Extended-spectrum β-lactamase production in Klebsiella pneumoniae and Escherichia coli at Jimma University Specialized Hospital, South-West, Ethiopia  

Shewki Moga Siraj1 , Solomon Ali2 , Beyene Wondafrash3
1. Ethiopian Public Health Institute (EPHI), National Tuberculosis Reference Laboratory, Addis Ababa, Ethiopia
2. Department of Medical Laboratory Science and Pathology, Jimma University, Ethiopia
3. Post Graduate Study Coordinator, Jimma University, Ethiopia
Author    Correspondence author
Molecular Microbiology Research, 2015, Vol. 5, No. 1   doi: 10.5376/mmr.2015.05.0001
Received: 02 Nov., 2014    Accepted: 18 Dec., 2014    Published: 23 Jan., 2015
© 2015 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article:

Siraj et al., 2015, Extended-spectrum β-lactamase production in Klebsiella pneumoniae and Escherichia coli at Jimma University Specialized Hospital, South-West, Ethiopia, Molecular Microbiology Research, Vol.5, No.1 1-9 (doi: 10.5376/mmr.2015.04.0001)


Background: Extended spectrum β-lactamases (ESBLs) have emerged as a major threat worldwide with limited treatment options. The prevalence of ESBL producing Escherichia coli and Klebsiella pneumoniae strains largely remain unknown inEthiopia.

Objectives: The study was aimed to determine the occurrence of extended spectrum β-lactamase-producing E. coli and K. pneumoniae among inpatient and outpatient settings, their antimicrobial resistance profile and associated risk factors in Jimma University Specialized Hospital (JUSH).

Methods: Laboratory based comparative cross-sectional study design was conducted from September 2011 to February 2012.

Result: A total of 471 consecutive, non repetitive clinical specimens were collected among inpatients (n=314) and outpatients (n=157). Among these, 112 isolates of K. pneumoniae (n=27) and E. coli (n=85) were recovered. Overall prevalence of extended spectrum beta lactamase (ESBL) producers was 38.4% (n=43) of total isolates. Extended spectrum beta lactamases were found in 28.2% (n=24) of E. coli and 70.4 % (n=19) of K. pneumoniae. Extended spectrum beta lactamase producers mediated very high resistance to both beta-lactams and non-betalactams and they were significantly higher among isolates from in-patients (46.4%) than out-patients (14.3%). On multivariare analysis, treatment with third generation cephalosporin was identified as a sole risk factor for acquisition of ESBL enzyme.

Conclusions: Our findings confirmed that infection due to extended spectrum beta lactamase -producing E. coli and K. pneumonia is prevalent in Jimma University Specialized Hospital (JUSH) and exposure to third generation cephalosporin was associated with these infections. Resistance of these isolates to antibiotics was also higher among inpatients.

Escherichia coli; Klebsiella pneumoniae; Extended spectrum β-lactamases; Inpatients; Outpatients

