The emergence of clinical resistance to tigecycline

International Journal of Antimicrobial Agents 41 (2013) 110–116

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Review

The emergence of clinical resistance to tigecycline Yan Sun 1 , Yun Cai 1 , Xu Liu, Nan Bai, Beibei Liang, Rui Wang ∗ Department of Clinical Pharmacology, PLA General Hospital, 28 Fu Xing Road, Beijing 100853, People’s Republic of China

a r t i c l e

i n f o

a b s t r a c t

Keywords: Tigecycline Multidrug resistance Mechanism

Tigecycline (TIG) exhibits broad-spectrum activity against many Gram-positive and Gram-negative pathogens. However, clinical resistance has emerged recently and has been detected following treatment with TIG. This observation suggests that long-term monotherapy may carry a high risk for TIG resistance. TIG resistance is observed most frequently in Acinetobacter baumannii and Enterobacteriaceae, especially in multidrug-resistant strains. Resistance–nodulation–cell division (RND)-type transporters and other efflux pumps may be factors for decreased sensitivity to TIG. Therefore, TIG should be cautiously used in the clinic, and efflux-mediated resistance should be closely monitored in order to prolong the lifespan of this useful antibiotic. © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction

meta-analysis found that TIG use correlated with increased clinical failure and a higher rate of septic shock development compared with other antibiotics [4]. Although the treatment failures could be attributed to many causes, resistance to TIG should be considered as possibly one of them. This review evaluates the available reports of worldwide TIG resistance and discusses the possible mechanisms of resistance in different types of bacteria.

Tigecycline (TIG), a derivative of minocycline that is modified to overcome tetracycline resistance, is the first of a novel class of glycylcyclines with expanded-spectrum properties. It is active in vitro against a broad range of Gram-positive and Gramnegative bacteria, anaerobes, ‘atypical’ bacteria as well as against many species of drug-resistant strains [e.g. vancomycin-resistant enterococci, meticillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and multidrugresistant (MDR) Acinetobacter baumannii]. Similar to tetracyclines, TIG inhibits protein translation by reversibly binding to the 30S subunit of the bacterial ribosome, which impedes amino acid synthesis. Although the ribosomal binding sites of TIG are similar to those of tetracycline, TIG binds five times more effectively than tetracyclines. This allows TIG to evade the common ribosomal protection mechanisms associated with resistance to tetracyclines [1]. Because of its long side chain that blocks binding to most efflux proteins and transporters, TIG also overcomes the efflux mechanisms of tetracycline resistance [2]. In particular, since New Delhi metallo␤-lactamase-1 (NDM-1) was found among Gram-negative bacteria, which were highly resistant to all antibiotics except TIG and colistin [3], TIG has received high attention and has been regarded as the last resort to treat pandrug-resistant bacteria. The US Food and Drug Administration (FDA) approved TIG in 2005 for the treatment of complicated intra-abdominal infections and complicated skin and skin-structure infections. However, reports of TIG resistance have increased year by year. In 2011, a

2. Clinical reports of tigecycline resistance Since 2007, reports of clinical resistance to TIG have increased over the years. Excluding one study reporting a TIG-resistant Grampositive Enterococcus faecalis strain selected from a 65-year-old patient following prolonged TIG therapy [5], all other studies have reported resistance to TIG in Gram-negative bacteria [6–16]. The most commonly reported was TIG resistance in A. baumannii, followed by Klebsiella pneumoniae and other Enterobacteriaceae strains (Table 1). There is also a report on TIG resistance of Bacteroides fragilis [17]. Resistance appears to occur typically after clinical treatment of patients who were initially responsive to TIG. Therefore, TIG monotherapy in patients may carry a high risk for resistance among Gram-negative pathogens. Combination therapy with TIG and other antimicrobial agents has been studied in vitro and in animal models [18–20]. Although some combinations showed good synergistic effect, more studies are needed to prove their potent efficacy in the clinic and their ability to forestall the emergence of resistance. 3. Worldwide reports of tigecycline resistance rates

∗ Corresponding author. Tel.: +86 10 6693 7909; fax: +86 10 8821 4425. E-mail address: [email protected] (R. Wang). 1 These two authors contributed equally to this work.

TIG is used as a last line of defence against MDR strains, and increasing rates of resistance are a growing concern clinically.

0924-8579/$ – see front matter © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. http://dx.doi.org/10.1016/j.ijantimicag.2012.09.005

Y. Sun et al. / International Journal of Antimicrobial Agents 41 (2013) 110–116

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Table 1 Worldwide case reports of tigecycline (TIG) resistance. Reference

Report type

Pathogen

MIC (mg/L)

Area

Description

Rodríguez-Avial et al., 2012 [6]

Case report

Klebsiella pneumoniae

8

Spain

Neonakis et al., 2011 [7]

Case report

K. pneumoniae

>8

Greece

Al-Qadheeb et al., 2010 [8]

Case report

K. pneumoniae

≥8

Saudi Arabia

Hornsey et al., 2011 [9]

Case report

Acinetobacter baumannii

16

UK

Chen et al., 2011 [10]

Case series

A. baumannii

≥8

Taiwan

Kopterides et al., 2010 [11]

Case report

A. baumannii

8

Greece

Gallagher and Rouse, 2008 [12]

Case series

A. baumannii

3–8

USA

Reid et al., 2007 [13]

Case report

A. baumannii

24

USA

Peleg et al., 2007 [14]

Case report

A. baumannii

4 and 16

USA

Anthony et al., 2008 [15]

Case series

A. baumannii

12

USA

Daurel et al., 2009 [16]

Case report

Enterobacter hormaechei

3/4a

France

Werner et al., 2008 [5]

Case report

Enterococcus faecalis

1/2a

Germany

Sherwood et al., 2011 [17]

