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Introduction The objectives of the study were to report the prevalence as well as the characteristics of the extended-spectrum β-lactamases (ESBL) and carbapenemases producing Enterobacteriaceae isolated from patients in provincial Hospital Hassan II in Settat-Morocco. Methods From January 2012 to December 2014, non-duplicate 183 strains of Enterobacteriaceae were isolated from hospitalized patients. Resistance genes were characterized by polymerase chain reaction with specific primers for ESBL, carbapenemases and AmpC cephalosporinases. PCR products of ESBL genes were sequenced. The molecular epidemiology was investigated using pulsed field gel electrophoresis (PFGE). Results The overall prevalence of ESBL producing Enterobacteriaceae (ESBL-E) was 24.59% (45/183), among these, 44.4% (n=20) were Klebsiella pneumoniae, 42.2% (n=19) were Escherichia coli, 11.1% (n=5) were Enterobacter cloacae and 2.2% (n=1) were Morganella morganii. The most frequent ESBL genes were blaCTXM-15(35/45, 77.8%). Plasmid mediated Amp-C β-lactamases DHA-1 was found in one E. cloacae. The prevalence of carbapenemases producing Enterobacteriaceae (CPE) isolates was 5.46% (10/183) and all these CPE isolates were found to carry the blaOXA-48 gene. Previously hospitalization, diabetes mellitus, urinary tract infection, central venous catheter and mechanical ventilation were found as significant risk factors. PFGE typing for carbapenemase producing strains revealed five pulsotypes for K. pneumoniae and three for E. cloacae. Conclusions Our data have shown a high frequency of ESBL and CPE with the emergence of CTX-M-15 and OXA-48 producers. This remarkable increase at the provincial hospital Hassan II in Settat urges us to opt for specific strategies for regular surveillance.
The extended-spectrum β-lactamase producing Enterobacteriaceae (ESBL-E) represent a global public health problem. These enzymes provide resistance to most beta-lactam antibiotics and monobactams (aztreonam), but not cephamycins or carbapenems.1 They have been found in Europe, North America, Asia and Africa and initially ESBL-E resistance was due to point mutations in plasmid-mediated enzymes such as SHV-1 (Sulfhydryl reagent variable β-lactamase), OXA-10, TEM (Temoneira β-lactamase) 1 and TEM2. The CefoTaXime-M (CTX-M) enzymes are now more prevalent2 and disseminated globally. Resistance of Enterobacteriaceae to third generation cephalosporins and fluoroquinolones has led to an increased use of carbapenems in hospitals, one of the most widely used antimicrobial spectrums against Gram negative bacilli. Carbapenems became the first line of treatment against infections with multidrug-resistant Enterobacteriaceae.However, the extensive use of carbapenems led to a more serious problem, the emergence of carbapenem resistance all over the world which eventually became a significant therapeutic challenge to the hospital setting.3
The increasing threat of carbapenemase producing Enterobacteriaceae (CPE) in the world became a major public health risk. Carbapenem resistance develops by several mechanisms which include enzyme production, porin mutations, efflux pumps, AmpC hyperproduction, and alterations in penicillin-binding proteins.4 However, of these several mechanisms the main resistance mechanism is enzyme production. The Enterobacteriaceae generally develop resistance by producing ESBL, carbapenemases and/or chromosomal or plasmid mediated AmpC type enzymes.3 The location of the corresponding genes is mostly in the plasmid, in addition to their association with multiple movable genetic structures: insertion sequences, integrons, and transposons. The transfer of conjugative plasmids and the mobilizable gene transfer can be made through the mobile genetic elements (MGEs) which subsequently enables their dissemination into various bacterial species that lack these genes.5 The combinations of these mechanisms can cause high levels of resistance to carbapenems in bacterial species such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii.
This study aimed to determine the prevalence of ESBL and carbapenemase producing Enterobacteriaceae isolated from various clinical samples from hospitalized patients in different wards at the Hassan II Hospital, Settat-Morocco. Our goal was to identify the types of beta-lactamase producers (ESBL, AmpC cephalosporinase and carbapenemase) as well as to sequence the genes encoding ESBL-E.
Bacterial isolates
Along a three-year period, January 2012 to December 2014, 183 Enterobacteriaceae isolates have been identified from hospitalized patients in several wards noting: Intensive Care Units (ICU), Surgery, Medicine, Pediatrics, Obstetrics and Gynecology wards in Hassan II Provincial Hospital in Settat city, Morocco. The hospital's structure has a capacity of 268 beds. The strains were identified by conventional methods and the biochemical tests by API 20E collection (bioMérieux, France).