The problem of microbial drug resistance has achieved a global dimension and an alarming magnitude, being one of the leading unresolved problems in public health. The relentless evolution of resistance, in the face of a decrease in the development of new antimicrobial agents active against resistant pathogens, has led to an increasing number of cases in which the pathogen is resistant to most, or even all, drugs available for clinical use (Rossolini and Mantengoli, 2008). β-lactam agents such as penicillins, cephalosporins, monobactams and carbapenems are among the most frequently prescribed antibiotics worldwide (Pitout et al., 2005). β-lactams account for approximately 50% of global antibiotic consumption (Livermore, 1998). Bacterial resistance to β-lactam antibiotics occurs by three mechanisms: failure of the β-lactam to reach the penicillin-binding proteins (PBPs), low-affinity binding to the PBPs and inactivation of the drug by β-lactamases (Holbrook and Lowy, 1998). Among this β-Lactamases are the commonest cause of bacterial resistance to β-lactam antimicrobial agents (Livermore, 1995).
The introduction of third-generation cephalosporins into clinical practice in the early 1980s was heralded as a major breakthrough in the fight against β-lactamase-mediated bacterial resistance to antibiotics. The first report of plasmid-encoded β-lactamases capable of hydrolyzing the extended- spectrum cephalosporins was published in 1983 in Germany (Lautenbach et al., 2001). Later these enzymes were named extended-spectrum β-lactamases (ESBLs) (Shah et al., 2004). Since then, several outbreaks have been reported in a number of European countries and the USA, and the problem has reached endemic dimensions in several places worldwide (Giamarellou, 2005).
An Extended-Spectrum β-lactamase is any β-lactamase that can confer resistance to the oxyiminocephalosporins (e.g. cefotaxime, ceftriaxone, ceftazidime) and monobactams (e.g. aztreonam), but not to the cephamycins (e.g. cefoxitin and cefotetan) and carbapenems (e.g. imipenem, meropenem, and ertapenem), and which can be inhibited by β-lactamase inhibitors such as clavulanic acid (Pitout and Laupland, 2008). ESBLs are known as extended-spectrum because they are able to hydrolyze a broader spectrum of β-lactam antibiotics than the simple parent β-lactamases from which they are derived (Al-Jasser, 2006). More than 500 variants of ESBL have been described and the majority of these belong to the TEM (Temoniera), SHV (sulfhydryl variable) and CTX-M (Cefotaximase-Munich) family (http://www.lahey.org/studies/webt.htm).
K. pneumoniae and E. coli remain the major ESBL-producing organisms isolated worldwide, but these enzymes have also been identified in several other members of the Enterobacteriaceae family (Pitout and Laupland, 2008). ESBL -producing E. coli and K. pneumoniae (ESBL-EK) pathogens are of great concern for many reasons. First, ESBL-EK isolates are often difficult to treat because they carry plasmids that confer resistance to multiple antibiotics. Second, patients with ESBL-EK infections may experience a delay in appropriate therapy because current methods of identification can leave them undetected. Third, patients with ESBL-EK infections have significantly longer hospital stays and incur greater hospital charges than do patients without these infections. Finally, patients with ESBL-EK infections have an increased risk of death compared with patients with non-ESBL-EK infections (Bisson et al., 2002). A report from the Infectious Diseases Society of America listed ESBL-producing Klebsiella spp. and E. coli as one of the six drug-resistant microbes to which new therapies are urgently needed (Pitout and Laupland, 2008).
So far, no study has been conducted on ESBL production on both E. coli and K. pneumoniae simultaneously in Ethiopia. The aim of this study is to determine prevalence and antibiotic susceptibility pattern of ESBL producing E. coli and K. pneumoniae from inpatients and outpatients that attend Jimma university specialized hospital (JUSH) as well as to identify possible risk factors for infections with ESBL producing E. coli and K. pneumoniae.
1 Methods and Materials
Laboratory based comparative cross-sectional study design was conducted in JUSH, Ethiopia. The hospital is a 300 bed teaching hospital which covers population of over 1 million. Sample size was estimated using Epi-info statistical software package (version 3.4.3, WHO Atlanta) for cross sectional studies of two population proportion to attain inpatient to outpatient ratio of 2:1. Patients' demographic data, clinical diagnosis, risk factor and specimen types were recorded for all patients included during the study period by using a questionnaire. All collected specimens were inoculated on the MacConkey agar (Oxoid, England). E. coli and K. pneumoniae were identified by their characteristic colony appearance: pink or yellow to colorless colonies (due to fermentation of lactose) from MacConkey agar, gram-staining reaction and confirmed by the pattern of biochemical profiles using standard procedures (Koneman EW et al., 2006).An isolate was considered as E. coli when it is Indole positive, citrate negative, lysine positive, gas and acid producer, ferments mannitol, urea negative and motile. An isolate was identified as K. pneumoniae when it is indole negative, citrate positive, ferments mannitol, lysine positive, urea slow producing and non-motile. The antimicrobial susceptibility was done by using Kirby-Bauer disc diffusion technique on Mueller Hinton agar (Oxoid, England) with commercially available antimicrobial discs. Strains were tested against the following antimicrobial agents: cefotaxime (30μg), ceftazidime (30μg), ceftriaxone (30μg), amoxicillin-clavulanic acid (20/10μg), cephalothin (30μg), ampicillin (10μg), carbenicillin (100μg), trimethoprim-sulfamethoxazole (25µg), chloramphenicol (30µg), norfloxacin (10µg), ciprofloxacin (5µg), nitrofurantoin (300μg), nalidixic acid (30μg), gentamicin (10µg), amikacin (30µg), and tetracycline (30µg).
All E. coli and K. pneumoniae isolates were screened for ESBL production by disc diffusion method using ceftazidime (30μg), cefotaxime (30μg) and ceftriaxone (30μg) antibiotic discs (Oxoid & MAST) as recommended by Clinical and Laboratory Standards Institute (CLSI, 2005). Each disc was placed on Muller Hinton agar manually and incubated for 16-18 hours at 35 0C. Isolates with reduced susceptibilities to cefotaxime (zone diameter of ≤27mm), ceftazidime (zone diameter of ≤22mm) and/or ceftriaxon (zone diameter of ≤25 mm) was suspected as a potential ESBL producer (Clinical and Laboratory Standard Institute, 2005). Potential ESBL producers were confirmed by Double Disc Synergy Test (DDST). A susceptibility disc containing amoxicillin–clavulanate was placed in the centre of a Mueller-Hinton agar plate, and a disc containing 30 of ceftazidime, ceftriaxone and cefotaxime were placed 15 mm (centre to centre) from the amoxicillin–clavulanate disc. Plates were incubated at 37oC for 16-18 hours. Enhancement of inhibition zone of any these of cephalosporin discs on the side facing the amoxicillin-clavulanate disc was interpreted as ESBL positive (Jarlier et al., 1988). Multidrug resistance was defined as resistance to 2 or more classes of antibiotics (quinolones, trimethoprim- sulfamethoxazole, tetracycline or aminoglycosides).
The data were processed and analyzed for descriptive statistics using SPSS statistical software, version 16.0. All variables were examined by univariate analysis using the chi-square or Fisher’s exact test, as appropriate. Multivariate analysis was performed for variables that were independently associated with ESBL-infection on univariate analysis. P- value of less than 0.05 was considered statistically significant. The study was done after gaining a full approval from the Ethical Review Board of Jimma University and JUSH.
2 Result
2.1 Patient population and source of specimens
Overall, 471 patients were included in the study (314 inpatients and 157 outpatients). From these 273 (58%) were females and 198 (42%) were males. The mean age of participants was 31.15 years (±16.97 SD). E. coli and K. pneumoniae were recovered from 112 (23.8 %) clinical specimens, constituting 85 (18%) and 27 (5.7%) of total prevalence, respectively. Of 112 isolates, 46 (40.2%) were from urine, 25 (22.3%) from vaginal swab, 18(17%) from sputum, 14 (12.5%) from pus, 6 (5.4%) from eye discharge and 3 (2.7%) from blood. Three-fourth (n=84) of isolates were obtained from inpatients and the remaining one-fourth (n=28) was from outpatients. ESBL producing E. coli and K. pneumoniae were detected in 43/112 (38.4%) of the isolates. The mean age of patients infected by ESBL producers was 36.79 years (±18.89 SD). The majority 31/43 (72.1%) of ESBL isolates were obtained from females and the rest 12/43 (27.9%) were isolated from males. There was no association between ESBL production and specific sex groups (P >0.05) (Table 2). Nineteen (70.4%) isolates of K pneumoniae were found to be positive for ESBL. ESBL production was significantly higher among K. pneumoniae than E. coli isolate (p<0.01). The prevalence of ESBL-producing E. coli and K. pneumonia was 4/157 (2.5%) in outpatients and 39/314 (12.4 %) in inpatients, and thus the risk of development of ESBL-productionwas 5 times higher in inpatients as compared to outpatients with significant difference (P <0.05) (Table 1).