Case report

Bacteroides fragilis

>16

USA

Renal transplant patient suffering from recurrent urosepsis; after TIG therapy the K. pneumoniae developed resistance to TIG A 62-year-old female was recurrently admitted due to cholangitis and TIG was extensively used. Klebsiella pneumoniae was isolated and showed resistance to all antimicrobials, including TIG A 75-year-old male after a prolonged stay in a critical care unit revealed a carbapenemase-producing K. pneumoniae evolving resistance to TIG A. baumannii isolated from a single patient was initially susceptible, but after TIG therapy became resistant A. baumannii from 66 patients who received TIG; TIG use was associated with decreased susceptibility A 70-year-old man who developed severe Clostridium difficile infection received TIG; during TIG treatment, development of colonisation with A. baumannii resistant to TIG 29 patients received TIG for treatment of A. baumannii infections. Most patients did not have clinically or microbiologically favourable outcomes. No isolate was fully susceptible to TIG A 53-year-old woman experienced a MDR A. baumannii urinary tract infection. The TIG MIC for the A. baumannii isolate increased from 1.5 ␮g/mL to 24 ␮g/mL Two patients with bloodstream infection caused by TIG-non-susceptible A. baumannii occurring in patients receiving TIG for other indications 18 patients received TIG as treatment for infection, and evolution of resistance was observed during therapy. One isolate of A. baumannii was observed to acquire full resistance to TIG during treatment Patient infected by a multiply antibiotic-resistant strain; TIG was used as the last resort. No improvement in clinical status, and a mutant with intermediate susceptibility was selected Stable TIG-resistant E. faecalis strain was selected from a 65-year-old patient after prolonged TIG therapy Apparent clinical failure in a 23-year-old man after long-term carbapenem therapy, and eventual change to TIG. TIG resistance was then confirmed

MIC, minimum inhibitory concentration; MDR, multidrug-resistant. a MIC determined by Etest and broth microdilution methods.

Resistance has been reported in many types of pathogens including Acinetobacter spp., Klebsiella spp., Enterobacter spp., E. faecalis, S. aureus, S. pneumoniae and Serratia marcescens. Furthermore, the prevalence of these resistances varies worldwide and is further discussed below (Table 2).

<15% in Germany and Spain [38,39], these studies were performed in 2006 and 2007, shortly after TIG was approved by the FDA. In North America, two studies from the USA [40] and Mexico [41] reported non-susceptible rates of 5% and 3%, respectively, which were much lower than those in Asia and Europe. In South America, non-susceptible rates of 20% were reported in Chile [42].

3.1. Acinetobacter baumannii 3.2. Enterobacteriaceae Acinetobacter baumannii is an emerging cause of nosocomial outbreaks worldwide and is considered one of the top six deadliest micro-organisms by the Infectious Diseases Society of America (IDSA). Of particular concern is the multidrug resistance of A. baumannii, which is defined as resistance to almost all available antibiotics. Colistin and TIG commonly remain the only active antibiotics. However, TIG resistance in A. baumannii is a rising concern. In Asia, most of the non-susceptible rates of A. baumannii to TIG were >10% [21–31]. Two reports from Thailand [32] and Lebanon [33] reported non-susceptible rates of <3%. A study from Israel reported the highest rate (78%) [27]. Three additional studies from India and three from Taiwan reported non-susceptible rates ranging from 12% to 58% [21,23,29] and from 18% to 45.5% [25,28,30], respectively. Two studies from South Korea reported rates of 23.4% and 9.7%, respectively [24,34]. A study of TIG activity against a worldwide collection of Acinetobacter spp. reported a lower rate of 3% [35]. In Europe, studies from Italy reported higher rates of 27.5% in 2008 and 50% in 2009 [36,37]. Although reported rates were

Enterobacteriaceae mainly include K. pneumoniae, Escherichia coli, Enterobacter spp. and S. marcescens. Carbapenem-resistant Enterobacteriaceae are an increasing problem that includes strains of multiple species. These pathogens possess metallo-␤-lactamases (MBLs) and non-metallo enzymes as well as extended-spectrum ␤lactamases (ESBLs) and AmpC enzymes that mediate resistance to a range of antibiotics. Most strains are broadly resistant to ␤-lactams and have multiple aminoglycoside-modifying enzymes. Those with NDM-1 carbapenemase typically also have 16S rRNA methylases, conferring complete aminoglycoside resistance [43]. TIG is an alternative antimicrobial to treat infections caused by Enterobacteriaceae. A study from Greece reported a non-susceptible rate to TIG of 7.9% in a total of 152 MDR Enterobacteriaceae isolates [44]. TIG was only active against 38/81 isolates (46.9%) of carbapenemresistant Enterobacteriaceae from a UK hospital [43]. A Taiwanese study observed that against MBL-producing Enterobacteriaceae TIG showed a non-susceptible rate of 37.9% [45]. A study from Pakistan reported that TIG retained an 89% susceptible rate against

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Table 2 Worldwide reports of tigecycline resistance rates in different pathogens. Pathogen

Area

Susceptibility breakpoints (mg/L)

Non-susceptible rate (%)

Taneja et al., 2011 [21] Al-Sweih et al., 2011 [31] Manoharan et al., 2010 [23] Mendes et al., 2010 [35] Kim et al., 2010 [24] Park et al., 2009 [34] Chang et al., 2012 [25] Ricciardi et al., 2009 [37] Dizbay et al., 2008 [26] Capone et al., 2008 [36] Navon-Venezia et al., 2007 [27] Tiengrim et al., 2006 [32] Seifert et al., 2006 [38] Lee et al., 2009 [28] Scheetz et al., 2007 [40] Behera et al., 2009 [29] Liu et al., 2008 [30] Insa et al., 2007 [39] García et al., 2009 [42] Araj and Ibrahim, 2008 [33]

Acinetobacter spp. Acinetobacter spp. Acinetobacter spp. Acinetobacter spp. Acinetobacter spp. (imipenem-non-susceptible) Acinetobacter spp. (colistin-resistant) Acinetobacter baumannii (MDR) A. baumannii (MDR) A. baumannii (MDR) A. baumannii (MDR) A. baumannii (MDR) A. baumannii (MDR) A. baumannii (MDR) A. baumannii (imipenem-non-susceptible) A. baumannii (carbapenem-non-susceptible) A. baumannii A. baumannii A. baumannii Klebsiella spp.; A. baumannii Klebsiella pneumoniae; Acinetobacter spp.