These strains were cultured from the clinical samples including urine (n=124), vaginal samples (n=28), bronchial samples and expectoration (n=10), blood (n=13), and pus (n=8).
Several epidemiological data were systematically sought in the clinical records of patients infected by ESBL-E and CPE (Table 1).
Antimicrobial susceptibility testing
The antimicrobial drug susceptibility testing was performed by the disk diffusion method on Mueller-Hinton (MH) agar medium, according to the Clinical and Laboratory Standards Institute guidelines.6 The following antimicrobial agents were tested: amoxicillin (10 µg), amoxicillin/clavulanic acid (20 µg / 10 µg), cephalothin (30 µg), cefoxitin (30 µg), cefotaxime (30 µg), ceftazidime (30 µg), aztreonam (30 µg), ciprofloxacin (5 µg), gentamicin (10 µg), amikacin (30 µg), trimethoprim/sulfamethoxazole (1.25 µg / 23.75 µg), imipenem (10 µg) and ertapenem (10 µg).
ESBL-E and CPE phenotypic screening
ESBL production was screened by the double-disk synergy test using amoxicillin-clavulanic acid disk, cefotaxime, ceftazidime, aztreonam and cefepime on MH-agar as previously described.6 The detection of ESBL among AmpC hyperproducers was assessed by a double-disk synergy test on MH agar supplemented with cloxacillin (250 µg/mL). The standard strains E. coli (ATCC 25922) and K. pneumoniae (ATCC 700603) were used respectively as negative and positive controls of ESBL production.
Activity of carbapenemases were investigated using Modified Hodge Test (MHT) performed according to CLSI recommendations.6 All the isolates with a reduced susceptibility to imipenem (inhibition zone <23 mm) or ertapenem (inhibition zone < 21 mm) were screened by this test. The phenotypic detection for Class B metallo-β-lactamases (MBL) activity was performed by the combined-disk test using imipenem and EDTA as described previously.7
ESBL and carbapenemases genotypic screening
Screening of the genes resistant to β-lactams (TEM, SHV and CTX-M group 1 and group 9), in addition to the genes encoding AmpC β-lactamases, were performed by PCR. Conditions for PCR and primers were used as described previously.8 The known β-lactamase-producing strains E. coli U2A1790 (CTX-M-1), Salmonella spp. U2A1446 (TEM-1 and SHV-12), E. cloacae U2A 2242 (KPC-3) and K. pneumoniae U2A 2016 (VIM-1) were used as a positive control, and E. coli K12J5. Detection of the genes encoding carbapenemase resistance (blaVIM, blaNDM, blaIMP,blaGES, blaKPC, and blaOXA-48) was performed by PCR (Table 2) using specific primers and conditions based on the previously published protocols.8
PCR products were run on 1.5% agarose gel (FMC Bioproduct, USA) containing 1 µg/mL of ethidium bromide, visualized under UV light, and analysed using a Digi-Doc-it software (UVP, Upland, USA).
Sequencing of the PCR products
Purified amplicons from 45 ESBL-E were sequenced for blaSHV, blaTEM and blaCTX-M, using the Genetic Analyser 3130 x1 Sequencer (Applied Biosystems, USA) with the same primers used for PCR amplification. Nucleotide sequences were analyzed with the software available in the internet at the national center for biotechnology information website (NCBI BLAST).9
Pulsed field gel electrophoresis (PFGE)
PFGE was performed to determine the genetic relatedness among K. pneumoniae and E. cloacae strains producing carbapenemase following a standardized protocol.8 PFGE restriction was obtained using XbaI (New England Biolabs, USA) as the restriction enzyme. The Dice similarity coefficient was calculated between pairs of lanes and the relatedness was calculated using the strains which were grouped using the dendrogram construction utility Dendro Unweighted Pair Group Method with arithmetic mean. The isolates were considered to be genetically related if their restriction patterns differed by bands or the Dice coefficient of correlation was 80% or greater.
Statistical analysis
The statistical data were analyzed by SPSS version 20.0 for Windows (IBM Corp., USA) using Fisher’s test and Chi2 test. The multivariate logistic regression was performed to analyze the multiple factors associated with bacterial producing of ESBL and carbapenemases. A p-value <0.05 was considered statistically significant.
