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JAC Advance Access originally published online on June 26, 2007
Journal of Antimicrobial Chemotherapy 2007 60(3):483-489; doi:10.1093/jac/dkm231
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Relationship between the AdeABC efflux system gene content, netilmicin susceptibility and multidrug resistance in a genotypically diverse collection of Acinetobacter baumannii strains

Alexandr Nemec1,2,*, Martina Maixnerová1, Tanny J. K. van der Reijden3, Peterhans J. van den Broek3 and Lenie Dijkshoorn3

1 Centre of Epidemiology and Microbiology, National Institute of Public Health, Prague, Czech Republic 2 3rd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic 3 Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

* Correspondence address. Centre of Epidemiology and Microbiology, National Institute of Public Health, Srobárova 48, 100 42 Prague 10, Czech Republic. Tel: +420-267082266; Fax: +420-267082538; E-mail: anemec{at}szu.cz

Received 20 April 2007; returned 12 May 2007; revised 30 May 2007; accepted 31 May 2007


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Objectives: To assess the occurrence of the genes of the AdeABC efflux system and their association with antimicrobial resistance in Acinetobacter baumannii.

Methods: A set of 116 strains selected for their diversity both in genotypic properties and geographic origin was investigated for the presence of the structural (adeA, adeB and adeC) and regulatory (adeR and adeS) genes of the AdeABC system by PCR, for resistance to 11 antimicrobials by disc diffusion, for MIC of netilmicin and for the presence of aacC2 and aacA4, encoding netilmicin-modifying enzymes.

Results: Ninety-five strains were positive for adeA, adeB, adeR and adeS, 10 were positive for 1 to 3 of these genes and 11 were negative for all genes. The adeC gene was found in 49 strains with one or more of the other genes. Forty-one strains were resistant to a maximum of one agent and 75 strains to two or more agents. Netilmicin MICs showed an almost bimodal distribution with respective peaks of 0.5–1 and 8 mg/L; aacC2 or aacA4 was found in six strains with netilmicin MIC of ≥64 mg/L. All 61 strains with netilmicin MICs ≥ 4 mg/L were both adeABRS-positive and resistant to two or more agents, whereas netilmicin MICs ≤ 2 mg/L (n = 51) were found for all strains resistant to a maximum of one agent and those negative for one or more of the adeABRS genes.

Conclusions: The AdeABC genes are common in A. baumannii, but may be absent in some, mostly fully susceptible strains. Decreased susceptibility to netilmicin (MIC 4–32 mg/L) is associated with both the presence of these genes and multidrug resistance and may be indicative of AdeABC overexpression.

Keywords: European clones , AFLP , PCR detection


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Acinetobacter baumannii is notorious for its involvement in nosocomial infections and epidemic spread among severely ill patients.1 The organism is characterized by its ability to evolve resistance to multiple antibiotics and there are recent reports on strains resistant to all clinically relevant drugs.2 Over the last few decades, many resistance mechanisms have been identified in A. baumannii, of which ß-lactamases, aminoglycoside-modifying enzymes, tetracycline efflux pumps and alteration in quinolone target sites are considered to be the most important.2,3

In 2001, a novel resistance mechanism, the efflux pump system AdeABC, was identified in a multidrug-resistant (MDR) A. baumannii strain.4 This system was shown to be responsible for decreased susceptibility to a broad spectrum of antimicrobials. Although netilmicin and gentamicin appeared to be the best substrates for the pump, the activity of AdeABC has also been associated with other agents including ß-lactams, fluoroquinolones, tetracyclines4 and recently, with tigecycline.5 Three sequential, clustered genes adeA, adeB and adeC were found to encode proteins homologous to membrane fusion, drug transporter and outer membrane components, respectively, characteristic of the RND efflux pump family.6 It was further revealed that a susceptible A. baumannii strain containing the AdeABC genes could produce spontaneous resistant variants with mutations in the adeS or adeR genes, which encode a two-component system regulating AdeABC expression, and the reduction in susceptibility associated with the efflux system has been attributed to its constitutive overexpression.7

Elucidation of the AdeABC complex at the molecular and functional levels has been based mainly on the study of a single A. baumannii strain, BM4454.4,7 Relatively little is known about its distribution and biological significance at the population level. So far, only two studies have reported its occurrence among multiple A. baumannii strains. Huys et al.8 found adeB in 49 out of 51 strains originating almost exclusively from Europe, whereas in another study, 39 out of 56 strains from Hong Kong tested adeB positive.9 However, the strains of the first study belonged mostly (80%) to three groups of genetically related strains (clones), whereas no epidemiological or microbiological data on strains were shown in the second study.

