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 ~  Materials and Me...
 ~ Results
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 36  |  Issue : 1  |  Page : 43-48
 

High-level aminoglycoside resistance in Acinetobacter baumannii recovered from Intensive Care Unit patients in Northeastern India


1 Department of Biotechnology and Bioinformatics, North Eastern Hill University, Shillong, Meghalaya, India
2 Department of Microbiology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, Meghalaya, India
3 Department of Anesthesiology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, Meghalaya, India
4 Department of Microbiology, Assam University, Silchar, Assam, India

Date of Web Publication2-May-2018

Correspondence Address:
Dr. Santa Ram Joshi
Department of Biotechnology and Bioinformatics, North Eastern Hill University, Shillong - 793 022, Meghalaya
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_17_225

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 ~ Abstract 

Background: Acinetobacter baumannii has emerged as an important nosocomial pathogen, its ability to acquire resistance to carbapenems and aminoglycosides, has complicated their treatment regimen. The present study investigates the prevalence and diversity of aminoglycoside-modifying enzymes and 16S methyltransferases in A. baumannii isolates recovered from patients admitted in Intensive Care Unit (ICU) of a tertiary referral hospital in Northeastern India. Materials and Methods: We investigated the high-level aminoglycoside-resistance (HLAR) (gentamicin and amikacin minimum inhibitory concentration ≥ 512 μg/ml) among 164 multidrug-resistant A. baumannii obtained from ICU. Genes encoding aminoglycoside-modifying enzymes, 16S methyltransferase and coexisting beta-lactamases were amplified. Horizontal transferability, plasmid stability and elimination assays were performed. Clonality and sequence types were evaluated by repetitive extragenic palindromic-polymerase chain reaction and multilocus sequence typing (MLST) respectively. Results: A total of 130 (79.2%) isolates were found to exhibit HLAR, with acquired aminoglycoside-resistance genes in 109 (83.8%) isolates along with coexisting extended-spectrum beta-lactamases and metallo-beta-lactamases. Genes aph (3') I, aph (3') VIa and armA were predominant and horizontally transferable. Plasmids were eliminated with single sodium dodecyl sulphate treatment. Seventeen haplotypes were found responsible for the infection. MLST revealed circulation of ST583 and ST188 in ICU. Conclusions: This study reveals the presence of aminoglycoside-resistance genes in combination with blaCTXM and blaNDM, which are highly stable and not frequently reported from this geographical region. Further, the study could predict limited treatment option and need for formulating infection control strategy.


Keywords: Acinetobacter, aminoglycosides, antimicrobial resistance, beta-lactamase, methyltransferases


How to cite this article:
Upadhyay S, Khyriem AB, Bhattacharya P, Bhattacharjee A, Joshi SR. High-level aminoglycoside resistance in Acinetobacter baumannii recovered from Intensive Care Unit patients in Northeastern India. Indian J Med Microbiol 2018;36:43-8

How to cite this URL:
Upadhyay S, Khyriem AB, Bhattacharya P, Bhattacharjee A, Joshi SR. High-level aminoglycoside resistance in Acinetobacter baumannii recovered from Intensive Care Unit patients in Northeastern India. Indian J Med Microbiol [serial online] 2018 [cited 2018 Jul 20];36:43-8. Available from: http://www.ijmm.org/text.asp?2018/36/1/43/231662



 ~ Introduction Top


Acinetobacter baumannii has emerged as one of the most troublesome pathogens in hospital-associated infections. This pathogen, especially targets immunocompromised patients in critical care units, posing risk for high mortality. It has remarkable abilities to acquire resistance to a wide range of antimicrobial agents, including broad-spectrum beta-lactams, aminoglycosides and fluoroquinolones.[1],[2],[3] Thus, the treatment regimen becomes complicated and severely compromised for the clinicians. Aminoglycosides are still widely used to treat severe bacterial infections, often together with beta-lactams in synergistic combinations.[4] Resistance to aminoglycosides in A. baumannii is mostly caused by the production of aminoglycoside-modifying enzymes such as – acetyltransferases (aac), nucleotidyltransferases (ant) and phosphotransferases (aph).[5] However, in the recent past, plasmid-encoded 16S methyltransferases have emerged as a new mechanism showing high-level level aminoglycoside resistance (HLAR) in clinical A. baumannii isolates.[6],[7],[8],[9]

These resistance determinants are found on horizontally transferable plasmid or other mobile genetic elements, often associated with mechanisms conferring resistance to other antibiotic classes. Some of the resistance mechanisms commonly reported in A. baumannii includes chromosomally mediated and acquired AmpC, extended-spectrum beta-lactamases (ESBLs) such as TEM, CTX-M, PER and SHV [3] metallo-beta-lactamases (MBLs) such as IMP, VIM, NDM [10] and carbapenemases like KPC, OXA.[11],[12] The coexistence of these resistance mechanisms severely limits the option of combination therapy using beta-lactams and aminoglycoside antibiotics. The present investigation was carried out to evaluate the prevalence of acquired aminoglycoside modifying enzymes and 16s methyltransferase genes associated with HLAR in multidrug-resistant A. baumannii obtained from Intensive Care Units (ICU) patients of a tertiary referral hospital in Northeastern India.


