30 to 17.3% 19 andwerehigherthanthosein Scandinavian countries, but lower than those in most countries of Southern Europe. 41 With regard to studies evaluating various clinical samples, data from the Tigecycline Evaluation and Surveillance Trial, including isolates only from Eastern Europe, showed that the percentage of ESBLs among E. coli and K. pneumoniae isolates was 25.8%. 42 On the other hand, in the study by Meropenem Yearly Susceptibility Test Information Collection reporting on various clinical samples from both Mediterranean- Eastern and Northern Europe, the proportion of ESBL-producing Enterobacteriaceae was low (5.3%). 43 Thus our study shows that the proportions of ESBL-producing Enterobacteriaceae in Africa are comparable to those in many European countries and tend to be lower or equal to the respective values in countries of Eastern and Southern Europe, but higher than those observed in Northern Europe. However, the aforementioned comparisons are only indicative, since surveillance systems use predefined protocols for the inclusion of data that are far different from the criteria used for the inclusion of the isolates in the studies of our review. Nonetheless, the lack of antibiotics in many low-resource African countries is juxtaposed with the overuse of antibiotics in Eastern and Southern Europe and this seems to be a rational reason for the relatively low proportions of ESBL-producing organisms in Africa. However, apart from the study from Malawi, no other studies presented data on the availability of antimicrobials. On the other hand, in low-resource countries, empirical antibiotic treatment is administered more commonly than definitive treatment, while low-quality drugs and antibiotics from unsanctioned providers, both observed in Africa, 44,45 may lead to suboptimal treatment or overtreatment, respectively. Furthermore, overcrowded hospitals with inadequate infection control measures pose an additional burden in the increase of antimicrobial resistance in Africa. 45 All these factors may counterbalance the economic differences and result in proportions of ESBL-producing Enterobacteriaceae in Africa comparable to those in European countries with high HDIs, or in comparable proportions of ESBL producers in African countries with different HDIs. In general, clinicians in each country should be aware of the local proportions of resistant pathogens, including ESBL-producing Enterobacteriaceae, and deliver timely, appropriate empirical antibiotic treatment. Specifically in Africa, apart from the improvement of clinical practice, knowledge of the proportion of resistant pathogens in the hospitals of each region could achieve cost savings for the weak healthcare systems through the prevention of nosocomial MDR infections. Interventions including infection control measures and restriction of low-quality antibiotics may also aid in controlling the spread of ESBL-producing pathogens and may actually prove cost-beneficial. In fact, a recent review reporting on MDR infections, including those due to ESBL-producing organisms, showed that the in-hospital costs attributed to multidrug resistance are alarmingly high. 46 Our study should be interpreted considering certain limitations. First, the studies that examined various clinical samples may include both samples collected due to suspected infection and samples collected for screening reasons (i.e. from stools or throat). Accordingly, if these studies include a large proportion of screening samples, the percentage of ESBL-producing Enterobacteriaceae may be underestimated. It should also be highlighted that relevant data were available only for 25% of the African countries. In addition, the majority of the included studies reported on UTIs, while limited data were available for other sites of infection, such as BSIs and IAIs. The currently available data deriving from a small number of countries suggest that the proportion of ESBL-producing isolates among Enterobacteriaceae may not be high overall in Africa, but is comparable to that of European countries and certainly is not negligible. Further studies from all African countries including as many types of infections as possible are needed to completely delineate the percentage of ESBLs in Enterobacteriaceae on that continent. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Coque TM, Baquero F, Canton R. Increasing prevalence of ESBLproducing Enterobacteriaceae in Europe. Euro Surveill 2008; 13: pii¼ FennellJ, VellingaA, HanahoeBet al. 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