The aim of the present study was to assess the occurrence of the structural and regulatory genes of the AdeABC system in a genetically and geographically heterogeneous collection of A. baumannii strains and to investigate the association of the AdeABC efflux genes with resistance to antimicrobial agents. In addition, the role of reduced susceptibility to netilmicin as a tentative phenotypical marker for the up-regulation of AdeABC was studied.


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Bacteria

One hundred and sixteen A. baumannii strains used in the present study were selected from the Leiden University Medical Center (LUMC) collection. This collection comprises more than 8000 Acinetobacter isolates of which approximately 2000 have been investigated for their genotype by AFLP whole genome fingerprint analysis (AFLPTM).10 Cluster analysis of AFLP fingerprints has allowed assessment of similarities among strains and revealed that similarities above 50%, ~80% and 90% are indicative of relatedness at the species, clone and strain level, respectively.11 Thus, using the dendrogram of all fingerprints (data not shown), unique strains (n = 45) or representatives of clusters of strains with similar genotypes (n = 71) were selected at a cluster cut-off level of ~80% in order to cover the overall diversity of the A. baumannii LUMC collection. The dendrogram of the 116 strains studied is shown in Figure 1. At a cut-off level of 83%, seven AFLP clusters of strains were distinguished; three of them corresponded to European clones I (n = 24), II (n = 19) and III (n = 10) described previously,11–13 whereas the four others (A–D) may represent new clonal lineages. The strains were obtained from 16 countries between 1982 and 2004 and were from human (n = 107) or animal (n = 8) specimens or from the hospital environment (n = 1), except for three reference strains (ATCC 19606T, NCTC 10303 and NCTC 7844) which had been isolated before 1963 (Figure 1).


Figure 1
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  		Figure 1. Dendrogram of cluster analysis of AFLP fingerprints of 116 A. baumannii strains included in this study. The origin of strains and the results of PCR detection of the AdeABC system-associated genes and of susceptibility testing are indicated. AFLP analysis was performed as described previously;10 clusters delineated at a cut-off level of 83% are indicated by boxes. The strains were from humans if not stated otherwise. The presence of the netilmicin-modifying genes is indicated in parentheses. A, adeA; B, adeB; C, adeC; R, adeR; S, adeS; —, no gene detected.

 
Gene detection

The presence of three structural (adeA, adeB and adeC) and two regulatory (adeS and adeR) genes of the AdeABC system, and two genes encoding netilmicin-modifying acetyltransferases AAC(3)-IIa and AAC(6')-Ib (aacC2 and aacA4, respectively), was determined by PCR. The primers were those described for adeB,4 for adeC, adeS and adeR7 and for aacC2 and aacA4.14 To detect adeA, new primers (A-am: 5'-GCTGAGCCACCACCGGCTAAAG-3' and A-av: 5'-ACCTTCAACAACGACTCTGTCACC-3') with an expected amplicon size of 990 bp were used in this study. PCR reactions were performed in a final volume of 20 µL containing 10 µL of Taq PCR Master Mix (Qiagen, Hilden, Germany), 0.2 µM each primer and 1.5 µL of a DNA suspension obtained by alkaline lysis.15 The PCR reactions were performed in a FTGENE2D thermal cycler (Techne, Duxford, UK) with these parameters: initial denaturation at 94°C for 2 min, 35 cycles of 94°C for 30 s, 55°C for 30 s and 72°C for 2 min and a final elongation at 72°C for 2 min. The presence and sizes of amplicons were assessed by electrophoresis in 2% agarose gels stained with ethidium bromide.