India Kuwait India Worldwide South Korea South Korea Taiwan Italy Turkey Italy Israel Thailand Germany Taiwan USA India Taiwan Spain Chile Lebanon

14.2 13.6 12 3 23.4 9.7 45.5 50 25.8 27.5 78 2.7 14.9 18 5 58 18–29 12 7; 20 19; 2

Naesens et al., 2009 [49]

Belgium France Spain USA Poland Canada Italy UK

≤2, FDA ≤2, FDA; ≤1, EUCAST ≤2, FDA ≤2, FDA 2010 CLSI ≤2, FDA; ≤1, EUCAST ≤1, EUCAST and BSAC

50 33.3; 44.4 9.2 7.5 0.1 1.6; 3.2 33; 40; 22; 51

Greece Pakistan Taiwan UK USA Spain USA Europe Canada The Netherlands Germany China Taiwan Taiwan

≤2, FDA ≤1, EUCAST ≤2, FDA ≤1, EUCAST ≤2, FDA ≤0.25, FDA, BSAC and EUCAST ≥16, FDAb ≥16, FDAb ≤4, FDA ≤0.5, FDA ≤0.5, EUCAST N/A ≤1, EUCAST a ≤2, FDA

7.9 11 37.9 53.1 0.6 20.8; 7.7 5.4 1.7 34.1 1.5 0.7 16.1 4 3; 1; 8; 16

Garza-González et al., 2010 [41]

Klebsiella spp. (ESBL-producing); Escherichia coli (ESBL-producing); Enterobacter spp. (MDR) K. pneumoniae (NDM-1-producing) K. pneumoniae (more than one ESBL-producing) K. pneumoniae Klebsiella spp. E. coli E. coli (ESBL-producing) Klebsiella spp. (carbapenem-susceptible); Klebsiella spp. (carbapenem-resistant); Enterobacter spp. (carbapenem-susceptible); Enterobacter spp. (carbapenem-resistant) Enterobacteriaceae (MDR) Enterobacteriaceae (NDM-1-producing) Enterobacteriaceae (MBL-producing) Enterobacteriaceae (carbapenem-resistant) Enterobacteriaceae (KPC- or CTX-M-producing) Enterococcus faecalis; Enterococcus faecium Bacteroides fragilis B. fragilis B. fragilis MRSA Staphylococcus epidermidis Stenotrophomonas maltophilia S. maltophilia K. pneumoniae (ESBL-producing); Enterobacter cloacae; Enterobacter aerogenes; Serratia marcescens Staphylococcus aureus; K. pneumoniae; E. coli; E. cloacae; A. baumannii

N/A ≤2, FDA ≤2, FDAa ≤2 ≤1, BSACa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDAa ≤2, FDA a N/A Inhibition zones (mm): K. pneumoniae, ≥19; Acinetobacter spp., ≥16 ≤1, EUCAST

Mexico

9; 3; 4; 7; 3

Darabi et al., 2010 [65]

Streptococcus pneumoniae

S. aureus, ≤0.5; Enterobacteriaceae, ≤2; A. baumannii, ≤1 ≤ 0.06, FDA

Berc¸ot et al., 2011 [54] Vázquez et al., 2008 [55] DiPersio and Dowzicky, 2007 [56] Sekowska and Gospodarek, 2010 [53] Lagacé-Wiens et al., 2011 [51] Grandesso et al., 2010 [52] Woodford et al., 2007 [48]

Falagas et al., 2010 [44] Perry et al., 2011 [46] Liao et al., 2011 [45] Livermore et al., 2011 [43] Castanheira et al., 2010 [47] Tubau et al., 2010 [64] Snydman et al., 2011 [57] Nagy et al., 2011 [59] Karlowsky et al., 2012 [58] Verkade et al., 2010 [62] Kresken et al., 2011 [63] Zhang et al., 2012 [60] Wu et al., 2012 [61] Hsu et al., 2011 [50]

North America; Europe; Asia-Pacific Rim; Latin America; South Africa; Middle East

100; 35; 96

9.6; 11.7; 8; 12.5; 4.4; 2.9

N/A, not available; FDA, US Food and Drug Administration; BSAC, British Society for Antimicrobial Chemotherapy; MDR, multidrug-resistant; ESBL, extended-spectrum ␤-lactamase; EUCAST, European Committee on Antimicrobial Susceptibility Testing; CLSI, Clinical and Laboratory Standards Institute; MBL, metallo-␤-lactamase; MRSA, meticillin-resistant Staphylococcus aureus. a Susceptibility breakpoints for Enterobacteriaceae were used. b Resistance breakpoints were provided.