 ~ Materials and Methods Top


Bacterial strains

A total of 164 multidrug-resistant A. baumannii strains were recovered from September 2014 to August 2015 in patients admitted in ICUs of a tertiary referral hospital in Northeastern India. Of the 164 A. baumannii strains, 112 isolates were from endotracheal aspirates, 16 from tracheal secretion, 18 from wound swab, 8 from pus, 8 from sputum and 2 from the catheter tip. Majority of the patients were on ventilators, and the samples were mostly aspirates from ventilation tubes.

Identification of organism was done by conventional methods [13] as well as by performing polymerase chain reaction (PCR) for the presence of OXA-51-like genes as described previously.[14]

Minimum inhibitory concentration and susceptibility testing for high-level aminoglycoside resistance

To recognize the isolates positive for HLAR (gentamicin and amikacin minimum inhibitory concentrations [MICs] higher than 512 μg/mL),[15] MIC for amikacin and gentamicin (Himedia, Mumbai, India) were determined by the agar dilution method on Mueller-Hinton agar (Himedia, Mumbai, India) according to the CLSI guidelines.[16]Escherichia coli ATCC 25922 was used as negative control. Antimicrobial susceptibility pattern of all the multidrug-resistance isolates was determined by Kirby-Bauer disc diffusion method, and the results were interpreted as per CLSI guidelines.[16] Following antibiotics were tested: Amikacin (30 μg), gentamicin (10 μg), kanamycin (30 μg), tobramycin (10 μg), netilmicin (30 μg), streptomycin (10 μg), cefotaxime (30 μg), cefoxitin (30 μg), ceftazidime (30 μg), ciprofloxacin (5 μg), trimethoprim/sulphamethoxazole (1.25/23.75 μg), imipenem (10 μg), meropenem (10 μg) (Hi-Media, Mumbai, India).

Polymerase chain reaction assay

Extraction of bacterial DNA was performed by the boiling-centrifugation method.[17] PCR was performed to detect 15 genes encoding aminoglycoside modifying enzymes, namely: Aac (3) I, aac (3) IIc, aac (6') Ib and aac (6') II encoding acetyltransferases; aph (4) Ia, aph (3') I, aph (3') IIb, aph (3') IIIa, aph (3') VIa, aph (2″) Ib, aph (2″) Ic and aph (2) Id for phosphotransferases and ant (2″) Ia, ant (3″) I, ant (4') Ia for nucleotidyltransferases.[15] The 16S methyltransferase genes investigated included armA, rmtA, rmtB, rmtC, rmtD and npmA.[18] Reaction mixture was prepared using Promega 2X PCR mix (Promega, Madison, USA). Reactions were run under the following conditions: Initial denaturation 95°C for 5 min, 32 cycles of 95°C for 30s, 56°C for 1 min, 72°C for 1 min and final extension at 72°C for 7 min. PCR amplification was performed with a PCR System 9700 (Applied Biosystems, USA). The amplicons were sequenced and compared by performing BLAST (http://blast.ncbi.nlm.nih.gov/Blast.cgi). E. coli ATCC 25922 was used as negative control in the PCR reaction.

The co-existence of ESBL and MBL genes was detected by multiplex PCR using bacterial DNA as template. PCR conditions and primers were as described previously.[19],[20],[21],[22]

Transmission dynamics

Plasmid DNA was extracted from clinical isolates using a Plasmid Midi kit (Qiagen Inc., Chatsworth, CA, USA). Transformation experiments were conducted by heat shock method using E. coli DH5α as recipient. Transformants were selected on kanamycin (10 μg/ml) supplemented LB agar plates and subjected to PCR assay for the presence of aminoglycoside-modifying enzymes and 16S methyltransferase genes.

The conjugation experiment was performed between the donor (transformants) and E. coli J53 as the recipient. The transconjugants were selected on agar plates containing sodium azide (100 mg/L) supplemented with amikacin (8 mg/L).

Plasmid elimination

The elimination of plasmid harbouring different aminoglycoside -resistance genes within A. baumannii was performed using sodium dodecyl sulphate (SDS) treatment method as described previously.[23] About50 μl of A. baumannii suspension was inoculated into five replicate samples of 5 ml of LB medium, to which 200, 100, 50, 25 or 12.5 μl of 10% SDS was added and then incubated overnight at 37°C.

