Molecular characterization of multidrug-resistance in Gram-negative bacteria from the Peshawar teaching hospital, Pakistan.
Journal: 2019/November - New Microbes and New Infections
ISSN: 2052-2975
Abstract:
Extended-spectrum β-lactamases, carbapenemases, 16S rRNA methylases conferring pan-drug aminoglycoside resistance and colistin resistance were investigated among Gram-negative bacteria recovered from clinical samples (infections) from 200 individuals hospitalized at the Khyber Teaching Hospital of Peshawar, north Pakistan, from December 2017 to March 2018. Out of 65 isolates recovered, 19% were carbapenem resistant and 16% carried a blaNDM-1 gene, confirming the widespread distribution of NDM producers in this country. The association of the NDM carbapenem-resistance determinant, together with the extended-spectrum β-lactamase CTX-M-15 and 16S rRNA methylases, was frequent, explaining the multidrug-resistance pattern observed. All isolates remained susceptible to colistin.
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New Microbes New Infect 32: 100605

Molecular characterization of multidrug-resistance in Gram-negative bacteria from the Peshawar teaching hospital, Pakistan

Abstract

Extended-spectrum β-lactamases, carbapenemases, 16S rRNA methylases conferring pan-drug aminoglycoside resistance and colistin resistance were investigated among Gram-negative bacteria recovered from clinical samples (infections) from 200 individuals hospitalized at the Khyber Teaching Hospital of Peshawar, north Pakistan, from December 2017 to March 2018. Out of 65 isolates recovered, 19% were carbapenem resistant and 16% carried a blaNDM-1 gene, confirming the widespread distribution of NDM producers in this country. The association of the NDM carbapenem-resistance determinant, together with the extended-spectrum β-lactamase CTX-M-15 and 16S rRNA methylases, was frequent, explaining the multidrug-resistance pattern observed. All isolates remained susceptible to colistin.

Keywords: Carbapenemases, Extended spectrum β-lactamase, Pakistan, ST 215, ST 231, 16S rRNA methylases

Introduction

The increasing occurrence of resistance to carbapenems is a major issue for global public health. Resistance to carbapenems is often mediated by carbapenemases, with NDM-1 (New Delhi metallo-β-lactamase) being one of the most commonly identified carbapenemases worldwide, its main reservoir corresponding to the Indian subcontinent [1]. Accordingly, several studies reported a high occurrence of NDM-1 producers in India and Pakistan [2,3]. Most of the carbapenemase producers are co-resistant to other antibiotic families, so it is interesting to obtain further characterization about those co-resistance markers [4]. Our aim was to characterize the carbapenemases, extended-spectrum β-lactamases (ESBLs), 16S rRNA methylases conferring pan-aminoglycoside resistance, and colistin resistance (plasmid-mediated mcr genes) from a series of clinical isolates obtained in acute-care facilities from Peshawar, Pakistan.

Materials and methods

Bacterial isolates

A total of 200 samples were collected from 200 individuals between December 2017 and March 2018 at the Khyber Teaching Hospital of Peshawar, north Pakistan. Those samples included urine, blood, pus and broncheal lavage specimens. Samples were plated on URIselect-4™ medium (Bio-Rad, Cressier, Switzerland) and identification was performed using the API-20E system (bioMérieux, La Balme-les-Grottes, France). Antimicrobial susceptibility testing was performed using the disc diffusion method and interpreted according to the CLSI recommendations [5], except for colistin. Resistance to colistin was evaluated first by using the Rapid Polymyxin test [6], and then by determination of MIC values of colistin by broth microdilution, as recommended by European Committee on Antimicrobial Susceptibility Testing (EUCAST) (www.eucast.org). Carbapenemase and ESBL activities were detected using the Carba NP test [7] and the ESBL NP test [8], respectively.

Molecular analysis

A series of acquired resistance genes were searched by PCR, including those encoding ESBLs (blaTEM-, blaSHV- and blaCTX-M-like genes), carbapenemases (blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-48, blaOXA-181), 16S rRNA methylases genes (armA, rmtA to rmtH and npmA), and mcr-like genes (mcr-1 to mcr-8) [[9], [10], [11], [12], [13], [14]]. The obtained amplicons were sent for sequencing (Microsynth®, Balgach, Switzerland).

