Meta-analysis of proportion estimates of Extended-Spectrum-Beta-Lactamase-producing Enterobacteriaceae in East Africa hospitals

The production of beta-lactamases is the most common mechanism for bacteria to acquire resistance to broad-spectrum beta-lactam antibiotics. These hydrolytic enzymes are encoded by various gene variants. TEM, named after Temoneira, is one of the first enzymes identified in Europe in the 1960s in Escherichia coli [1]. Since then, several other enzymes like CTX, SHV, OXA have been reported in different parts of the world [2‐8]. Extended-Spectrum-Beta-Lactamase (ESBL) producing Enterobacteriaceae can be defined as those producing β-lactamases capable of conferring bacterial resistance to the penicillins, first-, second-, and third-generation cephalosporins, and aztreonam (but not the cephamycins or carbapenems) by hydrolysis of these antibiotics, and which are inhibited by β-lactamase inhibitors such as clavulanic acid [9].

The proportion of ESBL-producing bacteria causing common infections in all regions of the world is high, making antibiotic resistance due to ESBL being a major global public health problem [10]. Patients infected with ESBL not only have an increased risk of treatment failure, sometimes resulting in death, but also require more health-care resources. ESBL bacterial infections are becoming challenging because physicians run out of drug options. Although there might be differences in magnitude depending on region or country, ESBLs used to be considered primarily nosocomial. Currently they can be frequently found in both hospitals and communities, though magnitudes reported in community-based surveys are generally lower [4, 6‐8, 11‐13]. Several risk factors have been documented to be associated with ESBL acquisition, including: previous hospitalisation, previous use of antibiotics such as third generation cephalosporins, hospital overcrowding, bed sharing when hospitalised, and international travel [3, 14‐19].

Due to regional differences in the ESBL proportion and distribution, therapeutic decisions should be based on local guidelines derived from local epidemiological data [20]. In resource-rich countries many surveillance systems have been set up to estimate the burden of bacterial infections including ESBL and to determine risk factors for acquisition of ESBL bacteria as well as the clinical outcomes associated with their infection [10, 21‐23]. In East Africa however, only scarce and scattered information is available on ESBL epidemiology and risk factors associated with ESBL bacterial infection. When available, the data mostly originates from hospital-based studies [7, 24‐28]. To gain a better insight in the proportion estimates and molecular epidemiology of ESBL-producing Enterobacteriaceae in East Africa, we retrieved available peer-reviewed articles and collated the information in this review article. The PRISMA statement was used to guide the meta-analysis [29]; the PRISMA checklist is available as supplemental material (Additional file 1).

The scarcity of studies available from the East African region warrants caution in drawing conclusions. Little information overall is available, with no studies on Burundi and only one on Rwanda. However, this review finds high proportion estimates of ESBL-producing Enterobacteriaceae across hospitals in the East African region.

The overall pooled ESBL proportion estimate for East African hospitals (42 %) is close to estimates for Ghana (49 %), Cameroon (54 %), Gabon (45 %) and Morocco (43 %) [18, 32‐34]. This estimate is also close to data reported for China, where a nationwide survey that included 30 hospitals reported over 46 % resistance due to ESBL [35]. However the East African proportion is considerably higher than averages reported for resource-rich countries. For instance, the average ESBL proportion estimates reported in a nationwide hospital survey in Germany for 2012 were in the 10 to 15 % range [36]. In 2012, a study for nine US census regions reported ESBL proportion estimates in the 4 to 12 % range [37], while a 9-year survey in Japan recorded a proportion estimate of 6.3 % in 2003 increasing to 10–20 % in 2011 [38]. It should be noted that this study focused on community-acquired infections whereas the other studies concerned nosocomial-infections.

In this review, inter-country and inter-study results show a wide and statistically significant degree of variation in proportion estimates (p < 0.05 in all cases). There are several possible factors that may account for the variations seen in this review. The first factor is the difference in sensitivity and specificity between methods used in estimating proportions. Some studies reviewed estimated ESBL proportions using purely phenotypic methods, while others used both phenotypic and molecular-based methods. The study done in Uganda shows the proportion estimate using genotypic methods being higher (44 %) than when the same isolates were screened for ESBL using phenotypic methods (18 %) [39].

A second factor contributing to the variation in proportion estimates is type of wards or units, site of infection, type of specimen collected and whether patients were attending out-patient or in-patient departments. Hospitalised patients especially in intensive care units are generally at a higher risk of acquiring nosocomial infections, which are likely to be ESBL-producers than patients attending out-patient departments [6, 7, 40‐42]. The Rwanda study [15] reports ESBL proportions of 38 % and 5.9 % among inpatients and outpatients respectively, within a single hospital. Similar findings have been documented in Cameroon where ESBL proportions were 23.1 and 6.7 % among outpatients and healthy volunteers respectively [16].

Many reports have documented the difference in ESBL proportion estimates between hospitals and congested centers (such as orphanages) versus community-based surveys [15, 16, 43‐46]. The lack of any estimates for community-based ESBL carriage in East Africa underscores an urgent need for surveillance in the region. Infection control in hospitals including hand hygiene and rational antibiotic use can be effective measures to stop further spread of the ESBL-producing Enterobacteriaceae in both hospitals and communities.

We noted that few (33.3 %) articles investigated different genes encoding ESBL [6, 12, 24, 31, 39, 47‐49]. The most common gene variants in these articles are those encoding CTX, TEM and SHV. However one study in Tanzania reported occurrence of genes such as NDM that confer resistance to Carbapenem [47]. With such little information in hand, it is difficult to devise focused and effective interventions for containing resistance. Data from other parts of the world, notably from resource-rich countries, might not be generalisable to African settings.

Risk factors associated with resistance due to ESBL are key for planning the optimal approach to managing the problem. Of the reviewed articles only the one study done in Rwanda investigated these factors. It was concluded that previous use of ciprofloxacin, third-generation cephalosporin and being an inpatient or hospitalised are risk factors for ESBL carriage [15]. Similarly, several studies done in other sub-Saharan African countries have documented the previous use of antibiotics (ciprofloxacin), previous hospitalisation, overcrowding in hospitals, and bed sharing to be associated with ESBL colonisation [14, 16, 17]. These findings are consistent with several studies done outside of Africa [50‐58].

When interpreting the data compiled in this review, a number of limitations must be taken into account. All studies took place in university teaching or referral hospitals, which will have a different case-mix from peripheral health centres, and will generally be located in urban areas. Another source of bias is the fact that no study included community-based findings. As in any meta-analysis, the pooled proportions across studies must be interpreted with care, as protocols for observational studies are not standardised across the studies included in the review. A notable factor contributing to variation is the different mix of in- and outpatients between the studies. Finally, the authors acknowledge that more data on ESBL in East Africa may be available from sources other than those searched for this review.

The burden of antibiotic resistance due to ESBL is present across East African region. Little information overall is available, and close to none for Burundi. The available studies present proportion estimates due to ESBL with a wide degree of variation. The scarcity of data on predictors, clinical outcomes, magnitudes and gene variants encoding resistance due to ESBL-producing Enterobacteriaceae calls for active surveillance systems, which can help understand the current epidemiology of ESBL within the region. Furthermore this can aid in developing national and regional guidelines for proper screening of ESBL as well as developing standardized approaches for managing patients colonized with ESBL-producing Enterobacteriaceae.