Y. Sun et al. / International Journal of Antimicrobial Agents 41 (2013) 110–116

Reference

Y. Sun et al. / International Journal of Antimicrobial Agents 41 (2013) 110–116

64 NDM-1-positive isolates of Enterobacteriaceae in vitro [46]. A US study reported the lowest non-susceptible rate of 0.6% in KPC-producing or CTX-M-producing Enterobacteriaceae [47]. For Enterobacter spp., carbapenem-resistant isolates were often less sensitive to TIG than carbapenem-susceptible isolates (nonsusceptible rates 51% vs. 22%, respectively) [48]. In a Belgian study, 96% (26/27) of the MDR Enterobacter spp. were non-susceptible to TIG [49]. Non-susceptible rates for Enterobacter cloacae and Enterobacter aerogenes were reported to be <10% [41,50]. For E. coli, non-susceptible rates from Canada [51], Italy [52] and Mexico [41] were <5%. However, a study from Belgium reported a 35% nonsusceptible rate in ESBL-producing E. coli [49]. 3.3. Klebsiella pneumoniae TIG resistance in Klebsiella spp. is frequently reported in European countries, with non-susceptible rates ranging from 7.5% to 50% [48,53–55]. A Belgian study reported an alarmingly high rate of 100%, but only 10 strains of ESBL-producing Klebsiella spp. were included in that study [49]. Woodford et al. [48] observed that the non-susceptible rates in carbapenem-resistant isolates (35/89; 39.3%) were higher than those of carbapenem-susceptible strains (148/451; 33%). Reports from North America, South America and Asia demonstrated that the non-susceptible rates were <10% [41,42,50,56], except for one report from Lebanon that presented a rate of 19% [33]. 3.4. Bacteroides fragilis A number of studies have reported resistance to TIG in B. fragilis. A report from the USA showed relatively stable low resistance to TIG (5.4%) [57]. However, the non-susceptible rate was relatively high in Canada (34.1%) [58]. A European study involving 13 countries reported the lowest resistance rate (1.7%) to TIG in B. fragilis [59]. 3.5. Stenotrophomonas maltophilia Resistance to TIG in S. maltophilia has been all reported from China. One study of 442 clinical isolates of S. maltophilia collected from nine hospitals in four Chinese provinces reported a resistance rate of 16.1% [60], whilst another result from 77 non-duplicate S. maltophilia isolates collected from 38 hospitals in Taiwan reported a non-susceptible rate of only 4% [61]. 3.6. Gram-positive strains TIG resistance is also reported in Staphylococcus spp., E. faecalis and S. pneumoniae. Verkade et al. [62] reported that TIG showed good activity against MRSA strains in vitro among 202 MRSA strains, only 3 (1.5%) of which had a minimum inhibitory concentration (MIC) for TIG of >0.5 mg/L, which is considered to be non-susceptible. A study from Germany [63] also indicated that TIG demonstrated very good activity against S. aureus, with 100% activity both against meticillin-susceptible S. aureus and MRSA isolates. However, a report from Mexico presented a 9% TIG non-susceptible rate in S. aureus [41]. For E. faecalis and Enterococcus faecium, a study from Spain reported non-susceptible rates of 20.8% and 7.7% [64]. A worldwide study reported non-susceptible rates for S. pneumoniae in different regions (North America 9.6%, Europe 11.7%, Asia-Pacific Rim 8%, Latin America 12.5%, South Africa 4.4% and Middle East 2.9%) [65]. 4. Mechanisms of tigecycline resistance Generally, although the exact mechanisms of resistance could not be definitely determined, a common finding from the TIG

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resistance literature is overexpression of different efflux pumps both in naturally susceptible isolates as well as in the naturally resistant species (Table 3). TIG is not effective against certain organisms, particularly Pseudomonas spp., Proteus spp. and Burkholderia cepacia. A number of studies have shown that the reduced effectiveness of TIG over time is attributed to multidrug efflux pumps from the resistance–nodulation–cell division (RND) family, specifically the MexXY–OprM pump in Pseudomonas aeruginosa [66] and the AcrAB efflux pump in Proteus mirabilis [67]. Burkholderia cepacia complex also possesses efflux pumps that may confer resistance to TIG, and use of an inhibitor of these pumps could restore their sensitivity to TIG [68]. TIG resistance in Enterobacteriaceae has been attributed to RND-type efflux pumps. Hirata et al. [69] examined the activity of TIG against E. coli strains harbouring plasmids encoding various tetracycline-specific efflux transporter genes [tet(B), tet(C) and tet(K)] and multidrug transporter genes (acrAB and acrEF). The results suggested that TIG is not recognised by the Tet efflux transporter, whilst TIG is a possible substrate of AcrAB and its close homolog AcrEF. Another study analysing decreased susceptibility to TIG in clinical isolates of E. coli by transcriptional profile analysis, reverse transcription PCR (RT-PCR) and transposon mutagenesis indicated that overexpression of MarA, a transcriptional activator regulating expression of the AcrAB efflux pump, is a key factor that leads to overproduction of AcrAB and to decreased TIG susceptibility in E. coli [70]. For Salmonella enterica, one study implied that the combination of two low-level resistance mechanisms, i.e. Tn1721–tet(A) and inactivation of ramR, results in complete resistance to TIG. Mutations in ramR, which have only been described in Salmonella resistance to ciprofloxacin, are able to confer resistance to TIG by upregulating ramA [71]. Horiyama et al. also suggested that the AcrAB and AcrEF systems play a primary role in resistance to TIG [72]. In addition, overexpression of ramA and inactivation of ramR conferred increased (four-fold) resistance to TIG in an AcrAB-dependent manner [72]. Overexpression of RamA, a positive regulator of the AcrAB efflux system, has been observed in TIGresistant K. pneumoniae strains [73–75] as well as in TIG-resistant E. cloacae isolates [76,77]. Hentschke et al. further identified a gene in K. pneumoniae with homology to ramR, a repressor of ramA in S. enterica, which is mutated in strains resistant to TIG [78]. For A. baumannii, several studies demonstrated that overexpression of adeABC, an RND-type pump, resulted in reduced TIG susceptibility [79–81]. For S. marcescens, upregulation of endogenous SdeXY, one of the RND-type efflux transporters described in S. marcescens, is associated with TIG resistance [82]. A new resistance mechanism against TIG that involves flavindependent monooxygenase TetX has been described. The TetX protein modifies first- and second-generation tetracyclines and requires NADPH, Mg2+ and O2 for activity. TIG is a substrate for TetX, and bacterial strains containing the tetX gene are resistant to TIG [83]. A study from Hungary showed that tetX and tetX1 in Bacteroides strains exhibited elevated MICs for TIG, but a direct predictive value for TIG resistance could only be observed for the presence of the tetX1 gene [84]. TetX1 is an N-terminal truncate with 66% identity to the tetX gene. Moreover, X-ray crystallographic structures of the native TetX from Bacteroides thetaiotaomicron and its complexes with tetracyclines have been determined [85]. To date, this enzyme has only been found in Bacteroides, which is an obligate anaerobe. Although it is of no clinical relevance now because tetX only functions aerobically and tetX has not been isolated from any clinically resistant strains, these results provide an alert for the surveillance of resistant strains that may contain tetX. TIG resistance is seldom reported in Gram-positive strains and related studies of the resistance mechanisms are scarce. Isolation of mutants with reduced susceptibility was evaluated for two

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Table 3 Possible mechanism of tigecycline (TIG) resistance. Reference

Pathogen

Possible mechanism

Dean et al., 2003 [66] Visalli et al., 2003 [67]

Pseudomonas aeruginosa Proteus mirabilis

Rajendran et al., 2010 [68]

Burkholderia cepacia complex

Hirata et al., 2004 [69]

Escherichia coli

Keeney et al., 2008 [70]

