Carbapenem Resistant Enterobacteriaceae in Africa

Carbapenems are regarded as unique among the β-lactam antibiotics due to their broad spectrum of activity and ability to resist β-lactamase hydrolysis. Carbapenems are the only β-lactam antibiotics with efficacy in severe infections caused by extended-spectrum betalactamase (ESBL) producing bacteria. However, recent reports of carbapenem resistance particularly among members of Enterobacteriaceae that are responsible for diseases such as gastrointestinal infections, septicemia, pneumonia, meningitis, peritonitis as well as urinary tract infections, call for concerns. In Africa, the problem of carbapenem-resistant Enterobacteriaceae (CRE) is aggravated by factors such as the high rate of infections, poor diagnostic tools, sub-optimal disease surveillance, and abuse of antibiotics. Besides, the problem of CRE in Africa is understudied. This review distills available literature on the spread of CRE in Africa, CRE genes in circulation, and the need to pay attention to this emerging threat to lives in developing countries.


INTRODUCTION
The development of resistance to antimicrobials, which presents a major global public health threat has been evolving rapidly in recent years and spread almost all over the world (Codjoe & Donkor, 2017;Ventola, 2015).
Globally, annual mortality rate due to antimicrobial resistance (AMR) is estimated at 700,000 and by the year 2050 AMR is estimated to claim up to 10 million lives with an annual economic burden of US $100 trillion (Tadesse et al., 2017). In Africa, paucity of CRE data as presented in Figure 1 has hindered estimates of the magnitude of the problem, in addition to increased cases of treatment failure that has resulted in grave socioeconomic indices for the affected population (Kariuki & Dougan, 2014).  (Iovleva & Doi, 2017). Unfortunately, resistance to carbapenems have been reported. The first case of carbapenem resistance was detected from Aeromonas hydrophila isolate in 1980s in Japan and subsequent cases were reported in London, UK (1982) from Serratia marcescens, California, USA (1984) and France (1990), both from Enterobacter cloacae (Codjoe & Donkor, 2017).
Enterobacteriaceae, are a group of rod-like Gramnegative bacteria, the most commonly encountered bacteria in clinical samples and may be responsible for approximately 80% of clinically significant Gramnegative bacilli and 50% of all clinically significant bacteria (Perovic et al., 2016). In Africa, the problem is inflamed by suboptimal disease surveillance and healthcare system, ineffective infection control policies, indiscriminate use of antibiotics, poor diagnostic tools and lack of effective antibiotic stewardship programs in most parts of the continent (Manyi-Loh et al., 2018). In this review, we provide an up-to-date synthesis of CRE data in Africa, highlighting the need for more research within the continent on the surveillance of CRE genes.  (Kelly et al., 2017).

ACQUISITION OF CRE
Isolation of patients helps reduce patient-to-patient transmission of CRE, and has led to a significant reduction of CRE infections in patients with confirmed CRE colonisation at the time of admission, whether symptomatic or not (Magiorakos et al., 2017). The number of individuals that develop infection after colonisation remains unclear (Dortet et al., 2014). In a systematic review where 1,806 hospitalised patients identified as colonised with CRE at the time of admission were studied, only 299 (16.5%) were found to develop infection (Tischendorf et al., 2016). Evidence suggests that longterm hospitalisation plays a critical role in the dissemination of CRE. Therefore, early detection of CRE in patients admitted to health facilities may help mitigate institutional outbreaks and halt regional spread of CRE (Codjoe & Donkor, 2017).
The dissemination of CRE in the community is largely through carriage in commensal microflora, which might go undetected unless disease symptoms manifest (Kumarasamy et al., 2010). In poor communities with limited health facilities in Africa, even when symptoms develop, limited diagnostic and treatment options continues to promote dissemination of CRE among the population in affected communities (Maphumulo & Bhengu, 2019).
The link between community and healthcare acquisition of CRE has been previously described by Dortet et al. (2014) (Lowman et al., 2011).
In the same year, the first blaKPC case in South Africa (blaKPC-2) reported from E. cloacae and K. pneumonia was also identified in K. pneumoniae (Brink et al., 2012).

RESISTANCE AMONG ENTEROBACTERIACEAE
Carbapenem resistance among members of enterobacteriaceae has been reported to be on the increase globally (Okoche et al., 2015). Mechanisms of carbapenems resistance include release of β-lactamases, efflux pumps, and mutations that interfere with the expression and/or function of porins and PBPs.
Combinations of these mechanisms can cause high levels of carbapenem resistance in bacteria (Robin et al., 2010).
While some bacterial strains may possess intrinsic resistance, some others may possess genetic elements such as plasmids or transposons which produce carbapenem-destroying β-lactamases (Kieffer et al., 2016).
The acquired carbapenemases in the Ambler class A group which K. pneumoniae carbapenemases predominate, are the commonest type of β-lactamase enzymes encountered globally (Moussounda et al., 2017;Mitgang et al., 2018). Other carbapenem resistance mechanisms include hyper-expression of AmpC gene or decreased permeability of the outer membrane due to porin loss coupled with the expression of AmpC enzymes or ESBLs (Sangare et al., 2017).