Table 1 Distribution of ESBL-production according to isolates and settings

Table 2 Characteristics of ESBL-EK and non-ESBL-EK infected patients among inpatient and outpatient settings

Associated factors for ESBL-EK
All included variables were evaluated among inpatients and only five variables were analyzed among outpatients. On univariate analysis, Prior exposure to antibiotic was associated with ESBL-production among both hospitalized and non hospitalized patients. Treatment with third generation cephalosporins, severity of illness, length of hospital stay and chronic heart failure (CHF) and medical ward admission were additionally associated with ESBL production among hospitalized patients. On multivariate analysis, treatment with third generation cephalosporin (ceftriaxone) is the only risk factor being associated with ESBL infection.
2.3 Antibiotic resistance profile ofESBL-EK
The ESBLproducing E. coli and K. pneumoniae were significantly resistant to third-generation cephalosporins compared to non producers (p<0.05) (Table 3). Resistance conferred by ESBL producing K. Pneumoniae and E. coli to ceftazidime, cefotaxime and ceftriaxone was 97.7%, 100% and 100% respectively. On the other hand, non ESBL isolates were almost susceptible to third generation cephalosporins with 91.3%, 98.6% and 100% susceptibility against ceftazidime, cefotaxime and ceftriaxone respectively. Good susceptibility was observed with amikacin in both ESBL (83.7%) and non ESBL producers ((97.1%). Both ESBL producer and non-producer isolates were completely (100%) resistant to carbenicillin.