The eradication of plasmids in test strains was confirmed by PCR. Antibiotic-resistance profiles of plasmid-harbouring and plasmid-cured strains were tested by disc diffusion method as per the CLSI recommendation.

Plasmid stability by serial passage

Plasmid stability of isolates harbouring aminoglycoside -resistance genes, including donor strains as well as their transformants were analysed by serial passages method. Serial passage was done for consecutive 120 days in ratio of 1:1000 dilutions in LB broth without antibiotic pressure. After each passage, 1 ml of the culture was diluted into 10 − 3 dilution with normal saline, and 50 ml of the diluted sample was spread on to the LB agar plate. After overnight incubation, 50 colonies from plates were randomly chosen and subjected to PCR assay targeting aminoglycoside resistance, ESBLs and MBLs.[24]

Typing

Clonal relatedness of the isolates was analysed by repetitive extragenic palindromic-polymerase chain reaction (REP-PCR), using bacterial DNA as template. Reaction mixture was prepared using Promega 2X PCR mix (Promega, Madison, USA) with REP1 and REP2 primers. Reactions were run under the following conditions: Initial denaturation 95°C for 8 min, 32 cycles of denaturation at 95°C for 1 min, annealing at 45°C for 1 min, extension at 72°C for 2 min and final extension at 72°C for 16 min.[25]

Multilocus sequence typing

Oxford multilocus sequence typing (MLST) scheme was used for sequence type determination (http://mlst.zoo.ox.ac.uk). Seven chromosomal genes were PCR amplified and sequenced as described previously.[26]


 ~ Results Top


One hundred and thirty (79.2%) isolates showed HLAR property. Among HLAR isolates, 109 (83.8%) were harbouring aminoglycoside-resistance genes including aminoglycoside modifying genes (AMG) and 16S methyltransferases. Thirty-nine isolates (35.7%) were harbouring one or more of the evaluated AMG and 21 isolates (19.2%) contained either single or multiple 16s methyltransferase genes. The most common AMG was aph (3') I followed by aph (3') Via, while armA was the predominantly reported 16S methyltransferase gene. The aminoglycoside-resistance gene profiles of 130 HLAR A. baumannii are presented in [Table 1].
Table 1: Distribution of extended-spectrum beta-lactamases and metallo-beta-lactamases in Acinetobacter baumannii isolates harbouring aminoglycoside-resistance genes

Click here to view


It was noted that the isolates harbouring 16s methyltransferase genes (armA, rmtA and rmtD) displayed very high MIC for gentamicin and amikacin (MIC ≥ 1024 mg/L), while isolates with only AMG showed slightly high MIC for amikacin (≥256 mg/L). Susceptibility testing revealed the highest resistance towards kanamycin (86%) followed by gentamicin (84%), amikacin (82%), streptomycin (80%), neomycin (76%), tobramycin (66%) and netilmicin (52%). HLAR strains displayed more than 85% resistance towards all the tested cephalosporins, carbapenems, ciprofloxacin and trimethoprim/sulphamethoxazole. All the isolates were susceptible to tigecycline and polymyxin B. The co-carriage of MBL and ESBL genes were identified in 70 (64.2%) and 35 (32.1%) isolates, respectively. The distribution of MBLs and ESBLs among 109 aminoglycoside-resistant isolates is given in [Table 1].

The ant (2') Ia, aph (3') I, aph (3') VIa, armA and rmtD genes were successfully conjugatively transferred to the recipient demonstrating their carriage within the plasmid. The MIC results revealed that E. coli recipient strain simultaneously exhibited an elevated level of resistance to aminoglycosides as well as beta-lactams.

Vertical transmission of genes encoding aminoglycoside -modifying enzymes and 16S methyltransferase revealed that aph (3') I, aph (3') VIa, rmtD and armA were stable up to 105 consecutive serial passages in the absence of any antibiotic pressure. [Table 2] depicts the proportion of plasmid loss in isolates positive for genes encoding aminoglycoside, cephalosporin and carbapenem resistance.
Table 2: Plasmid stability of aminoglycoside, cephalosporin and carbapenem resistance

Click here to view


The elimination of the plasmid carrying aminoglycoside modifying and 16S methyltransferase genes was successful after a single-SDS treatment which was confirmed by PCR analysis. Further, the susceptibility analysis showed the loss of resistance of all the cured strains towards aminoglycosides, quinolone and beta-lactam antibiotics.

On performing REP-PCR for 109 HLAR A. baumannii strains, 17 different haplotypes were obtained. MLST analysis revealed the prevalence of A. baumannii sequence type ST188 and ST583 among ICU patients.