Susceptibility testing

Susceptibility was determined by disc diffusion following the CLSI (formerly NCCLS) guidelines16 using Mueller–Hinton agar (Oxoid, Basingstoke, UK) and 11 antimicrobial agents, which are primarily effective against susceptible A. baumannii strains. The cut-off values for resistance were adjusted according to the known distribution of inhibition zone diameters among A. baumannii strains.11 These values were identical to those recommended by the CLSI guidelines16 for intermediate susceptibility except for tetracycline and piperacillin, for which the CLSI values for resistance were used.16 The agents (content in micrograms/disc; resistance breakpoint in millimetres) included gentamicin (10; ≤ 14), netilmicin (30; ≤ 14), tobramycin (10; ≤ 14), amikacin (30; ≤ 16), ampicillin + sulbactam (10 + 10; ≤ 14), piperacillin (100; ≤ 17), ceftazidime (30; ≤ 17), imipenem (10; ≤ 15), ofloxacin (5; ≤ 15), sulfamethoxazole + trimethoprim (23.75 + 1.25; ≤ 15) and tetracycline (30; ≤ 14) (Oxoid). MIC of netilmicin (MAST Group, Bootle, UK) was determined by the agar dilution method, according to the CLSI guidelines.16 The netilmicin susceptibility and resistance breakpoints used were ≤8 and ≥32 mg/L, respectively.16 All susceptibility tests were carried out in duplicate and were repeated twice if discordant results had been obtained.


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Detection of the genes associated with the AdeABC efflux system

PCR results for all five AdeABC-associated genes are shown in Figure 1 and Table 1. Among 116 strains, 47 (40.5%) were PCR positive for all genes, 48 (41.4%) were positive for all genes except for adeC, 1 (0.9%) was positive for all genes except for adeS, 9 (7.8%) were positive for 1 to 3 genes and 11 (9.5%) were negative for all 5 genes. Strains belonging to the same AFLP cluster yielded the same combination of PCR reactions except for one clone II strain with negative reaction for adeS and for the strains of AFLP cluster B, which had variable reactions for adeB and/or adeS (Table 1). The strains positive for all five genes belonged to clone I (n = 24), clone II (n = 18) or had unique AFLP genotypes (n = 5), whereas strains positive for all genes but adeC were associated with 25 unique genotypes and 4 AFLP clusters.


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  		Table 1. PCR detection of the structural and regulatory genes of the AdeABC efflux system in 116 A. baumannii strains classified according to their AFLP genotype

 
Resistance to antimicrobial agents

The percentages of strains resistant to an antimicrobial agent according to disc diffusion were as follows: gentamicin (56%), netilmicin (18%), tobramycin (25%), amikacin (28%), ampicillin + sulbactam (24%), piperacillin (56%), ceftazidime (32%), imipenem (6%), ofloxacin (42%), sulfamethoxazole + trimethoprim (65%) and tetracycline (62%). Table 2 shows the distribution of the number of agents to which individual strains were resistant and demonstrates that the vast majority of the strains were either susceptible to all antimicrobial agents (29%) or resistant to three or more agents (59%), although only 12% of the strains were resistant to one or two agents.


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  		Table 2. Distribution of the strains according to the degree of multiresistance and netilmicin MIC

 
Susceptibility to netilmicin

The distribution of netilmicin MICs among the 116 strains is shown in Figure 2. The MIC values ranged between 0.25 and ≥128 mg/L with MIC50 and MIC90 being 8 and 16 mg/L, respectively, and showed an almost bimodal distribution with the respective peaks being 0.5–1 and 8 mg/L. The genes aacC2 and aacA4, which encode the netilmicin-modifying enzymes most commonly found in A. baumannii, were found in five strains and one strain (Figure 1), respectively, all of which had netilmicin MIC ≥ 64 mg/L.


