1828 https://www.journal-imab-bg.org J of IMAB. 2017 Oct-Dec;23(4)

Original article

ANTIMICROBIAL SUSCEPTIBILITY OFCLINICALLY SIGNIFICANT ISOLATES OFENTEROBACTER SPP., OBTAINED FROMPATIENTS, HOSPITALISED IN VARNAUNIVERSITY HOSPITAL DURING THE PERIOD2014 – 2016

Dobromira Dimitrova1, Temenuga Stoeva1, Rumyana Markovska2, PetyaStankova2, Milena Bozhkova1, Gergana Nedelcheva1, Ivan Mitov2

1) Department of Microbiology and Virology, Medical University, Varna2) Department of Medical Microbiology, Medical University, Sofia, Bulgaria.

Journal of IMAB - Annual Proceeding (Scientific Papers). 2017 Oct-Dec;23(4)Journal of IMABISSN: 1312-773Xhttps://www.journal-imab-bg.org

ABSTRACTPurpose: Rapidly increasing antimicrobial resistance

in medically important bacterial species from family En-terobacteriaceae is one of the most significant microbio-logical, clinical and epidemiological issues of modern medi-cine. The aim of this study is to investigate the antibioticsusceptibility of clinically significant isolates ofEnterobacter spp., obtained from patients, hospitalized inUniversity Hospital “Saint Marina” – Varna during the pe-riod 2014 – 2016.

Material and methods: a total of 433 clinical iso-lates of Enterobacter spp. from blood cultures, urine andwound secretions were studied. The species identificationwas made by conventional, semi-automated (Crystal, BD)and automated systems (Phoenix, BD). The susceptibilityto piperacillin/tazobactam (TZP), ceftazidime (CAZ),meropenem (MEM), gentamicin (Gm), amikacin (Ak),ciprofloxacin (CIP), levofloxacin (LVX), trimethoprime/sulfamethoxazole (SXT) and tetracycline (Tet) was testedby disc-diffusion method and / or automated system Phoe-nix 100, BD. The results were interpreted according toEUCAST 2016 guidelines.

Results: The resistance in the studied collection ofisolates, shown in increasing order is as follows: Ak, 4.2%< LVF, 25.4% < TZP, 37.4% < Tet, 38.7% < SXT, 40% <CIP, 44.1% < Gm, 49.7% < CAZ, 57%. Meropenem dem-onstrated fully preserved activity. In the group of CAZ re-sistant isolates, the levels of antimicrobial resistance are:Ak, 5.7% < LVF, 42.9% < Tet, 52.4% < SXT, 60.3% < TZP,64.4% < CIP, 84.6% < Gm, 86.2%. The rate of CAZ resist-ant Enterobacter spp. was 66.9% among the urine isolates,61.9% - among those from blood culture and 46.3% - inthe group of isolates from wound secretions. In the threementioned groups of isolates, the lowest level of resistancewas detected to Ak (1.6%; 4%; 6.9%). The isolates fromwound and blood cultures demonstrated the highest levelof resistance to Gm (60.3%, 42.9%) and the urine isolates– to Tet (60%) and CIP (56.9%).

Conclusions: CAZ resistant Enterobacter spp. dem-

onstrated significantly higher levels of resistance in com-parison to the whole studied group especially to quinolonesand aminoglycosides. The highest level of CAZ resistantEnterobacter spp. was detected in the group of urine iso-lates.

Keywords: Enterobacter spp., antimicrobial suscep-tibility, resistance.

INTRODUCTIONSpecies from genus Enterobacter are ubiquitous bac-

teria, widely distributed in nature. They are part of the nor-mal enteric flora of humans and animals but also can causenosocomial infections predominantly in immunocompro-mized patients and patients from the ICUs [1, 2].

Recently, a selected group of bacteria has been de-scribed by the acronym of ESKAPE, and they cause mostof the healthcare-associated infections: Enterococcusfaecium, Staphylococcus aureus, Klebsiella pneumoniae,Acinetobacter baumannii, Pseudomonas aeruginosa, andEnterobacter species. These bacteria are clinically impor-tant not only because are causative agents of nosocomialinfections but also because are a paradigm for pathogenesis,transmission and resistance [3]. Bacteria from genusEnterobacter are associated predominantly with bactere-mia, pneumonia, urinary tract and intra-abdominal infec-tions, endocarditis, skin and soft tissue infections [1].