E. coli

Hentschke et al., 2010 [71]

Salmonella enterica

Horiyama et al., 2011 [72]

S. enterica

Ruzin et al., 2005 [73]

Klebsiella pneumoniae

Bratu et al., 2009 [74]

K. pneumoniae

Rosenblum et al., 2011 [75] Keeney et al., 2007 [76]

K. pneumoniae Enterobacter cloacae

Hornsey et al., 2010 [77]

E. cloacae

Hentschke et al., 2010 [78] Peleg et al., 2007 [79]

K. pneumoniae Acinetobacter baumannii

Sun et al., 2010 [80] Ruzin et al., 2010 [81] Hornsey et al., 2010 [82] Moore et al., 2005 [83]

A. baumannii Acinetobacter calcoaceticus–A. baumannii complex Serratia marcescens Bacteroides fragilis

Bartha et al., 2011 [84]

B. fragilis

Volkers et al., 2011 [85]

Bacteroides thetaiotaomicron

McAleese et al., 2005 [86]

MRSA

MexXY–OprM efflux pump-mediated TIG resistance AcrAB transport system appears to be associated with the intrinsic reduced susceptibility to TIG Efflux pump proteins have evolved in resistance to TIG. These pumps can be inactivated using competitive inhibitors to restore the activity of TIG TIG is a possible substrate of AcrAB and AcrEF, which are RND-type multicomponent efflux transporters Loss of MarR functionality owing to a frameshift mutation resulted in constitutive overproduction of MarA and AcrAB and in decreased susceptibility Combination of the two low-level resistance mechanisms, Tn1721–tet(A) and inactivation of ramR, results in complete resistance to TIG AcrAB and AcrEF confer resistance to TIG in Salmonella. RamA and RamR are also involved in TIG resistance in an AcrAB-dependent manner RamA is associated with decreased TIG susceptibility owing to its role in expression of the AcrAB multidrug efflux pump Overexpression of regulatory genes (soxS and ramA) and the acrAB operon occurs when isolates develop high-level resistance to TIG ramA overexpression and subsequent acrA upregulation lead to reduced sensitivity to TIG Decreased susceptibility is the result of RamA-mediated overexpression of the AcrAB efflux pump Exposure to ciprofloxacin selected for AcrAB upregulation, which resulted in cross-resistance to TIG Deletions, insertions and point mutation in ramR might lead to reduced sensitivity to TIG TIG efflux mediated by the RND-type transporter AdeABC plays a role in reduced susceptibility Overexpression of the adeABC efflux pump resulted in TIG non-susceptibility Overexpression of AdeABC efflux pump is a prevalent mechanism for decreased susceptibility Upregulation of endogenous SdeXY–HasF-mediated efflux is associated with TIG resistance Modification of TIG by TetX to form 11a-hydroxytigecycline, which shows a weakened ability to inhibit protein translation compared with TIG Presence of tetX and tetX1 genes in some of the strains exhibiting elevated MICs for TIG, and this might be the possible reason for resistance The flavin-dependent monooxygenase TetX confers resistance to all clinically relevant tetracyclines, including TIG Overexpression of mepA but not tet(M) may contribute to decreased susceptibility

RND, resistance–nodulation–cell division; MIC, minimum inhibitory concentration; MRSA, meticillin-resistant Staphylococcus aureus.

MRSA strains by serial passage in increasing concentrations of TIG. Overexpression of mepA, a novel MATE family efflux pump, can contribute to decreased susceptibility of TIG in S. aureus [86]. 5. Conclusion Although TIG is a promising antibiotic for the treatment of infections caused by problematic pathogens as well as tetracycline-resistant bacteria, resistance mechanisms mediating the effectiveness of this antibiotic have been ascribed to RNDtype transporters and other efflux pumps. Analysis of clinical studies suggests that long-term TIG monotherapy may carry a higher risk for developing TIG resistance. TIG resistance is most frequently observed in A. baumannii and Enterobacteriaceae, especially in MDR strains. TIG should be carefully used in the clinic, and efflux-mediated resistance should be closely monitored in order to prolong the lifespan of this useful antibiotic resource. Funding: This study was supported by the National Natural Science Foundation of China (grant 81000755), the Beijing Natural Science Foundation of China (grant 7122167) and the Beijing Science and Technology New Star Program of China (grant 2010B079). Competing interests: None declared. Ethical approval: Not required. References [1] Bauer G, Berens C, Projan SJ, Hillen W. Comparison of tetracycline and tigecycline binding to ribosomes mapped by dimethylsulphate and drug-directed Fe2+ cleavage of 16S rRNA. J Antimicrob Chemother 2004;53:592–9.

[2] Someya Y, Yamaguchi A, Sawai T. A novel glycylcycline,9-(N,Nis neither dimethylglycylamido)-6-demethyl-6-deoxytetracycline, nor recognized by the transposon Tn10-encoded transported antiporter. Antimicrob Agents Chemother metal–tetracycline/H+ 1995;39:247–9. [3] Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 2010;10:597–602. [4] Yahav D, Lador A, Paul M, Leibovici L. Efficacy and safety of tigecycline: a systematic review and meta-analysis. J Antimicrob Chemother 2011;66: 1963–71. [5] Werner G, Gfrörer S, Fleige C, Witte W, Klare I. Tigecycline-resistant Enterococcus faecalis strain isolated from a German intensive care unit patient. J Antimicrob Chemother 2008;61:1182–3. [6] Rodríguez-Avial C, Rodríguez-Avial I, Merino P, Picazo JJ. Klebsiella pneumoniae: development of a mixed population of carbapenem and tigecycline resistance during antimicrobial therapy in a kidney transplant patient. Clin Microbiol Infect 2012;18:61–6. [7] Neonakis IK, Stylianou K, Daphnis E, Maraki S. First case of resistance to tigecycline by Klebsiella pneumoniae in a European university hospital. Indian J Med Microbiol 2011;29:78–9. [8] Al-Qadheeb NS, Althawadi S, Alkhalaf A, Hosaini S, Alrajhi AA. Evolution of tigecycline resistance in Klebsiella pneumoniae in a single patient. Ann Saudi Med 2010;30:404–7. [9] Hornsey M, Loman N, Wareham DW, Ellington MJ, Pallen MJ, Turton JF, et al. Whole-genome comparison of two Acinetobacter baumannii isolates from a single patient, where resistance developed during tigecycline therapy. J Antimicrob Chemother 2011;66:1499–503. [10] Chen LY, Chen TC, Chen YH, Lin CY, Lin WR, Lu PL. Microbial isolation and emergence of antimicrobial resistance associated with tigecycline usage. J Microbiol Immunol Infect 2011;44:352–7. [11] Kopterides P, Papageorgiou C, Antoniadou A, Papadomichelakis E, Tsangaris I, Dimopoulou I, et al. Failure of tigecycline to treat severe Clostridium difficile infection. Anaesth Intensive Care 2010;38:755–8. [12] Gallagher JC, Rouse HM. Tigecycline for the treatment of Acinetobacter infections: a case series. Ann Pharmacother 2008;42:1188–94.