Figure 2
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  		Figure 2. Distribution of netilmicin MICs among the 116 A. baumannii strains classified according to the presence of the genes associated with the AdeABC system. Black bars, positive for adeA, adeB, adeR and adeS, and variable reactions for adeC; white bars, negative reactions for all five genes; shaded bars, the remaining combinations of positive and negative reactions for all genes (Table 1). The vertical arrows indicate the published data for strain BM4454 with the up-regulated system (16 mg/L) and its derivative with inactivated adeB (0.5 mg/L).4 Numbers of strains with the genes encoding netilmicin-modifying enzymes are indicated in parentheses. Interpretation according to the CLSI breakpoints16 is depicted above the columns. S, susceptible; I, intermediate; R, resistant.

 
Relationship between the AdeABC system gene content, netilmicin susceptibility and multidrug resistance

Figure 2 and Table 2 show the relationships between the content of the efflux genes, MICs to netilmicin and multidrug resistance. As adeC was shown not to be essential for the efflux function,7 this gene was not included in the following comparisons. Thus, the strains could be classified into three groups: (i) positive for all four genes (n = 95); (ii) negative for all genes (n = 11) and (iii) positive for one to three genes (n = 10) (Figure 2). Except for four, all strains (n = 75) resistant to two or more agents were positive for all essential genes, whereas among 41 strains resistant to less than two agents, as many as 17 (41%) strains yielded negative results for one or more genes (Figure 1). Figure 2 shows that all strains with netilmicin MICs ≥ 4 mg/L were positive for all four genes, whereas all strains negative for one or more of these genes had netilmicin MICs ≤ 2 mg/L. As indicated in Table 2, all strains (n = 59) with netilmicin MICs ≥ 4 mg/L were resistant to two or more agents, whereas strains (n = 51) with netilmicin MICs ≤ 2 mg/L included all fully susceptible strains.


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The results of the present study suggest that the AdeABC system occurs in the vast majority of the A. baumannii population. At least one of the five genes associated with AdeABC was found in 91% of all strains. Even if only one representative per AFLP cluster is considered, as many as 82% of strains were positive for at least one gene (Figure 1). Most of the 116 strains (82%) yielded positive PCR results for all efflux genes, except for adeC, which was found in only 35% of them. The absence of adeC, which is thought to encode an outer membrane porin, may be explained by the fact that this porin is not essential for the efflux function.7 However, negative PCR results obtained with the specific primers inferred from one sequence have to be interpreted with caution, as they may result from the polymorphism of DNA regions targeted by primers. Similarly, 10 strains yielded different combinations of positive and negative results for adeA, adeB, adeS or adeR (Table 1) and further studies are required to determine whether the negative results truly indicate the absence of parts of the efflux system gene cluster considered essential for the system to function.

To assess the involvement of the AdeABC system in antimicrobial susceptibility, a simple phenotypic marker of the efflux up-regulation is needed. Ideally, such a marker should clearly differentiate between the strictly regulated and up-regulated efflux forms and should not be affected by other resistance mechanisms. Even though such a marker is unlikely to be found among clinically used antimicrobials, the published data show that decreased susceptibility to netilmicin might serve as an indication of the up-regulated AdeABC. First, among different antimicrobial agents, netilmicin and gentamicin showed the highest differences between the MICs for the MDR strain BM4454 and its derivative with the disrupted adeB gene.4 Secondly, although clinically relevant aminoglycoside resistance in A. baumannii has been attributed mainly to enzymatic modification of antibiotics,17,18 modification of netilmicin—in contrast to gentamicin—may be infrequent, especially in countries where the prescription of netilmicin is low.15 For the identification of modifying enzymes which can decrease susceptibility to netilmicin, the detection of genes known to encode these enzymes in A. baumannii can be used.15