Table 3 Comparison of the Susceptibility Profiles of ESBL-Producing and Non–ESBL-Producing EK

Resistance Pattern between Outpatient and Inpatient Isolates
Generally, inpatient isolates showed higher rates of resistance to most tested antibiotics compared with outpatient isolates. The difference in susceptibility between inpatient and outpatient isolates was statistically significant for 12 (75%) of 16 tested antibiotics (p<0.05). However, the rates of resistance to amikacin, chloramphenicol, ampicillin and carbenicillin, were not significantly different between inpatient and outpatient isolates (Table 4).
2.5 Multi drug resistant ESBL-EK
The resistance rates of ESBL isolates to 2 or more classes of antibiotics are given in Table 5, descending from the lowest to the highest resistant isolates. ESBL-EKgenerally showed higher rates of resistance to antibiotics tested than non-producers. About 88.4 % of ESBL isolate were multi drug resistant exhibiting cross-resistance against both cotrimoxazole and tetracycline. Resistance to three non beta-lactam antibiotics was observed among 35 (81.4%) isolates; in addition approximately 70% of ESBL positive isolates were cross-resistant to four non beta-lactam antibiotics (tetracycline, cotrimoxazole, nalidixic acid and gentamicin). The coexistence of ESBL phenotypes with five, six and seven types of non beta-lactam antibiotics were 26 (60.5%), 22 (51.2%) and 9 (20.9%) respectively. Three (7%) ESBL isolates were completely resistant to all panels of antibiotics tested.

Table 4 Resistance to specific antimicrobials in isolates from inpatients versus outpatients

Table 5 The resistance rates of ESBL isolates to 2 or more classes of non beta lactam antibiotics