Enterobacter species are with intrinsic resistance toaminopenicillins, amoxicillin/clavulanic acid, cefoxitinand first-generation cephalosporins because of the produc-tion of chromosomally encoded, inducible Amp C â-lactamase [1, 4, 5]. This enzyme does not hydrolysecarboxy- and ureidopenicillins, II, III and IV generationcephalosporins and carbapenems [4, 5]. During the last dec-ades Enterobacter isolates, resistant to extended spectrumcephalosporins have been reported more frequently [1, 4].Usually, these isolates are associated with the productionof plasmid encoded Extended Spectrum Beta Lactamases(ESBLs) and/or derepressed production of Amp C enzymes

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[1, 4]. The ESBLs are most widely dessiminated, and causehydrolyses to penicillins and all generations cephalo-spoirins [6, 7]. Such isolates of Enterobacter spp. demon-strate very often cross-resistance to other antimicrobialagents - aminoglycosides, quinolones, trimethoprim/sulpha-mothoxazole, etc. [8]. The resistance to β-lactams, quino-lones, aminoglycosides, trimethoprim/sulphamothoxazoleis higher in the European, Asian and some countries inSouth America than in the USA and Canada [9, 10]. Veryworrisome is the fact that worldwide carbapenem-resistantisolates of Enterobacter have been reported with increas-ing frequency [1, 4].

The study aimed to investigate the antimicrobialsusceptibility of a collection of clinically significant iso-lates of Enterobacter spp., obtained from patients, hospi-talized in the University Hospital “Saint Marina” – Varna,Bulgaria during the period 2014 -2016.

MATERIALS AND METHODSBetween January 2014 and December 2016, a total

of 433 clinically significant Enterobacter spp. isolates werecollected from patients, hospitalized in different wards ofthe University Hospital “Saint Marina” in Varna, Bulgaria.

The isolates were recovered from various clinical speci-mens: urine samples - 130; blood - 126; wound secretions- 177. Species identification was made by the semi-auto-mated and automated systems Crystal (BD) and Phoenix100 (BD). Antimicrobial susceptibility to set of antimicro-bial agents (ceftazidime, meropenem, tetracycline, gen-tamicin, amikacin, trimethoprime/sulphometoxazole,ciprofloxacin, levofloxacin) was determined by disk - dif-fusion method and/or by the automated system Phoenix100 (BD). The results were interpreted according toEUCAST 2016 guidelines [11].

RESULTSThe results from the antimicrobial susceptibilty test-

ing are presented on Figures 1, 2 and 3.The antimicrobial resistance in the whole collection

of isolates (n=433), shown in increasing order, is as follows:amikacin, 4.2% < levofloxacin, 25.4% < piperacillin/tazobactam, 37.4% < tetracycline, 38.7% < trimethoprime/sulphometoxazole, 40% < ciprofloxacin, 44.1% < gen-tamicin, 49.7% < ceftazidime, 57%. Meropenem demon-strated fully preserved activity (no resistance detected) (Fig-ure 1).

Fig. 1. Antimicrobial resistance in the whole collection of Enterobacter spp. isolates (n=433)

CAZ - ceftazidime, TZP – piperacillin/tazobactam, Gm - gentamicin, Ak - amikacin, T - tetracycline, SXT -trimethoprime/sulphometoxazole, CIP - ciprofloxacin, LVX – levofloxacin.

In the group of ceftazidime resistant isolates (n=247),the levels of antimicrobial resistance, presented in increas-ing order, are as follows: amikacin, 5.7% < levofoxacin,42.9% < tetracycline, 52.4% < trimethoprime/sulphometo-xazole, 60.3% < piperacillin/tazobactam, 64.4% <ciprofloxacin, 84.6% < gentamicin, 86.2% (Figure 2).

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Fig. 2. Antimicrobial resistance of 247 clinical isolates of Enterobacter spp., resistant to ceftazidime (%).

CAZ - ceftazidime, TZP – piperacillin/tazobactam, Gm - gentamicin, Ak - amikacin, T - tetracycline, SXT -trimethoprime/sulphometoxazole, CIP - ciprofloxacin, LVX - levofloxacin.

CAZ - ceftazidime, TZP – piperacillin/tazobactam, Gm - gentamicin, Ak - amikacin, T - tetracycline, SXT -trimethoprime/sulphometoxazole, CIP - ciprofloxacin, LVX - levofloxacin.

Antimicrobial resistance of the tested isolates according to their site of isolation is presented on Figure 3.

Fig. 3. Antimicrobial resistance of 433 clinical isolates of Enterobacter spp. according to their site of isolation(%).

A total of 126 isolates of Enterobacter spp. were ob-tained from blood cultures. The resistance rate to III gen-eration cephalosporins was 61.9%. The resistance to pipera-cillin/tazobactam was 50% and above 40% for ciproflo-xacin (49.2%), tetracycline (50.9%), trimethoprime/sulpho-metoxazole (52.4%) and gentamicin (60%) (figure 3). Themost active antimicrobial agents were meropenem (100%susceptibility), amikacin (98.4%) and levofloxacin (86.1%).In the group of ceftazidime resistant isolates from bloodcultures, the levels of antimicrobial resistance, presentedin increasing order, were as follows: levofoxacin, 25.4% <trimethoprime/sulphometoxazole, 60.7% < tetracycline,75% < piperacillin/tazobactam, 81.5% < ciprofloxacin,85.0% < gentamicin, 90.0%.