Y. Sun et al. / International Journal of Antimicrobial Agents 41 (2013) 110–116 [13] Reid GE, Grim SA, Aldeza CA, Janda WM, Clark NM. Rapid development of Acinetobacter baumannii resistance to tigecycline. Pharmacotherapy 2007;27:1198–201. [14] Peleg AY, Potoski BA, Rea R, Adams J, Sethi J, Capitano B, et al. Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report. J Antimicrob Chemother 2007;59:128–31. [15] Anthony KB, Fishman NO, Linkin DR, Gasink LB, Edelstein PH, Lautenbach E. Clinical and microbiological outcomes of serious infections with multidrugresistant Gram-negative organisms treated with tigecycline. Clin Infect Dis 2008;46:567–70. [16] Daurel C, Fiant AL, Brémont S, Courvalin P, Leclercq R. Emergence of an Enterobacter hormaechei strain with reduced susceptibility to tigecycline under tigecycline therapy. Antimicrob Agents Chemother 2009;53: 4953–4. [17] Sherwood JE, Fraser S, Citron DM, Wexler H, Blakely G, Jobling K, et al. Multidrug resistant Bacteroides fragilis recovered from blood and severe leg wounds caused by an improvised explosive device (IED) in Afghanistan. Anaerobe 2011;17:152–5. [18] Aliskan H, Can F, Demirbilek M, Colakoglu S, Kilic S, Arslan H. Determining in vitro synergistic activities of tigecycline with several other antibiotics against Brucella melitensis using checkerboard and time–kill assays. J Chemother 2009;21:24–30. [19] Dizbay M, Tozlu DK, Cirak MY, Isik Y, Ozdemir K, Arman D. In vitro synergistic activity of tigecycline and colistin against XDR-Acinetobacter baumannii. J Antibiot (Tokyo) 2010;63:51–3. [20] Entenza JM, Moreillon P. Tigecycline in combination with other antimicrobials: a review of in vitro, animal and case report studies. Int J Antimicrob Agents 2009;34:8e1–9e. [21] Taneja N, Singh G, Singh M, Sharma M. Emergence of tigecycline & colistin resistant Acinetobacter baumanii in patients with complicated urinary tract infections in north India. Indian J Med Res 2011;133:681–4. [22] Al Sweih N, Salama MF, Jamal W, Al Hashem G, Rotimi VO. An outbreak of CTXM-15-producing Klebsiella pneumoniae isolates in an intensive care unit of a teaching hospital in Kuwait. Indian J Med Microbiol 2011;29:130–5. [23] Manoharan A, Chatterjee S, Madhan S, Madthai D. Evaluation of tigecycline activity in clinical isolates among Indian medical centers. Indian J Pathol Microbiol 2010;53:734–7. [24] Kim CK, Lee Y, Lee H, Woo GJ, Song W, Kim MN, et al. Prevalence and diversity of carbapenemases among imipenem-nonsusceptible Acinetobacter isolates in Korea: emergence of a novel OXA-182. Diagn Microbiol Infect Dis 2010;68:432–8. [25] Chang KC, Lin MF, Lin NT, Wu WJ, Kuo HY, Lin TY, et al. Clonal spread of multidrug-resistant Acinetobacter baumannii in eastern Taiwan. J Microbiol Immunol Infect 2012;45:37–42. [26] Dizbay M, Altuncekic A, Sezer BE, Ozdemir K, Arman D. Colistin and tigecycline susceptibility among multidrug-resistant Acinetobacter baumannii isolated from ventilator-associated pneumonia. Int J Antimicrob Agents 2008;32:29–32. [27] Navon-Venezia S, Leavitt A, Carmeli Y. High tigecycline resistance in multidrugresistant Acinetobacter baumannii. J Antimicrob Chemother 2007;59: 772–4. [28] Lee YT, Huang LY, Chiang DH, Chen CP, Chen TL, Wang FD, et al. Differences in phenotypic and genotypic characteristics among imipenem-non-susceptible Acinetobacter isolates belonging to different genomic species in Taiwan. Int J Antimicrob Agents 2009;34:580–4. [29] Behera B, Das A, Mathur P, Kapil A, Gadepalli R, Dhawan B. Tigecycline susceptibility report from an Indian tertiary care hospital. Indian J Med Res 2009;129:446–50. [30] Liu JW, Wang LS, Cheng YJ, Hsu GJ, Lu PL, Liu YC, et al. In vitro activity of tigecycline against clinical isolates of Acinetobacter baumannii in Taiwan. Int J Antimicrob Agents 2008;32(Suppl. 3):S188–91. [31] Al-Sweih NA, Al-Hubail MA, Rotimi VO. Emergence of tigecycline and colistin resistance in Acinetobacter species isolated from patients in Kuwait hospitals. J Chemother 2011;23:13–16. [32] Tiengrim S, Tribuddharat C, Thamlikitkul V. In vitro activity of tigecycline against clinical isolates of multidrug-resistant Acinetobacter baumannii in Siriraj Hospital, Thailand. J Med Assoc Thai 2006;89(Suppl. 5):S102–15. [33] Araj GF, Ibrahim GY. Tigecycline in vitro activity against commonly encountered multidrug-resistant Gram-negative pathogens in a Middle Eastern country. Diagn Microbiol Infect Dis 2008;62:411–5. [34] Park YK, Choi JY, Song JH, Ko KS. In vitro activity of tigecycline against colistin-resistant Acinetobacter spp. isolates from Korea. Int J Antimicrob Agents 2009;33:289–90. [35] Mendes RE, Farrell DJ, Sader HS, Jones RN. Comprehensive assessment of tigecycline activity tested against a worldwide collection of Acinetobacter spp, (2005–2009). Diagn Microbiol Infect Dis 2010;68:307–11. [36] Capone A, D’Arezzo S, Visca P, Petrosillo N. In vitro activity of tigecycline against multidrug-resistant Acinetobacter baumannii. J Antimicrob Chemother 2008;62:422–3. [37] Ricciardi R, Ricciardi AM, Danzi G. In vitro activity of tigecycline against multidrug-resistant Acinetobacter baumannii clinical isolates. Infez Med 2009;17:236–9. [38] Seifert H, Stefanik D, Wisplinghoff H. Comparative in vitro activities of tigecycline and 11 other antimicrobial agents against 215 epidemiologically defined multidrug-resistant Acinetobacter baumannii isolates. J Antimicrob Chemother 2006;58:1099–100.