Clonal diversity

Clonal relationship of the isolates was evaluated by pulsed-field gel electrophoresis (PFGE) [15]. Total DNA from Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. were digested using the XbaI enzyme (New England Biolabs, Ipswich, MA, USA). The generated fragments were separated by PFGE using a CHEF-DR III System (Bio-Rad) creating a unique PFGE profile for each clonal strain. Multilocus sequencing typing was performed for pan-drug aminoglycoside-resistant strains belonging to the species E. coli (strain no. 31) and K. pneumoniae (strain no. 62) [16]. Sequence types (STs) were investigated using the online databases (http://genomicepidemiology.org/).

Bacterial isolates

A total of 200 samples were collected from 200 individuals between December 2017 and March 2018 at the Khyber Teaching Hospital of Peshawar, north Pakistan. Those samples included urine, blood, pus and broncheal lavage specimens. Samples were plated on URIselect-4™ medium (Bio-Rad, Cressier, Switzerland) and identification was performed using the API-20E system (bioMérieux, La Balme-les-Grottes, France). Antimicrobial susceptibility testing was performed using the disc diffusion method and interpreted according to the CLSI recommendations [5], except for colistin. Resistance to colistin was evaluated first by using the Rapid Polymyxin test [6], and then by determination of MIC values of colistin by broth microdilution, as recommended by European Committee on Antimicrobial Susceptibility Testing (EUCAST) (www.eucast.org). Carbapenemase and ESBL activities were detected using the Carba NP test [7] and the ESBL NP test [8], respectively.

Molecular analysis

A series of acquired resistance genes were searched by PCR, including those encoding ESBLs (blaTEM-, blaSHV- and blaCTX-M-like genes), carbapenemases (blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-48, blaOXA-181), 16S rRNA methylases genes (armA, rmtA to rmtH and npmA), and mcr-like genes (mcr-1 to mcr-8) [[9], [10], [11], [12], [13], [14]]. The obtained amplicons were sent for sequencing (Microsynth®, Balgach, Switzerland).

Clonal diversity

Clonal relationship of the isolates was evaluated by pulsed-field gel electrophoresis (PFGE) [15]. Total DNA from Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. were digested using the XbaI enzyme (New England Biolabs, Ipswich, MA, USA). The generated fragments were separated by PFGE using a CHEF-DR III System (Bio-Rad) creating a unique PFGE profile for each clonal strain. Multilocus sequencing typing was performed for pan-drug aminoglycoside-resistant strains belonging to the species E. coli (strain no. 31) and K. pneumoniae (strain no. 62) [16]. Sequence types (STs) were investigated using the online databases (http://genomicepidemiology.org/).

Results

A total of 65 Gram-negative bacteria were recovered including 46 E. coli, 10 Enterobacter spp. (9 Enterobacter cloacae, 1 Enterobacter sakazakii), 6 K. pneumoniae, 2 Alcaligenes faecalis and 1 Citrobacter freundii.

Thirty-eight of the 65 Gram-negative bacteria produced a carbapenemase, as assessed by the results of the Rapid Carba NP test, whereas 32 of those 65 isolates produced an ESBL according to the results of the ESBL NP test. Among the 46 E. coli isolates, 12 produced NDM-1, 5 co-produced NDM-1 and CTX-M-15, 2 co-produced NDM-1 and OXA-181, 2 isolates co-producing OXA-181 and CTX-M-15, a single isolate producing OXA-48. Twelve E. coli isolates produced CTX-M-15 without any carbapenemase associated. A single blaNDM-1-positive E. coli isolate produced the 16S rRNA methylase RmtB.

Among the six K. pneumoniae isolates, one isolate co-produced NDM-1 and CTX-M-15, another co-produced NDM-1, OXA-181 and CTX-M-15, and a single isolate co-produced NDM-1, OXA-232 and CTX-M-15 together with the 16S rRNA methylase RmtB (see Table 1).

