Multidrug resistant and carbapenemase producing Enterobacteriaceae among patients with urinary tract infection at referral Hospital, Northwest Ethiopia

Urinary tract infections (UTIs) are one of the most common infectious diseases ranking next to upper respiratory tract infection. Urinary tract infections are often associated with significant morbidity and mortality. Worldwide, about 150 million people are diagnosed with UTI each year, costing the global economy in excess of 6 billion dollars [1]. In developing countries, including Ethiopia, the facilities for urine culture and antimicrobial susceptibility testing are still not sufficiently available, leading to improper diagnosis and irrational antibiotic treatment of UTI, which expedites the emergence of multidrug resistant (MDR) strains [2]. Gram negative bacteria, especially the family enterobacteriaceae are the common cause of both community and hospital acquired UTIs. Escherichia coli and Klebsiella pneumoniae are most commonly implicated among patients with UTI [3,4].

Previously, the emergences of MDR among enterobacteriaceae were mainly due to the production of enzymes, such as pencillinases, cephalosorinases, and extended spectrum β-lactamase (ESBL). However, recently carbapenemase production is one of the main mechanisms in the occurrence of drug resistance in the family of enterobacteriaceae. Carbapenemase producing enterobacteriaceae (CPE) are difficult to treat because they have high levels of resistance to antibiotics, which capable of break down all β-lactam agents including carbapenems and make it ineffective. Carbapenem such as imipenem, meropenem, ertapenem, & doripenem are considered as the last resort antibiotics to treat ESBL producing enterobacteriaceae [5,6].

Currently, increased burden of MDRE causing UTI compounded by harboring carbapenem resistance genes mainly among E. coli and K. pneumonia. These strains become a serious threat to public health, associated with high mortality rates and have the potential to spread widely. Infections are difficult, and in some cases impossible to treat and have been associated with mortality rates up to 50%. Due to the movement of patients throughout the health care system, if CPE is a problem in one facility, then typically they are a problem in other facilities in the region as well. Carbapenemase producing enterobacteriaceae are mostly endemic in specific geographical regions, but reports of their spread into other geographical locations are point of grave concern these days [5,7].

The aetiology of UTI and the antibiotic resistance of uropathogens have been changing over the past years, both in community and health care associated infections. Current knowledge on the burden and antimicrobial susceptibility pattern of the enterobacteriaceae isolates is essential for appropriate therapy, since those groups of bacteria are the main cause of UTIs and possess several mechanisms to dismantle currently available antibiotics including carbapenems and the condition in Ethiopia is not yet assessed. Therefore, the objective of this study was aimed to determine the prevalence and risk factors of MDR and CPE producing strains among patients with UTI at the University of Gondar Hospital, Ethiopia.

The overall prevalence of MDR among enterobacteriaceae isolates identified from patients with symptomatic UTI was 87.4% (95% CI; 82–92.3%), which is similar with the results from previous study in Gondar (85.5%) and Mozambique (88.2%) [11,12] while it was higher than reports from other study in Ethiopia: Gondar (68%), and Dessie (74.6%) [13,14] and many other countries, such as USA (19.1%), Belgium (62%), and Italy (62%), Nepal (40.1%, 64.04%) [15-19]. However, it was lower than reports from different parts of Ethiopia such as Gondar (93.5%), Bahirdar (95.6%), and Jimma (100%) [20-22]. The variation in prevalence of MDRE isolates could be due to increase trend of MDR strains with time, difference in study period and study population.

The present study showed that, K. pneumoniae (95.6%) and E.coli (92.9%) were found to be the principal MDR isolates. Although the rate of proportion of MDR is different in different area similar group of bacteria were reported in Bahirdar, Ethiopia E.coli (94.6%) & K. pneumoniae (80%) [21] and Nepal, E.coli (74%) and K. pneumoniae (44%) and Dakar, E. coli and K. pneumoniae (89%) [23] were the predominant MDR uropathogens [19]. These pathogens are the most common isolates in both hospital and community acquired urinary tract infections. Besides, these bacteria are frequently difficult to treat because of both their intrinsic and acquired resistance to multiple groups of antimicrobial agents [3,4].