ESBLs are widespread all over the world. The prevalence and genotype of ESBLs from clinical isolates vary according to the country and even hospital at which they are isolated from (Kim et al., 2010). The overall frequency of ESBLs in the current study was 38.4% (43/112). This frequency ishigher than continental surveys conducted in Europe (11%), South America (18.1%), North America (7.5%) and Asia-Pacific (14.2%) regions (Hawser et al., 2011; Turner, 2005). The higher prevalence seen in our study compared to developed countries might be explained by the fact that developed countries have strict infection control policies and practices, shorter average hospital stays, better nursing barriers that are known to substantially decrease the chances of acquisition and spread of ESBLproducing strains.
On the other hand, the prevalence of ESBL observed in this study is lower than a study done in Tanzania (45.2%) conducted variably on urinary isolates (Moyo et al., 2010). The decline observed in our study can be attributed to the inclusion of various types of specimens. Regardless of such myriad variation, this finding agrees with previous reports on ESBL production done in United Arab Emirates (Al-Zarouni et al., 2008).
Although E. coli ranks higher in the number of infection occurrences than K. pneumoniae, the predominant ESBL producer in our setting is K. pneumoniae. ESBL production was significantly higher among K. pneumoniae than E. coli (p<0.01).This finding is in agreement with previous report done among K. pneumoniae and E. coli with respective prevalence of 70% and 28% in Pakistan, and 51.5% and 39.1% in Tanzania, which demonstrated predominance of ESBL production by K. pneumoniae than E. coli (Shah et al., 2003; Moyo et al., 2010). Other study had also demonstrated conquest of ESBL producing K. pneumoniae not only over E coli but also over other group of gram negative bacilli including family Enterobacteriaceae (Galas et al., 2008). The predilection of ESBL production by K. pneumoniae has never been clearly explained (Mshana et al., 2009). Our observation that K. pneumoniae was significantly associated with ESBL production merely reflects local and worldwide epidemiology which clearly shows that ESBL production has been more frequently observed in these bacteria than in E. coli.
Undesirable turn of events transpired when ESBL producing E. coli were detected in the community. Three (75%) of the four ESBL producers from outpatients were E. coli. The occurrence of ESBL-producing E. coli isolates in the community is in keeping with the global trend of emergence of community-acquired infections caused by ESBL-producing strains, in particular those which harbor the CTX-M gene. These gene have been reported in Africa (Kariuki et al., 2007). A report from Japan showed that patients with fecal carriers of ESBL-producing E. coli contributed substantially to urinary tract infections (Niki et al., 2011). This tendency could markedly change the approach to the treatment of urinary tract infections and other infections due to ESBL producing E. coli that are encountered in the outpatient setting.
The interesting point of the present study was a correlation between multiple antibacterial resistances and ESBL positive phenotypes. This finding indicates that ESBL-producing strains of K. pneumoniae and E. coli are more likely to have diminished susceptibility to non-β-lactam antibiotics compared with non-ESBL-producing isolates, further curtailing the number of drugs useful against these bacteria.This result has been confirmed by others (Moyo et al., 2010; Mshana et al., 2009). This is mainly associated with unique property of the large ESBL plasmid which is capable of incorporating and subsequently coding for resistant determinants to non beta-lactam antimicrobial agents (Jacoby and Sutton, 1991). Thus our study results well support the fact that ESBLproducers not only confer high levels of resistance to third generation cephalosporins but also to non-beta lactams like aminoglycosides, fluoroquinolones, tetracyclines and cotrimoxazole.
Thirty-eight (88.8%) of ESBL isolates showed multi drug resistance from 2 to 8 types of non beta lactam antibiotics tested. Of particular concern is that three (7%) of ESBL producing isolates were resistant to all panels of antibiotics used. Thus, the presence of an ESBL is a good marker of the MDR phenotype. In the present study, amikacin has retained good susceptibility rates due to its absence of use as empirical therapy and nonexistence of considerable crossresistance with third generation cephalosporins. Similarly study from Egypt also showed the high percentage of susceptibility to amikacin among antibiotics tested (Zaki, 2007). These findings have significant implication for empirical management of patients infected with ESBL organisms using amikacin.
Third-generation cephalosporin specifically ceftriaxone is one of the most commonly used classes of antibiotics for hospitalized patients in Ethiopia, as observed during this study, exerting predominant selective pressure for the emergence of resistance among pathogenic microorganisms. On multivariable analysis, use of third generation cephalosporins was identified as the only risk factors significantly associated with infection due to ESBL producers. This finding is in accordance with previous studies disclosing that indiscriminate use of third-generation cephalosporins was related to the selection of ESBL-producing organisms (Lautenbach et al., 2001). Use of cephalosporins is not only associated with ESBL infection, but also it was found to be a risk factor for colonization with ESBL producing organisms (Levy et al., 2010). As a result the higher percentage of ESBL-producing E. coli or K. pneumoniae in the current study is may be due to the greater selective pressure imposed by extensive use of third-generation cephalosporins.This association has been best displayed by interventional study which demonstrated decline in the prevalence of ESBL-EK colonization from 7.9% to 5.7% following restriction of third-generation cephalosporins (Bisson et al., 2002). In general, the association of ESBLwith third-generation cephalosporins suggests that the best way to control these pathogens in our hospital is to reduce the use of these antibiotics.
ESBLs occurrence was significantly higher among isolates from inpatients than outpatients [39 (46.4%) vs. 4(14.3%)] (P £0.002). Nosocomial acquisition ofESBL producing E. coli and K. pneumoniae bacteremia has been reported indicating that hospital environment played a crucial role for maintenance of ESBL producing organism (Kang et al., 2006). Furthermore higher rate of fecal carriage of ESBL-producing organisms among inpatients (26.1%) than among outpatients (15.4%) is documented elsewhere in Saudi Arabia (Kader et al., 2007). This suggests that nosocomially acquired organisms are more likely to become ESBL producer.
More than 70% ofstrains isolated from both inpatient and outpatient groups showed resistance to ampicillin, cephalothin and carbenicillin. This may alarm the presence of the classic β- lactamase which was recognized among these isolates prior to isolation of ESBL enzymes (Livermore, 1995). In addition, marked resistance to tetracycline and co-trimoxazole was observed in the inpatient group (77.4% to tetracycline and 75% to TMP-SMZ) and with slight decrease in the outpatient group (51.7% to tetracycline and 48.3% to TMP-SMZ), this may be explained by the frequent use of both antibiotics in the community as well as in our hospital. Therefore, the use of this drug is questionable in suspected E. coli and K. pneumoniae infection in our setting.
Limitation-We are familiar with the limitation of study, as noted in all observational studies. Molecular epidemiological study and characterization of ESBL types were not conducted. Second, we did not assess certain clinical features such as ICU admission and urinary catheterization as potential risk factor for infection with ESBL producing EK due to few numbers of cases which are insignificant number to be included during study period. Third, our study was conducted in JUSH, and the results may not be generalized to other institutions.
Conclusion-Our data provide evidence that the ESBL producing bacteria are prevalent in JUSH. Majority of ESBL producing strains come from inpatients and only fewbeing community isolates. Therefore it is very urgent to address the problem of hospital acquired infections caused by ESBL-producing bacteria. Use of third generation cephalosporin was the only independent predictor of ESBL-producing E. coli or K. pneumoniae infection. These agents should not be used in infections due to confirmed ESBL producers because resistance to third-generation cephalosporin is often accompanied by resistance to fluoroquinolones, aminoglycosides TMP-SMX, and tetracyclines.
Our greatest gratitude goes to Jimma University Faculty of Medical Science, Department of Medical Laboratory Science and Pathology. We are grateful to all staff of Microbiology and Parasitology teaching laboratory of the department.The staffs of JUSH are acknowledged for their support in facilitating specimen collection and patient information.
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