Table 1

Information and genetic features of samples isolated in Peshawar teaching hospital, Pakistan

Patient/strain no.Site of isolationResidenceTreatmentStrainsCarbapenemaseESBL16S RNA methyltransferaseClonality
1PusPeshawarCiprofloxacinAlcaligenes faecalisVIM-4NoneNoneNone
2UrineMardanOfloxineAlcaligenes faecalisVIM-4NoneNoneNone
3UrineBatkhelaUnknownCitrobacter freundiiNoneCTX-M-15NoneEsC-7
4PusPeshawarCiprofloxacinEnterobacter cloacaeNDM-1NoneNoneEC-1
5UrinePeshawarUnknownEnterobacter cloacaeNDM-1CTX-M-15NoneEC-1
6UrineKohatUnknownEnterobacter cloacaeNDM-1CTX-M-15NoneEC-1
7BloodUnknownCefiximeEnterobacter cloacaeNDM-1CTX-M-15NoneEC-1
8UrineMardanOfloxineEnterobacter cloacaeNDM-1CTX-M-15NoneEC-1
9UrineAfghanistanUnknownEnterobacter cloacaeNDM-1CTX-M-15NoneEC-1
10UrineAfghanistanUnknownEnterobacter cloacaeNDM-1CTX-M-15NoneEC-1
11UrinePeshawarLevofloxacinEnterobacter cloacaeNDM-1CTX-M-15NoneNone
12UrinePeshawarLevofloxacinEnterobacter cloacaeNDM-1CTX-M-15NoneNone
13UrinePeshawarUnknownEnterobacter sakazakiiNDM-1CTX-M-15NoneNone
14FluidPeshawarCiprofloxacinEscherichia coliNDM-1NoneNoneNone
15PusCharsadaCiprofloxacinEscherichia coliNDM-1NoneNoneNone
16PusDirAmoxicillinEscherichia coliNDM-1NoneNoneNone
17PusPeshawarLevofloxacinEscherichia coliNDM-1NoneNoneNone
18PusPeshawarLevofloxacinEscherichia coliNDM-1NoneNoneNone
19PusPeshawarUnknownEscherichia coliNDM-1NoneNoneNone
20PusPeshawarUnknownEscherichia coliNDM-1NoneNoneNone
21UrinePeshawarCeftriaxoneEscherichia coliNDM-1NoneNoneNone
22UrinePeshawarCiprofloxacinEscherichia coliNDM-1NoneNoneNone
23UrinePeshawarUnknownEscherichia coliNDM-1NoneNoneNone
24UrinePeshawarUnknownEscherichia coliNDM-1NoneNoneNone
25UnknownPeshawarCefiximeEscherichia coliNDM-1NoneNoneNone
26BloodMardanUnknownEscherichia coliNDM-1CTX-M-15NoneNone
27BloodPeshawarUnknownEscherichia coliNDM-1CTX-M-15NoneEsC-15
28UrinePeshawarUnknownEscherichia coliNDM-1CTX-M-15NoneNone
29UrinePeshawarUnknownEscherichia coliNDM-1CTX-M-15NoneNone
30UrinePeshawarUnknownEscherichia coliNDM-1CTX-M-15NoneNone
31UnknownUnknownUnknownEscherichia coliNDM-1NonermtBST 215
