J Antimicrob Chemother 2014; 69: 1177 – 1184
doi:10.1093/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. Tansarli1, Panagiotis Poulikakos1,2, Anastasios Kapaskelis1,2 and Matthew E. Falagas1–3*
1
Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece; 2Department of Internal Medicine—Infectious Diseases, Mitera Hospital,
Hygeia Group, Athens, Greece; 3Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
*Corresponding author. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece. Tel: +30-694-61-10-000;
Fax: +30-210-68-39-605; E-mail: [email protected]
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 (409 215 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 nosocomial2 – 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 fluoroquinolones8,9 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 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: [email protected]
1177
Systematic review
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 2013. 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.
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 UTIs12 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
samples27 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
2012.39
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
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.
Ten studies (403737 isolates) reported on countries with medium
HDI, namely Morocco, Egypt and South Africa.14 – 16,21,22,24,27,29,35,37
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
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.12 – 37
Seven out of the 26 included studies were also included in one
of our previous studies, which focused on the antimicrobial
1178
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%.
JAC
Systematic review
Articles identified and
screened in PubMed
database (N = 171)
Articles identified and
screened during handsearching (N = 11)
Full-text articles
assessed (N = 58)
Full-text articles
assessed (N = 7)
Articles identified and
screened in Scopus
database (N = 74)
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 Trends40
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 Egypt35 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
First author, year
High HDI
Ben Haj
Khalifa, 2012
Nedjai, 2012
Country
Study
period
Infections or sources
of clinical samplesa
Study design
Total number of Enterobacteriaceae
isolates screened for ESBLs; pathogens
(number of isolates of each pathogen)
Proportion of ESBLs among
Enterobacteriaceae
Tunisia
2009
SC retrospective
UTI
198; Klebsiella spp.b (198)
20.2%
Algeria
2009
SC prospective
mostly SSI
31.4%
Algeria
2006– 07
SC retrospective
UTI
207; Klebsiella spp. (NR), Enterobacter
spp. (NR), Serratia marcescens (NR)
208; E. coli (147), other (61)
Algeria
2003– 07
MC prospective
all samples
505; E. coli (223), E. cloacae (149),
K. pneumoniae (112), S. marcescens
(6), Proteus mirabilis (7), Providencia
stuartii (8)
16.4%
Morocco
South Africa
2010
2007– 11
community-acquired UTI
urine
453; K. pneumoniae (453)
358843; E. coli (358843)
7.5%
8.1%
Brink, 2012
South Africa
2004– 09
MC prospective
MC retrospective
(surveillance)
MC prospective
IAI
808; E. coli (566), Klebsiella spp. (171),
P. mirabilis (71)
Keddy, 2012
Barguigua, 2011
South Africa
Morocco
2003– 09
2004– 09
MC prospective
MC prospective
invasive shigellosis
community-acquired UTI
263; Shigella spp. (263)
803; E. coli (767), K. pneumoniae (36)
Fam, 2011
Egypt
2007– 08
urinec
Saied, 2011
Egypt
2006– 07
SC prospective
(surveillance)
MC prospective
BSI
520; E. coli (291), K. pneumoniae (165),
other (64)
185; K. pneumoniae (162), E. coli (23)
Zohoun, 2010
Morocco
2008
SC retrospective
UTI
13.6%: 7.6% E. coli, 34.5%
Klebsiella spp., 11.3%
P. mirabilis
1.5%
1.5%: 1.3% E. coli, 5.6%
K. pneumoniae
16%: 19% E. coli, 14%
K. pneumoniae
75.8%: 80.6% K. pneumoniae,
40.9% E. coli
5%
Habte, 2009
South Africa
2005– 06
MC retrospective
urine
Brink, 2007
South Africa
2006
MC prospective
(surveillance)
all samples
39957; E. coli (28 412), K. pneumoniae
(7514), Enterobacter spp. (4031)
Nigeria
2008– 09
all samples
109; E. coli (109)
12.8%
Rwanda
2009
two-centre
prospective
two-centre
prospective
UTI
184; E. coli (119), Klebsiella spp. (37),
Proteus spp. (12), Enterobacter spp. (9),
Citrobacter spp. (7)
22.8%
Bouzenoune,
2009
Iabadene, 2009
Medium HDI
Barguigua, 2013
Bamford, 2012
Low HDI
Aibinu, 2012
Muvunyi, 2011
1099; E. coli (NR), Klebsiella spp. (NR),
Enterobacter cloacae (NR)
806; E. coli (482), Klebsiella spp. (239),
Proteus spp. (85)
4.3%
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.
Systematic review
1180
Table 1. Characteristics of the studies reporting on the proportion of ESBL-producing isolates among Enterobacteriaceae
Nigeria
2005– 07
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)
Kohli, 2010
Kenya
2003– 08
SC retrospective
BSI
107; E. coli (69), Klebsiella spp. (38)
Olowe, 2010
Nigeria
2006– 07
SC prospective
116; E. coli (116)
Bercion, 2009
Central African
Republic
2004– 06
SC retrospective
miscellaneous (including
UTI, gastrointestinal
infection, septicaemia)
UTI
Ahoyo, 2007
Benin
2005
SC prospective
143; E. coli (143)
Sire, 2007
Frank, 2006
2004– 06
2003– 05
MC prospective
SC prospective
1010; E. coli (1010)
450
3.8%
4%
Gray, 2006
Senegal
Central African
Republic
Malawi
2004– 05
SC prospective
miscellaneous (65%
suspected UTI)
community-acquired UTI
UTI, pneumonia, wound
infection, ear infectiond
BSI
12%: 8.1% E. coli, 29.8%
K. pneumoniae, 100%
Enterobacter spp., 100%
M. morganii
22%
0.7%
Blomberg, 2005
Tanzania
2001– 02
SC prospective
septicaemia
1191e; Klebsiella spp. (NR), E. coli (NR),
E. cloacae (NR)
125f; Klebsiella spp. (52), E. coli (36),
Salmonella spp. (37)
Dromigny, 2005
Senegal
2001– 03
SC prospective
community-acquired UTI
418; E. coli (357), K. pneumoniae (57),
Enterobacter spp. (3), M. morganii (1)
398; E. coli (398)
21.1%: 12.7% K. pneumoniae,
25% E. coli, 27.3%
P. mirabilis, 100% E. cloacae,
66.7% M. morganii, 100%
S. odorifera
14%; 14% E. coli, 13%
Klebsiella spp.
10.3%
Systematic review
Ogbolu, 2011
15.2%: 17.3% Klebsiella spp.,
25% E. coli, 2.7%
Salmonella spp.
6.3%
SC, single centre; MC, multicentre; NR, not reported.
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.
a
JAC
1181
Systematic review
above and comparisons are arbitrary. One study from a country
with low HDI30 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 and were higher than those in
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 MediterraneanEastern 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
1182
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.
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