 ~ Discussion Top


The present study describes the spread of A. baumannii conferring carbapenem and aminoglycoside resistance among ICU patients admitted in a hospital of Northeastern India.

The study revealed the high prevalence (79.2%) of multidrug-resistant clinical isolates of A. baumannii displaying HLAR. The association of these HLAR strains with wide spectrum of infections in ICU alarms a worrisome situation for their treatment.

Among the six methyltransferase genes detected, the present study demonstrates the predominance of armA, which is also correlated with the highly elevated aminoglycoside MIC (≥1024). Genes encoding aminoglycoside-modifying enzymes were mostly responsible for the moderate-level resistance (≥256 mg/L) to aminoglycosides. The elevated MIC among armA positive isolates indicated that the isolates are becoming extensively resistance day by day and thus raises an alarm. Our results show similarity with reports which demonstrated armA to be the only 16S methyltransferase gene detected in HLAR A. baumannii.[15],[27] In India, the presence of armA, rmtB, rmtC and rmtF were noted among Enterobacteriaceae and P. aeruginosa, but none of the studies revealed the presence of rmtA and rmtD among A. baumannii.[28],[29] To the best of our knowledge, this is the first study that reports the spread of rmtA and rmtD through A. baumannii.

Twenty-one HLAR strains, did not show the presence of any aminoglycoside-resistance genes, which could be due to other multifactorial mechanisms conferring aminoglycoside resistance including active efflux of the antimicrobial and reduced intake into the bacterial cell.

This study also showed the coexistence of ESBLs such ads blaCTX-M-15, blaTEM, blaSHV genes and MBLs including blaVIM and blaNDM-1 among the isolates harbouring AMG and 16S methyltransferase. Therefore, these strains showed high resistance to other wide-spectrum antimicrobial agents such as cephalosporins and carbapenems. To the best of our knowledge, this is one of the rare reports showing A. baumannii strains harbouring AMG and16S rRNA methylase (ArmA or RmtB) along with dreadful carbapenemases such as blaNDM-1, blaKPC and blaOXA-23 like genes emerging in ICU of medical settings in this region. The presence of CTX-M-15 and NDM-1, OXA-23 and KPC genes in any settings, itself represent an alarming situation. Besides this, the high prevalence of HLAR in ICU isolates might not allow the clinicians for combination therapy of aminoglycoside with beta-lactams against life-threatening infections of A. baumannii. Thus, the treatment options and outcomes become critical in such patients. For these isolates, colistin is somewhat promising approach. Tigecycline could be one such drug of choice but their clinical efficacy is not yet well understood. Despite being reliable drugs, colistin and tigecycline could no longer be very reliable choice due to their increasing trend of resistance from other part of world.[2],[30]

Our study revealed the presence of AMG (aph (3') I, aph (3') VIa, ant (2') Ia and aac (6') Ib and 16S methyltransferase (armA) on the same plasmid which were conjugatively transferable and highly stable even when the aminoglycoside pressure was withdrawn. Susceptibility results of transconjugants showed increased resistance towards aminoglycosides, cephalosporins and carbapenems documenting the presence of other resistance genes on the same plasmid. The simultaneous propagation of these associated genes by horizontal transfer is highly worrisome and warrants reinforcement of continuous monitoring. Further studies are required to assess the genetic environment of these genes and to determine their linkage with transposons or insertion elements.

MLST analysis demonstrated the circulation of ST188 and ST583 in ICU. REP-PCR results analysis classified the 109 isolates into 17 different haplotypes, thus indicating the clonal differentiation among them. Our findings suggest that these resistant determinants such as aph (3') I, aph (3') VIa, armA, rmtA and rmtD genes have spread by horizontal transfer at our settings. Few other reports verified that plasmids carrying 16S methyltransferase genes could be transferred from one species to another and also spread by cross infection.[31]


 ~ Conclusions Top


The present study describes the high prevalence of aminoglycoside modifying and 16S methyltransferase genes along with MBLs and ESBLs within A. baumannii. Further, their genetic location on mobile elements and transferability worsens the scenario. This offers the clinicians with no option of combination therapy of aminoglycoside and beta-lactams in A. baumannii infections. Therefore, to slow down further proliferation of these extensively drug-resistant A. baumannii in immunocompromised patients, there is an urgent need for vigilant monitoring as well as strategic implementation of proper infection control practices and routine surveillance.

Financial support and sponsorship

This work was financially supported by the University Grants Commission (UGC) under Dr. D.S. Kothari Postdoctoral Fellowship Scheme (No.F.4-2/2006 (BSR)/13-927/2013(BSR) to Dr. Supriya Upadhyay.

Conflicts of interest

There are no conflicts of interest.

 
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2004 - Indian Journal of Medical Microbiology
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