32UrinePeshawarCiprofloxacinEscherichia coliNDM-1; OXA-181NoneNoneEsC-10
33UrinePeshawarUnknownEscherichia coliNDM-1; OXA-181NoneNoneNone
34UrinePeshawarCiprofloxacinEscherichia coliOXA-48NoneNoneEsC-1
35BloodPeshawarCiprofloxacinEscherichia coliOXA-181CTX-M-15NoneEsC-5
36BloodPeshawarUnknownEscherichia coliOXA-181CTX-M-15NoneEsC-1
37BloodKohatUnknownEscherichia coliNoneCTX-M-15NoneEsC-14
38PusDirUnknownEscherichia coliNoneCTX-M-15NoneEsC-2
39PusPeshawarOfloxineEscherichia coliNoneCTX-M-15NoneEsC-2
40UrinePeshawarAmoxicillin-ClavulanateEscherichia coliNoneCTX-M-15NoneEsC-2
41UrinePeshawarLevofloxacinEscherichia coliNoneCTX-M-15NoneEsC-2
42Bronchial lavagePeshawarLevofloxacinEscherichia coliNoneCTX-M-15NoneEsC-3
43PusPeshawarCefiximeEscherichia coliNoneCTX-M-15NoneEsC-3
44UrinePeshawarUnknownEscherichia coliNoneCTX-M-15NoneEsC-3
45UrineKohatUnknownEscherichia coliNoneCTX-M-15NoneEsC-3
46UrinePeshawarCiprofloxacinEscherichia coliNoneCTX-M-15NoneEsC-9
47UrinePeshawarLevofloxacinEscherichia coliNoneCTX-M-15NoneEsC-12
48UrineAfghanistanLevofloxacinEscherichia coliNoneCTX-M-15NoneNone
49BloodPeshawarCefiximeEscherichia coliNoneNoneNoneEsC-16
50BloodUnknownCefiximeEscherichia coliNoneNoneNoneEsC-13
51PusAfghanistanUnknownEscherichia coliNoneNoneNoneEsC-11
52PusCharsadaCiprofloxacinEscherichia coliNoneNoneNoneNone
53PusPeshawarCiprofloxacinEscherichia coliNoneNoneNoneNone
54PusPeshawarLinezolidEscherichia coliNoneNoneNoneEsC-18
55UrineAfghanistanUnknownEscherichia coliNoneNoneNoneEsC-17
56UrinePeshawarCefiximeEscherichia coliNoneNoneNoneEsC-4
57UrinePeshawarUnknownEscherichia coliNoneNoneNoneEsC-4
58UrinePeshawarUnknownEscherichia coliNoneNoneNoneEsC-6
59UrinePeshawarUnknownEscherichia coliNoneNoneNoneEsC-8
60BloodPeshawarCefiximeKlebsiella pneumoniaeNDM-1CTX-M-15NoneKP-1
61PusDirAmoxicillinKlebsiella pneumoniaeNDM-1; OXA-181NoneNoneKP-1
62BloodMardanUnknownKlebsiella pneumoniaeNDM-1; OXA-232CTX-M-15rmtBST 231
63PusPeshawarCiprofloxacinKlebsiella pneumoniaeNoneNoneNoneKP-2
64UrineNoweshehraCiprofloxacinKlebsiella pneumoniaeNoneNoneNoneKP-2
65UnknownAfghanistanLevofloxacinKlebsiella pneumoniaeNoneNoneNoneNone