Prevalence of ESBL and CPE isolates
Of the 183 clinical strains of Enterobacteriaceae 45 (24.6%) were ESBL positive, they were isolated from the clinical samples as follows: 40 (88.9%) from urine, 2 (4.4%) from blood, 1 (2.2%) from vaginal sample, 1 (2.2%) from bronchial sample, and 1 (2.2%) from pus. These ESBL-E were isolated from patients in the Surgical (25/45), ICU (6/45), Medicine (12/45), Pediatric (1/45) and Gynecology-Obstetrical (1/45) wards.
Amongst the 45 ESBL-E positive strains we found that 44.5% were represented by K. pneumoniae (20/45), 42.2% by E. coli (19/45), then 11.1% by E. cloacae (5/45), and only 2.2% by M. morganii (1/45). Among the 45 ESBL-E isolates, 32 were resistant to cefoxitin and only 1 strain of E. cloacae (3.12%) produced AmpC cephalosporinase.
Of the 183 Enterobacteriaceae species, 10 (5.5%) (7 K. pneumoniae, 3 E. cloacae) were screened for carbapenemase production since all 10 strains were resistant to carbapenems (imipenem or/and ertapenem). The prevalence for K. pneumoniae was 3.82% (7/183) and 1.63% (3/183) for E. cloacae and they were isolated from various clinical specimens in ICU, Surgical, and Medicine wards.
Epidemiological characteristics
Most epidemiological characteristics of the infections caused by ESBL-producers and non-ESBL-producers are described in Table 1. The average age of patients with ESBL-producing isolates was found to be 54.4±18.0 years old. The hospitalization period for the patients infected by ESBL-producers was observed to be 9.3±3.8 days. In both patient groups, the most common site of infection was the urinary tract and 40 patients (89%) were infected by ESBL producers and 6 patients (60%) infected by carbapenemase-producers (Table 1).
Risk factors for acquisition of ESBL and CPE
Several factors were found to be significantly associated with an increased risk for developing infections with ESBL-E and CPE. The mean age of patients harboring ESBL-E was found to be 54.4±18.0 years old, whereas the mean age was 29.3±20.9 for the patients harboring non-ESBL-E isolates. The mean duration of hospitalization was observed as 9.3±3.7 days for the patients harboring ESBL producing strains. Also, previous hospitalization, diabetes mellitus, renal diseases, admission to surgical and ICU wards, urinary tract infection, central venous catheter and mechanical ventilation were found as significant risk factors for ESBL producers (Table 1). Amongst the 10 CPE producing OXA-48, the mortality rate from the infection was 30%.
Antimicrobial susceptibility testing
The pattern of antimicrobial susceptibility among 45 ESBL-E showed high prevalence of resistance to various antimicrobial agents: all isolates were resistant to amoxicillin, amoxicillin/clavulanic acid and cephalothin (Table 3). Overall, 44 (97.8%) isolates were resistant to sulfamethoxazole/trimethoprim, 38 (84.4%) to gentamicin, 42 (93.3%) to ciprofloxacin, 5 (11.1%) to amikacin, 36 (80%) strains to aztreonam, 44 strains (97.8%) to the third generation cephalosporins (ceftazidime and cefotaxime) – Table 3. Resistance to imipenem and ertapenem was observed in 8 (17.8 %) and 16 (35.6%) strains respectively, while 32 (71.1%) strains were resistant to cefoxitin (Table 3).
Table 3. Antimicrobial resistance of ESBL and carbapenemases-producing Enterobacteriaceae strains
Among the 10 carbapenemase-producing isolates, a significantly high antibiotic resistance was observed: 100% resistance for each of ertapenem, cefotaxime, ciprofloxacin, sulfamethoxazole/trimethoprim and gentamicin, 90% resistance for amikacin, aztreonam, cephalothin, ceftazidime and cefoxitin, and the resistance for imipenem was 70% (Table 3).
Types of ESBL-producing Enterobacteriaceae isolates and sequencing
In 45 ESBL-producing isolates, the genetic analysis showed a prevalence of 77.8% (n=35) for both blaCTX-M and blaTEM, while it showed 57.8% (n=26) for blaSHV. Sequence analysis showed that all blaCTX-M belonged to blaCTXM-15 (35/45, 77.8%), which were the most frequent genes, while blaSHV belonged to blaSHV-1(15/26, 57.8%) and blaSHV-12(11/26, 42.3%), although all blaTEM genes were characterized as blaTEM-1. The blaCTXM-15 gene is expressed in the 35 species studied: 16 K. pneumoniae (45.7%), 13 E. coli (37.1%), 5 E. cloacae (14.3%), and 1 M. morganii (2.85%). The blaCTX-M-15 gene was detected alone or in combination with other β-lactamase genes (CTX-M-15+TEM-1; CTX-M-15+SHV-1; CTX-M-15+TEM-1+SHV-1).