In the present study, the netilmicin MIC values showed an almost bimodal distribution (Figure 2) with the respective peaks near to the published values for strain BM4454 with up-regulated AdeABC efflux system (16 mg/L) and its derivative with inactivated adeB (0.5 mg/L).4 Another study7 showed that the challenge of a susceptible strain (gentamicin MIC, 1 mg/L) with gentamicin resulted in the selection of mutants with an up-regulated AdeABC system (gentamicin MIC, 12 mg/L). These results are also consistent with our data, assuming that the up-regulation of the AdeABC system leads to similar increased MIC values of both gentamicin and netilmicin.4 Such congruency between our data and the quoted data may suggest that the A. baumannii population forms two major groups according to efflux activity. It can be hypothesized that MICs of ~0.5–1 mg/L may reflect the inactivity of the system because of its stringent regulation, alteration or absence, whereas values ~8–16 mg/L could result from the constitutive expression of the system. This hypothesis is indirectly supported by our other data. First, all strains with netilmicin MICs ≥ 4 mg/L harboured all four genes essential for the efflux activity,4,7 whereas all strains negative for at least one of these genes had MICs ≤ 2 mg/L. Secondly, the genes encoding netilmicin-modifying enzymes were not detected in any of the strains with netilmicin MICs ≤ 32 mg/L. Finally, comparison of inhibition zone diameters produced by different aminoglycosides in individual strains did not indicate the involvement of permeability resistance (data not shown), which is indicated by a proportional decrease in susceptibility to all aminoglycosides.19 Thus, all strains with netilmicin MICs of 4–32 mg/L were associated with all essential efflux genes, although in none of them were non-efflux mechanisms detected. In 6 of 12 strains with MICs ≥ 64 mg/L, the genes encoding netilmicin-modifying enzymes were found, which could explain the high level of netilmicin resistance, whereas the absence of these genes in the other 6 strains may indicate the involvement of other factors.

It is noteworthy that studies conducted by the Schering-Plough Research Institute in the 1980s indicated a high prevalence of the aminoglycoside resistance phenotype similar to that of BM44544 among worldwide Acinetobacter spp. strains.18 This phenotype was characterized by low-level resistance to netilmicin and gentamicin, resistance to two non-clinical derivatives of netilmicin (2'-N-ethylnetilmicin and 6'-N-ethylnetilmicin) and by susceptibility to the other aminoglycosides. The hypothetical mechanism underlying this phenotype was provisionally designated AAC(3)-?, yet the corresponding acetyltransferase has never been identified.18 It is conceivable that the AdeABC system was responsible for AAC(3)-?, suggesting that the up-regulated form of this system was widespread among A. baumannii strains more than two decades ago.

In conclusion, the results of the present study are suggestive of the association between resistance to multiple agents and the up-regulated AdeABC system in A. baumannii, as indicated by the observed link between the presence of the genes essential for the activity of the AdeABC, decreased netilmicin susceptibility and multidrug resistance. However, although the up-regulated AdeABC system was shown to transport a wide range of structurally dissimilar compounds, the level of resistance to individual agents conferred by the system usually does not reach clinical resistance breakpoints.4,7,20 Values exceeding these breakpoints are therefore likely to result from the presence of other, more effective, mechanisms or from a combination of different mechanisms.6,21 It has been suggested that increased expression of chromosomally encoded efflux systems may be the first step in the bacterium becoming fully resistant.6 Thus, originally susceptible, AdeABC-positive strains may produce mutants with constitutive expression of the AdeABC. It confers low-level protection that may facilitate the initial survival of the organisms in an antimicrobial-rich environment such as the hospital and enable them to acquire subsequently specific, high-level resistance mechanisms. This could explain why genotypically distinct MDR strains harbouring different combinations of specific resistance mechanisms share the up-regulated AdeABC system.


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The study was supported by grant NR 8554-3 of the Internal Grant Agency of the Ministry of Health of the Czech Republic and by the NWO fellowship (B93-483), both awarded to A. N.


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None to declare.


   Acknowledgements
 
We thank all colleagues who generously provided strains that were included in this study. Part of this work was presented at the 7th International Symposium on the Biology of Acinetobacter, Barcelona, Spain, 2006 (Abstract P9).