Among 183 enterobacteriaceae isolates, 5(2.73%) were found to be carbapenemase producers. Comparable result were reported in studies from Morocco (2.8%) [24], Bangladesh (4.8%) [25], Taiwan (2.5%) [26], Belgium (3.5%) [27], and India (5.4%) [28]. However, this was lower than from studies in Pakistan (8.6%) [29], Turkey (10.9%) [30], India (12.9%) [31], Nigeria (14%, 33.5%) [32,33], Iran (14.5%) [34], and USA (21%) [35]. The difference in the prevalence of CPE in different studies may be due to trends in the utilization of carbapenems and other broad spectrum antibiotics, cultural/traditional relationships, cross boarder transfer of patients with other countries of high prevalence. Additionally, difference in target population, sample size and methodological variability could bring variation in the epidemiology of CPE.

Moreover, according to World Health Organization (WHO) 2014 report [36], the epidemiology of CPE has not well studied in developing countries, therefore the report insisted that integrated surveillance program and involvement of very active investigation have to be maximized in order to know the extent of resistant strains in these countries. Even though carbapenems drugs are not formally introduced in to Ethiopia, as the report claimed that increase international travel, globalization and migration might have contributing role in the dissemination of resistant strains from potentially risk countries [36]. Especially, in this study area; there is high tourist flow, and many of residences have relatives from abroad, which may have an impact on the emergence of carbapenemase producing strains in this locality, particularly.

All carbapenemase producing isolates were from hospital admitted patients. This was supported by the fact that inpatients admitted to critical care units for treatment of acute emergencies and chronic diseases are especially liable to get CRE infections because of the presence of highly resistant organisms available in an environment and selective pressure on them due to overuse of antibiotics [37].

In the present study K. pneumoniae, E.coli, and E. aerogenes were carbapenemase producers. This result was supported by the reports from European Antimicrobial Resistance Surveillance Network (EARS-Net) that many of carbapenemase producers were K. pneumoniae followed by E.coli and Enterobacter spp., [38]. The same situations were also notified in finding from Turkey and Morocco indicated that K. pneumoniae were the principal isolate followed by E.coli and K. oxytoca [30,35]. On the other hand, a study from Nigeria demonstrated that E.coli was the main carbapenemase producer followed by Proteus spp. and K. pneumoniae [32]. The variation among studies with regard to the proportion of carbapenemase producing isolates; could be due to difference in geographical distribution of isolates, target population, sample size, and methodology used in each investigation.

In Bivariate analysis, age (years), hospitalization within the past 12 months, prior antibiotic therapy in the past 6 months, and prior UTI in the past 12 months were associated with MDRE UTI in this study. Likewise, in multivariable analysis, age, being female, hospitalization within the past 12 months, and prior antibiotic use in the past 6 months were the independent risk factors for MDRE UTIs. The same result was documented in a study done from USA [15]. However, additional risk factors like health care associated risks (use of urinary catheter, mechanical ventilation, and hemodialysis) were identified in the former study, which were not indicated in this study.

High rates of multi-drug resistance were observed among enterobacteriaceae uropathogens, (87.4%). Very high resistance was reported to ampicillin, followed by cotrimoxazole and chloramphenicol. Isolates of K. pneumonia and E. coli were the principal MDR isolates. Overall prevalence of CPE was 2.73% and all CPE strains were 100% ESBL producer and completely resistant to ampicillin, cefotaxime, cefpodoxime, cotrimoxazole, chloramphenicol, and amoxicillin-calvulanic acid. The only drug that shows low resistance rate was ciprofloxacin. Being female, age, hospitalization, and prior antibiotic use were associated risk factors for MDRE. Therefore, efforts should be made to reduce patient hospital stay and maximize rational use of drugs. Additional and vigorous investigation especially on CPE should be encouraged.