Abbreviations: EC, Enterobacter cloacae clone X; ESBL, extended spectrum β-lactamase; EsC, Escherichia coli clone X; KP, Klebsiella pneumoniae clone X; ST, sequence type.

The ten Enterobacter spp. isolates (nine Enterobacter cloacae, one Enterobacter sakazakii) co-produced NDM-1 and CTX-M-15.

Two Alcaligenes faecalis isolates were identified, both producing a carbapenemase VIM-4.

The single C. freundii isolate did not produce any carbapenemase but was positive for CTX-M-15. None of the isolates was resistant to colistin. PFGE analysis showed a very high clonal diversity for all those isolates producing a carbapenemase, except among Enterobacter spp. with a single clone being identified among six patients (EC-1) that may have resulted from an outbreak.

By using MLST, we showed that the blaNDM-1 and rmtB-positive E. coli clone belonged to ST215 (strain no. 31) and that the multidrug-resistant K. pneumoniae isolate belonged to ST231 (strain no. 62).

Discussion

Here we evaluated the occurrence of multidrug resistance from infecting strains (not colonizers) from individuals hospitalized at the Khyber Teaching Hospital, Peshawar, north Pakistan from November 2017 to March 2018. A rate of 19% of carbapenem-resistant Enterobacteriaceae (38/200) was identified, among which 16% harboured the blaNDM-1 gene. This overall rate of 16% of NDM producers is in accordance with the estimated rate of NDM producers in Enterobacteriaceae in Pakistan (8.7%–18.5%). Actually, 18.5% stool samples were found to contain blaNDM-1-positive strains (mostly E. coli and Enterobacter cloacae) in military hospitals of Rawalpindi (Combined Military Hospitals and Military Hospital at Rawalpindi) [17], 8.7% of the isolates were NDM-1 positive (K. pneumoniae, E. coli, Pseudomonas aeruginosa) from two tertiary-care hospitals (Pakistan Institute of Medical Science, Islamabad and Mayo Hospital, Lahore) [18] and 14.6% of the strains carried blaNDM-1 (E. coli, Enterobacter cloacae, Pseudomonas putida and K. pneumoniae from three children's hospitals (The Children's Hospital, Islamabad, The Children's Hospital Multan and Nishtar Hospital, Multan) [19].

Interestingly, some strains were found to harbour two unrelated carbapenemase genes (blaNDM-1 and blaOXA-181), as observed previously in Singapore [20], Nigeria [21] and Romania [22].

In our study, co-resistance to multiple antibiotics was commonly observed among those carbapenem-resistant isolates, with 60% of them harbouring at least two other resistance genes (ESBL, or 16S rRNA methylase gene). A single K. pneumoniae isolate carried two carbapenemase genes, namely blaNDM-1 and blaOXA-232, along with the ESBL-encoding gene blaCTX-M-15 and the 16S rRNA methylase gene rmtB. That isolate was an ST231 clone, already described in South-East Asia [23,24] and Switzerland [25], and associated with OXA-232.

Among the 16S rRNA methylase genes, the methylase gene rmtB, rather than rmtF, was mostly identified here, which is not surprising owing to the spread of rmtB-positive strains in Pakistan [26]. Our study showed the frequent identification of the ESBL CTX-M-15 among those multidrug-resistant bacteria. It is possible that the spread of CTX-M-15 that is observed worldwide originated from the Indian subcontinent because we identified the first CTX-15 producers from India in 2001 [27]. Our study confirms the frequent association of those three important resistance markers that are NDM, ESBL of the CTX-M-15 type and 16S rRNA methylases as a source of multidrug resistance. This combination complicates the treatment of infected patients.

We also identified two A. faecalis isolates producing a same VIM-4 metallo-β-lactamase. Occurrence of carbapenemase production in that bacterial species is rare. Only a single case of A. faecalis carrying blaVIM-4 has been described in Gaza, Palestine [28]. Further work may identify the genetic basis of such acquisition of carbapenemase. Other reports about ESBL in clinical isolates of Alcaligenes species have been described in Malaysia [29], France [30] and Italy [31].

Finally, no resistance to colistin was observed whereas MCR-1-mediated colistin resistance isolates was observed recovered from E. coli in animals [32,33] and from a single patient [34] in Pakistan. Lack of colistin resistance among those multidrug-resistant isolates is good news as it would indicate the availability to use that drug for treating infected patients in this country.

Funding

This work was supported by the Swiss National Science Foundation (project FNS-31003A_163432) and by the University of Fribourg.

Conflicts of interest

None to declare.

Medical and Molecular Microbiology, Section of Medicine, Faculty of Science and Medicine, Switzerland
INSERM European Unit (IAME, France), University of Fribourg, Fribourg, Switzerland
Swiss National Reference Centre for Emerging Antibiotic Resistance, University of Fribourg, Switzerland
Section of Infectious Diseases, Department of Medicine, The Aga Khan University, Karashi, Pakistan
Infectious Diseases Research Group, Department of Microbiology, University of Haripur, Khyber Pakhtunkhwa, Pakistan
Institute for Microbiology, University of Lausanne and University Hospital Centre, Lausanne, Switzerland
L. Poirel: hc.rfinu@leriop.tnerual
Corresponding author: L. Poirel, University of Fribourg, Fribourg, Switzerland. hc.rfinu@leriop.tnerual
Received 2019 Jun 7; Revised 2019 Sep 12; Accepted 2019 Sep 29.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abbreviations: EC, Enterobacter cloacae clone X; ESBL, extended spectrum β-lactamase; EsC, Escherichia coli clone X; KP, Klebsiella pneumoniae clone X; ST, sequence type.

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