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1 Bergogne-Bérézin E, Towner KJ. Acinetobacter spp. as nosocomial pathogens: microbiological, clinical, and epidemiological features. Clin Microbiol Rev (1996) 9:148–65.[ISI][Medline]

2 Van Looveren M, Goossens H, ARPAC Steering Group. Antimicrobial resistance of Acinetobacter spp. in Europe. Clin Microbiol Infect (2004) 10:684–704.[CrossRef][ISI][Medline]

3 Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. Clin Infect Dis (2006) 43(Suppl 2):S49–56.[CrossRef][ISI][Medline]

4 Magnet S, Courvalin P, Lambert T. Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM4454. Antimicrob Agents Chemother (2001) 45:3375–80.[Abstract/Free Full Text]

5 Ruzin A, Keeney D, Bradford PA. AdeABC multidrug efflux pump is associated with decreased susceptibility to tigecycline in Acinetobacter calcoaceticus–Acinetobacter baumannii complex. J Antimicrob Chemother (2007) 59:1001–4.[Abstract/Free Full Text]

6 Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev (2006) 19:382–402.[Abstract/Free Full Text]

7 Marchand I, Damier-Piolle L, Courvalin P, et al. Expression of the RND-type efflux pump AdeABC in Acinetobacter baumannii is regulated by the AdeRS two-component system. Antimicrob Agents Chemother (2004) 48:3298–304.[Abstract/Free Full Text]

8 Huys G, Cnockaert M, Vaneechoutte M, et al. Distribution of tetracycline resistance genes in genotypically related and unrelated multiresistant Acinetobacter baumannii strains from different European hospitals. Res Microbiol (2005) 156:348–55.[Medline]

9 Chu YW, Chau SL, Houang ET. Presence of active efflux systems AdeABC, AdeDE and AdeXYZ in different Acinetobacter genomic DNA groups. J Med Microbiol (2006) 55:477–8.[Free Full Text]

10 Nemec A, De Baere T, Tjernberg I, et al. Acinetobacter ursingii sp. nov. and Acinetobacter schindleri sp. nov. isolated from human clinical specimens. Int J Syst Evol Microbiol (2001) 51:1891–9.[Abstract]

11 Nemec A, Dijkshoorn L, van der Reijden TJK. Long-term predominance of two pan-European clones among multi-resistant Acinetobacter baumannii strains in the Czech Republic. J Med Microbiol (2004) 53:147–53.[Abstract/Free Full Text]

12 Dijkshoorn L, Aucken HM, Gerner-Smidt P, et al. Comparison of outbreak and nonoutbreak Acinetobacter baumannii strains by genotypic and phenotypic methods. J Clin Microbiol (1996) 34:1519–25.[Abstract]

13 Van Dessel H, Dijkshoorn L, van der Reijden T, et al. Identification of a new geographically widespread multiresistant Acinetobacter baumannii clone from European hospitals. Res Microbiol (2004) 155:105–12.[Medline]

14 Noppe-Leclercq I, Wallet F, Haentjens S, et al. PCR detection of aminoglycoside resistance genes: a rapid molecular typing method for Acinetobacter baumannii. Res Microbiol (1999) 150:317–22.[Medline]

15 Nemec A, Dolzani L, Brisse S, et al. Diversity of aminoglycoside resistance genes and their association with class 1 integrons among strains of pan-European Acinetobacter baumannii clones. J Med Microbiol (2004) 53:1233–40.[Abstract/Free Full Text]

16 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Approved Standard M100-S15 (2005) Villanova, PA, USA: CLSI.

17 Shaw KJ, Rather PN, Hare RS, et al. Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol Rev (1993) 57:138–63.[Abstract/Free Full Text]

18 Miller GH, Sabatelli FJ, Naples L, et al. The most frequently occurring aminoglycoside mechanisms—combined results of surveys in eight regions of the world. J Chemother (1995) 7(Suppl_2):17–30.[Medline]

19 Miller GH, Sabatelli FJ, Hare RS, et al. Survey of aminoglycoside resistance patterns. Dev Ind Microbiol (1980) 21:91–104.

20 Heritier C, Poirel L, Lambert T, et al. Contribution of acquired carbapenem-hydrolyzing oxacillinases to carbapenem resistance in Acinetobacter baumannii. Antimicrob Agents Chemother (2005) 49:3198–202.[Abstract/Free Full Text]

21 Higgins PG, Wisplinghoff H, Stefanik D, et al. Selection of topoisomerase mutations and overexpression of adeB mRNA transcripts during an outbreak of Acinetobacter baumannii. J Antimicrob Chemother (2004) 54:821–3.[Abstract/Free Full Text]


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