A total of 130 isolates of Enterobacter spp. were ob-

tained from urine samples. The resistance rate to III genera-tion cephalosporins was 66.9%. The resistance to pipera-cillin/tazobactam was 39.2% and above 40% for trime-thoprime/sulphometoxazole (48.5%), levofloxacin (48.5%),gentamicin (52.3%), ciprofloxacin (56.9%) and tetracycline(60%). Lowest resistance rate was detected for meropenem(0%) and amikacin (6.9%) (Figure 3).

A total of 177 isolates of Enterobacter spp. were ob-tained from wound secretions. The resistance rate to III gen-eration cephalosporins was 46.3%. The resistance to pipera-cillin/tazobactam was 27.1% and above 30% for trime-thoprime/sulphometoxazole (31.6%), ciprofloxacin (31.1%),tetracycline (37.5%) and gentamicin (42.9%) (Figure 3). Themost active antimicrobial agents were meropenem (100%susceptibility), amikacin (96%) and levofloxacin (83.1%).

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DISCUSSIONDuring the last decade, the species from genus

Enterobacter are among the fifth most commonly isolatedbacterial species from clinical materials worldwide [2, 4].In Varna University Hospital “Saint Marina”, Enterobactercloacae takes the second place as a causitive agent ofbacteremia for 2015 and the fourth place for 2016 (not pub-lished data).

Our results demonstrate a worrisome increase of re-sistance to beta-lactam antibiotics: 57% of the isolateswere resistant to III generation cephalosporins (ceftazidime)and 37.4% to piperacillin/tazobactam. High resistance lev-els (above 25%) were detected for quinolones, gentamicin,tetracycline and trimethoprime/sulphometoxazole. Themost active antimicrobial agents were meropenem (no re-sistant isolates found) and amikacin (4.2%). For a collec-tion of 177 isolates of Enterobacter spp. Xie et al. reportedsimilar to our results regarding ceftazidime and amikacinresistance levels: 40% and 3.6% respectively [12]. Theseauthors reported lower levels of resistance to other groupsof antimicrobial agents: ciprofloxacin, 16.7%; levofloxa-cin, 10.5%; gentamicin, 15%; piperacillin/tazobactam,6.8%; cefepime, 17.3% and trimethoprime/sulphometo-xazole, 29.4%. The resistance to imipenem and meropenemwas 14.5% and 13.2% respectively [12]. In a recent study,Maraki et al. investigated the susceptibility and the resist-ance phenotype of 939 isolates of Enterobacter spp., col-lected during a 6-year period (2010-2015) [13]. The mostactive antimicrobial agents in this study were colistin(97.9% susceptibilty), followed by imipenem (96.1%) andgentamicin (95.7%). Resistance to beta-lactams was lowerthan our results with the exception of carbapenems: pipera-cillin/tazobactam, 26.0%; ceftazidime, 25.7%; cefepime,10.2%; imipenem, 3.4%; meropenem, 6.3%. The authorsreported low resistance levels to amikacin, 4.2%; gen-tamicin, 2.8%; ciprofloxacin, 6.4%; levofloxacin, 6.1% andtrimethoprime/sulphometoxazole, 11.1% [13]. In these re-ports, the resistance to III and IV generation cephalosporinsis found to be associated predominantly with Amp C, andall isolates are determined as multi-drug resistant (MDR)[13, 14].

In a recent study performed in our hospital in 2014,the ESBLs production in clinical isolates of Enterobacterspp., collected during the period 2007 – 2011 from hospi-talized patients was investigated. An increasing level ofESBL - producing Enterobacter spp. was detected: from28% in 2007 ã. to 36% and 39% in 2010 and 2011 [15].This was followed by the current study where we detected57% ceftazidime resistant isolates. This result shows theneed for urgent infection control measures.

In the present study higher levels of resistance to alltested antimicrobials were detected in the group of ceftazi-dime resistant isolates. This result probably is associatedwith the possible production of plasmid mediated ESBLsor/and Amp C production. Different types of plasmids, iden-tified in family Enterobacteriaceae, play an important rolein the dissemination of ESBL genes [16, 17]. Some of theseplasmids (IncFI, IncFII, Inc A/C, Inc M/L and IncHI2) carrynot only ESBLs genes, but also genes, that encode plas-

mid-mediated quinolone resistance (qnr, aac (6')-Ib-cr,qepA, oqxAB) and genes, associated with resistance toother antimicrobial agents (aminoglycosides, trimetho-prime/sulfametoxazole) [6, 9, 18, 19, 20, 21, 22, 23, 24].This fact explains the common association of ceftazidimeresistance (an indicator for ESBLs or/and AmpC produc-tion) with the resistance to other antimicrobial groups andthe MDR phenotype, usually exhibited by these isolates.