115

[39] Insa R, Cercenado E, Goyanes MJ, Morente A, Bouza E. In vitro activity of tigecycline against clinical isolates of Acinetobacter baumannii and Stenotrophomonas maltophilia. J Antimicrob Chemother 2007;59:583–5. [40] Scheetz MH, Qi C, Warren JR, Postelnick MJ, Zembower T, Obias A, et al. In vitro activities of various antimicrobials alone and in combination with tigecycline against carbapenem-intermediate or -resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2007;51:1621–6. [41] Garza-González E, Llaca-Díaz JM, Bosques-Padilla FJ, González GM. Prevalence of multidrug-resistant bacteria at a tertiary-care teaching hospital in Mexico: special focus on Acinetobacter baumannii. Chemotherapy 2010;56: 275–9. [42] García CP, Juliet LC, Fernández VA, San Martín SM, Cifuentes DM, Porte TL, et al. Multicenter study on the monitoring of in vitro susceptibility to tigecycline in Santiago, Chile. Rev Chilena Infectol 2009;26:220–6 [in Spanish]. [43] Livermore DM, Warner M, Mushtaq S, Doumith M, Zhang J, Woodford N. What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline. Int J Antimicrob Agents 2011;37:415–19. [44] Falagas ME, Maraki S, Karageorgopoulos DE, Kastoris AC, Mavromanolakis E, Samonis G. Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin. Int J Antimicrob Agents 2010;35:240–3. [45] Liao IC, Chen HM, Wu JJ, Tsai PF, Wang LR, Yan JJ. Metallo-␤-lactamaseproducing Enterobacteriaceae isolates at a Taiwanese hospital: lack of distinctive phenotypes for screening. APMIS 2011;119:543–50. [46] Perry JD, Naqvi SH, Mirza IA, Alizai SA, Hussain A, Ghirardi S, et al. Prevalence of faecal carriage of Enterobacteriaceae with NDM-1 carbapenemase at military hospitals in Pakistan, and evaluation of two chromogenic media. J Antimicrob Chemother 2011;66:2288–94. [47] Castanheira M, Sader HS, Jones RN. Antimicrobial susceptibility patterns of KPC-producing or CTX-M-producing Enterobacteriaceae. Microb Drug Resist 2010;16:61–5. [48] Woodford N, Hill RL, Livermore DM. In vitro activity of tigecycline against carbapenem-susceptible and -resistant isolates of Klebsiella spp. and Enterobacter spp. J Antimicrob Chemother 2007;59:582–3. [49] Naesens R, Ursi JP, Van Schaeren J, Jeurissen A. In vitro activity of tigecycline against multidrug-resistant Enterobacteriaceae isolates from a Belgian hospital. Eur J Clin Microbiol Infect Dis 2009;28:381–4. [50] Hsu MS, Liao CH, Liu CY, Yang CJ, Huang YT, Hsueh PR. In vitro susceptibilities of clinical isolates of ertapenem-non-susceptible Enterobacteriaceae to nemonoxacin, tigecycline, fosfomycin and other antimicrobial agents. Int J Antimicrob Agents 2011;37:276–8. [51] Lagacé-Wiens PR, Simner PJ, Forward KR, Tailor F, Adam HJ, Decorby M, et al. Canadian Antimicrobial Resistance Alliance (CARA). Analysis of 3789 in- and outpatient Escherichia coli isolates from across Canada—results of the CANWARD 2007–2009 study. Diagn Microbiol Infect Dis 2011;69:314–19. [52] Grandesso S, Sapino B, Mazzucato S, Alessandrini R, Solinas M, Gion M. Study on in vitro susceptibility of ESBL-positive Escherichia coli isolated from urine specimens. Infez Med 2010;18:162–8 [in Italian]. [53] Sekowska A, Gospodarek E. Susceptibility of Klebsiella spp. to tigecycline and other selected antibiotics. Med Sci Monit 2010;16:BR193–6. [54] Berc¸ot B, Poirel L, Dortet L, Nordmann P. In vitro evaluation of antibiotic synergy for NDM-1-producing Enterobacteriaceae. J Antimicrob Chemother 2011;66:2295–7. [55] Vázquez MF, Romero ED, García MI, Rodríguez JA, Bellido JL. Comparative in vitro activity of tigecycline against enterobacteria producing two or more extended-spectrum ␤-lactamases. Int J Antimicrob Agents 2008;32:541–3. [56] DiPersio JR, Dowzicky MJ. Regional variations in multidrug resistance among Enterobacteriaceae in the USA and comparative activity of tigecycline, a new glycylcycline antimicrobial. Int J Antimicrob Agents 2007;29:518–27. [57] Snydman DR, Jacobus NV, McDermott LA, Golan Y, Goldstein EJ, Harrell L, et al. Update on resistance of Bacteroides fragilis group and related species with special attention to carbapenems 2006–2009. Anaerobe 2011;17:147–51. [58] Karlowsky JA, Walkty AJ, Adam HJ, Baxter MR, Hoban DJ, Zhanel GG. Prevalence of antimicrobial resistance among clinical isolates of Bacteroides fragilis group in Canada in 2010–2011: CANWARD surveillance study. Antimicrob Agents Chemother 2012;56:1247–52. [59] Nagy E, Urbán E, Nord CE; ESCMID Study Group on Antimicrobial Resistance in Anaerobic Bacteria. Antimicrobial susceptibility of Bacteroides fragilis group isolates in Europe: 20 years of experience. Clin Microbiol Infect 2011;17:371–9. [60] Zhang R, Sun Q, Hu YJ, Yu H, Li Y, Shen Q, et al. Detection of the Smqnr quinolone protection gene and its prevalence in clinical isolates of Stenotrophomonas maltophilia in China. J Med Microbiol 2012;61:535–9. [61] Wu H, Wang JT, Shiau YR, Wang HY, Lauderdale TL, Chang SC, et al. A multicenter surveillance of antimicrobial resistance on Stenotrophomonas maltophilia in Taiwan. J Microbiol Immunol Infect 2012;45:120–6. [62] Verkade EJ, Verhulst CJ, Huijsdens XW, Kluytmans JA. In vitro activity of tigecycline against methicillin-resistant Staphylococcus aureus, including livestock-associated strains. Eur J Clin Microbiol Infect Dis 2010;29:503–7. [63] Kresken M, Becker K, Seifert H, Leitner E, Körber-Irrgang B, von Eiff C, et al. Resistance trends and in vitro activity of tigecycline and 17 other antimicrobial agents against Gram-positive and Gram-negative organisms, including multidrug-resistant pathogens, in Germany. Eur J Clin Microbiol Infect Dis 2011;30:1095–103. ˜ J, Rodríguez MD, Cercenado E, Aldea MJ, González-Romo F, et al. [64] Tubau F, Linares Susceptibility to tigecycline of isolates from samples collected in hospitalized