ESBL producing Enterobacteriaceae were predominant in the urine (40/45), followed by blood (2/45), and pus, expectoration, vaginal sample (1/45) for each respectively. The surgical department is the most affected by the ESBLs-E infections (55.6 %).
Plasmid mediated AmpC β-lactamases genes
In our study, DHA-1 type cephalosporinase was detected in one E. cloacae sample, isolated from the urine of patient aged 65 years, hospitalized for surgery. It was presented with the following combination: DHA-1+ CTX-M-15+ TEM-1.
Carbapenemase classes
All the 10 CPE were found to carry the blaOXA-48 gene but none of these were positive for blaIMP, blaVIM, blaGIM, blaNDM and blaKPC genes. These strains were coming from the ICU, the Surgery, and the Medicine wards. The carbapenemase OXA-48 was found alone or in combination with the ESBLs (CTX-M, TEM, and SHV) – Table 4.
Pulsed field gel electrophoresis (PFGE) analysis
In our study, the analysis of the epidemiological relationship by PFGE for 10 Enterobacteriaceae strains harboring OXA-48 carbapenemase revealed five clusters (from CK1 to CK5) for K. pneumoniae (Figure 1) which were isolated from the ICU, medicine and surgery wards. The clusters CK1, CK3, and CK4 were represented by only one isolate.
Clusters CK2 and CK5 were prevalent, each containing two K. pneumoniae isolates. The CK2 was composed of two strains with high-level similarity (100%); these strains were collected in the same ward but caused different clinical manifestations (septicemia and urinary infection). Interestingly, these clones were characterized by the presence of the same pattern of resistance and harboring the same resistance gene to carbapenemase and ESBL. Although the CK2 and the CK5 clone were isolated from a different ward, they were composed of two strains with high-level similarity and harbored the same pattern of resistance gene.
Concerning carbapenemase producing E. cloacae, three different clusters were found (CE1 to CE3) – Figure 2. Even though the three clusters were isolated from the same ward (Surgery) with the same site of isolation (urine), their similarity was <40%, implying the absence of any clonality.
In this study, the overall prevalence of ESBL was 24.6% and this frequency varies greatly according to the hospitals, the countries, the bacterial species in question and their origins. This frequency is lower than those found in another African country, Chad, with an overall ESBL prevalence of 47.72%.10 Another significant finding of our study was that K. pneumoniae producing ESBL has the highest occurrence (44.5%). This finding broadly is in line with several other studies which reported numerous epidemics caused by this particular enterobacterial species including the studies done in Italy11 as well as in South Africa.12 Our study found that the rate of ESBL-producing E. cloacae is 11.1%, which is much lower than that found in the hospitals of Annaba in Algeria (47.6%).13 This species is frequently implicated in several nosocomial infections (urinary, respiratory and sepsis), and has the ability to acquire resistance to the antibiotic currently used in hospitals.
Another important finding of our study was that the rate of M. morganii producing ESBL was 2.2% similar to a previously published report on this particular species.14 The ESBL producing isolates showed a high resistance to most of the antibiotics tested (penicillins, cephalosporins, ciprofloxacin, sulfamethoxazole/trimethoprim, and aztreonam). This resistance can be encoded on transferable plasmids and exchanged among the different species of bacteria.15
The most important clinically relevant finding of our study was that the risk factors for the acquisition of CPE and ESBL-E through mechanical ventilation, length of stay especially in ICU, advanced age and the use of central venous catheter. This finding supports the evidence from previous observation.15
In our study, CTX-M-15 type was the most common as it was present in all the tested ESBLs-E. Our results are consistent with the previous study which also identified CTX-M-15 as the most common variant, particularly in urine and especially the existence of the CTX-M-15 producing E. coli species in Morocco.16 The infection caused by E. coli producing CTX-M-15 has a pandemic potential due to the existence of a virulent clone (O25: H4-ST131) and also because it can be transmittable by plasmids.17 The most remarkable finding of our study was the detection of CTX-M-15 producing M. morganii as it has never been documented in any previous study of hospitalized patients in Morocco.