The antimicrobial resistance of the studied isolatesvaried according to their site of isolation (blood, urine andwound secretions). The urine isolates were more resistantto most of the tested antimicrobial agents: ceftazidime(66.9%), amikacin (6.9%), ciprofloxacin (56.9%),levofloxacin (48.5%) and tetracycline (60%). As part ofSMART Program 2013 – 2015, Karlowsky et al. report thefollowing rates of resistance among 165 isolates ofEnterobacter spp. isolated from hospitalized patients withurinary tract infections in Latin American countries:ceftazidime - 35.8%, cefepime - 27.9%, amikacin - 4.9%,imipenem - 7.3%, levofloxacin - 22.4%, piperacillin/tazobactam - 19.4% [25]. A similar study on 154 isolatesof Enterobacter spp., isolated from hospitalized patientswith urinary tract infections in Asia - Pacific countries dur-ing the period 2013 – 2015, demonstrates similar levels ofresistance: ceftazidime - 37.7%, cefepime - 18.2%,amikacin - 8.4%, imipenem - 6.5%, levofloxacin - 14.9%,piperacillin/tazobactam - 14.9% [26]. In contrast to thesestudies, we detected higher rates of resistance to extendedspectrum cephalosporins (66.9%) and the quinolonesciprofloxacin (56.9%) and levofloxacin (48.5%).

Similar to the urine isolates, high levels of resistanceto all tested antimicrobials were also detected in the groupof blood culture isolates. Most of the ceftazidime resistantisolates from blood samples demonstrated multi-drug resist-ance. The high rate of resistance to extended spectrumbeta-lactams, quinolones and aminoglycosides is a serioustherapeutic challenge, as well as a significant factor for theoutcome of blood stream infections caused by Enterobacterspp. In this study carbapenems and amikacin exhibit, thehighest in vitro activity against Enterobacter spp., isolatedfrom blood cultures with no resistance detected forcarbapenems and 1.6% resistance for amikacin. Many au-thors report results that clearly demonstrate the advantageof carbapenem therapy for blood stream infections causedby ESBL - producing E. cloacae [27, 28].

In contrast to the urine and blood culture isolates,the isolates from wound secretions exhibit lower levels ofresistance to most of the tested antimicrobials: ceftazidime– 46.9%, gentamicin – 42.9%, ciprofloxacin – 31.1%, tet-racycline – 37.5%, trimethoprime/sulphometoxazole –31.6%, piperacillin/tazobactam – 27.1%.

In all three groups of isolates (blood, urine andwound secretions) the most active antimicrobial agents werecarbapenems with fully preserved activity and amikacinwith resistance levels varying between 1.6%, 4% and 6.9%.

In conclusion, the studied collection of 433 isolatesof Enterobacter spp. is associated with high levels of re-sistance to commonly used antimicrobial agents in the

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clinical practice: piperacillin/tazobactam, ceftazidime,quinolones and gentamicin. In comparison to the wholestudied group, ceftazidime resistant Enterobacter spp. dem-onstrated significantly higher levels of resistance to mostof the tested antimicrobials as well as MDR phenotype. Thehighest level of ceftazidime resistant Enterobacter spp. wasdetected in the group of urine isolates.

In the studied collection of isolates, the resistanceto amikacin is the lowest, and the susceptibility tocarbapenems is fully preserved. These antimicrobials areagents of the first choice in cases of severe infectionscaused by Enterobacter spp. or in cases of infections asso-ciated with MDR Enterobacter spp.

Abbreviations:CAZ – ceftazidime;TZP – piperacillin/tazobactam;Gm – gentamicin;Ak – amikacin;T – tetracycline;SXT - trimethoprime/sulphometoxazole;CIP – ciprofloxacin;LVX – levofloxacin;

Acknowledgments: The study was funded by grantNo.8383/07.12.2016 and contract No.D-59/2.05. 2017 fromMedical University - Sofia, Bulgaria.

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Address for correspondenceAssoc. Prof. Temenuga Stoeva, MD, PhDDepartment of Microbiology and Virology, Medical University, Varna,55, Marin Drinov Str., Varna, Bulgaria.E-mail: temenuga.stoeva@abv.bg

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Please cite this article as: Dimitrova D, Stoeva T, Markovska R, Stankova P, Bozhkova M, Nedelcheva G, Mitov I.Antimicrobial susceptibility of clinically significant isolates of Enterobacter spp., obtained from patients, hospitalisedin Varna University Hospital during the period 2014 – 2016. J of IMAB. 2017 Oct-Dec;23(4):1828-1833.DOI: https://doi.org/10.5272/jimab.2017234.1828

Received: 29/08/2017; Published online: 18/12/2017