Moreover, in our study, the SHV-12 sub-group was observed in E. coli and K. pneumoniae. Our observation was similar to other studies in Morocco where it was detected in both E. coli and E. cloacae strains as well.18,19 The blaSHV-12 gene can be located either on the chromosome or on a plasmid or both and can be transmitted horizontally and/or vertically.20 In our study, the blaTEM-1 gene, was identified in K. pneumoniae, E. coli and E. cloacae, generally in association with blaCTX-M and blaSHV. These associations are in accordance with the previously published reports.13,18
AmpC β-lactamases are important cephalosporinases produced by many Enterobacteriaceae
species and they mediate resistance to cephalothin, cefoxitin, penicillins, and β-lactam/β-lactam inhibitor combinations.21 In our finding, the blaDHA gene was observed only in one E. cloacae isolated from urine, which is in accordance with the previously published reports from Morocco18 and Algeria.13 This gene has been presented with the following combination: blaDHA-1+blaCTX-M-15+blaTEM-1, which was reported in an Algerian study.22 All the 10 CPE were resistant to ertapenem and 7 among them were resistant to imipenem. Recently, the resistance to carbapenems became a serious problem in terms of healthcare-associated infections. CPE were reported in Moroccan hospitals in the city of Casablanca.8
This study is the first to investigate the CPE in the hospitalized patients in Morocco. The prevalence of CPE in our findings was 5.46%, which was higher compared to 1.8% which was found in 2017 at the NICU university hospital in Fez, Morocco.23 The prevalence of carbapenemase-producing K. pneumoniae in our study was lower than that in Casablanca (6%).8 The infections caused by CPE are dominated by urinary tract infections (UTIs), followed by respiratory infections. Therefore, they present a serious public health problem.
Our study shows that all these CPE strains were found to carry the blaOXA-48 gene. In Morocco, the carbapenemases produced by Enterobacteriaceae detected so far belong to classes B (NDM-1, VIM-1) and class D (OXA-48).24 The blaOXA-48gene was mainly detected in K. pneumoniae and E. cloacae. The present study confirmed that six strains amongst 10 CPE isolates co-expressed blaOXA-48genes, identified by the following combinations: blaOXA-48+blaCTX-M-15+blaTEM-1,blaOXA-48+blaCTX-M-15+blaSHV-1+blaTEM-1,blaOXA-48+blaCTX-M-15+blaSHV-1. Our results are in consensus with a study conducted during the same period at Casablanca’s University hospital in Morocco.18
In our findings, the mortality rate due to the infections caused by Enterobacteriaceae producing OXA-48 was 30%. However, some authors reported that the overall mortality rate of patients infected with CPE was 56.7%.25 The PFGE results show a high-level similarity for CK2; the two K. pneumoniae were strongly epidemiologically linked. This similarity would probably be due to the transmission of the organisms via hands or a healthcare worker.
The PFGE profiles of three E. cloacae isolates harboring blaOXA-48 gene were not similar, this could be explained by the self-contamination of patients. It is therefore important to increase the hygiene measures, in collaboration with the healthcare stakeholders (the infection control committee, the operational hygiene team, and the pharmacists).
Limitations of the study
As limitations are concerned, during our study period there was a lack of previous studies on the topic. The majority of available data at the concerned period of the study was either historic or theoretical data around the world which were on a different scope than Morocco and North Africa. Prior literature on the extended-spectrum β-lactamases and carbapenemases producing Enterobacteriaceae was limited in the time of the study.
However, our results show data of the first epidemiological study of ESBL in Morocco, with our research we contributed to nurturing the literature on the topic of research for further ESBL studies. Post discussion of our results with the provincial hospital, we have created a framework with the CLIN: the Prevention of Nosocomial Infection Committee, that displays significant measures of change such as hand hygiene obligations and reminders, training for healthcare professionals, awareness raising for patients, patient affected by multi-resistant bacteria isolation procedures and infectious risk management in the hospital milieu.
Our data showed higher rates of ESBL-E and CPE with a multidrug-resistance emergence in Settat, Morocco. Therefore, it is necessary to detect and identify these bacteria immediately, to reinforce vigorously the strict measures of hygiene and to adopt a permanent supervision of multidrug-resistant Enterobacteriaceae in our hospital as well as in the community local, in order to evade and eradicate clinical and epidemiological consequences.
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