116

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

Y. Sun et al. / International Journal of Antimicrobial Agents 41 (2013) 110–116 patients with secondary peritonitis undergoing surgery. Diagn Microbiol Infect Dis 2010;66:308–13. Darabi A, Hocquet D, Dowzicky MJ. Antimicrobial activity against Streptococcus pneumoniae and Haemophilus influenzae collected globally between 2004 and 2008 as part of the Tigecycline Evaluation and Surveillance Trial. Diagn Microbiol Infect Dis 2010;67:78–86. Dean CR, Visalli MA, Projan SJ, Sum PE, Bradford PA. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob Agents Chemother 2003;47:972–8. Visalli MA, Murphy E, Projan SJ, Bradford PA. AcrAB multidrug efflux pump is associated with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis. Antimicrob Agents Chemother 2003;47:665–9. Rajendran R, Quinn RF, Murray C, McCulloch E, Williams C, Ramage G. Efflux pumps may play a role in tigecycline resistance in Burkholderia species. Int J Antimicrob Agents 2010;36:151–4. Hirata T, Saito A, Nishino K, Tamura N, Yamaguchi A. Effects of efflux transporter genes on susceptibility of Escherichia coli to tigecycline (GAR-936). Antimicrob Agents Chemother 2004;48:2179–84. Keeney D, Ruzin A, McAleese F, Murphy E, Bradford PA. MarA-mediated overexpression of the AcrAB efflux pump results in decreased susceptibility to tigecycline in Escherichia coli. J Antimicrob Chemother 2008;61:46–53. Hentschke M, Christner M, Sobottka I, Aepfelbacher M, Rohde H. Combined ramR mutation and presence of a Tn1721-associated tet(A) variant in a clinical isolate of Salmonella enterica serovar Hadar resistant to tigecycline. Antimicrob Agents Chemother 2010;54:1319–22. Horiyama T, Nikaido E, Yamaguchi A, Nishino K. Roles of Salmonella multidrug efflux pumps in tigecycline resistance. J Antimicrob Chemother 2011;66:105–10. Ruzin A, Visalli MA, Keeney D, Bradford PA. Influence of transcriptional activator RamA on expression of multidrug efflux pump AcrAB and tigecycline susceptibility in Klebsiella pneumoniae. Antimicrob Agents Chemother 2005;49:1017–22. Bratu S, Landman D, George A, Salvani J, Quale J. Correlation of the expression of acrB and the regulatory genes marA, soxS and ramA with antimicrobial resistance in clinical isolates of Klebsiella pneumoniae endemic to New York City. J Antimicrob Chemother 2009;64:278–83. Rosenblum R, Khan E, Gonzalez G, Hasan R, Schneiders T. Genetic regulation of the ramA locus and its expression in clinical isolates of Klebsiella pneumoniae. Int J Antimicrob Agents 2011;38:39–45.

[76] Keeney D, Ruzin A, Bradford PA. RamA, a transcriptional regulator, and AcrAB, an RND-type efflux pump, are associated with decreased susceptibility to tigecycline in Enterobacter cloacae. Microb Drug Resist 2007;13: 1–6. [77] Hornsey M, Ellington MJ, Doumith M, Scott G, Livermore DM, Woodford N. Emergence of AcrAB-mediated tigecycline resistance in a clinical isolate of Enterobacter cloacae during ciprofloxacin treatment. Int J Antimicrob Agents 2010;35:478–81. [78] Hentschke M, Wolters M, Sobottka I, Rohde H, Aepfelbacher M. ramR mutations in clinical isolates of Klebsiella pneumoniae with reduced susceptibility to tigecycline. Antimicrob Agents Chemother 2010;54:2720–3. [79] Peleg AY, Adams J, Paterson DL. Tigecycline efflux as a mechanism for nonsusceptibility in Acinetobacter baumannii. Antimicrob Agents Chemother 2007;51:2065–9. [80] Sun JR, Chan MC, Chang TY, Wang WY, Chiueh TS. Overexpression of the adeB gene in clinical isolates of tigecycline-nonsusceptible Acinetobacter baumannii without insertion mutations in adeRS. Antimicrob Agents Chemother 2010;54:4934–8. [81] Ruzin A, Immermann FW, Bradford PA. RT-PCR and statistical analyses of adeABC expression in clinical isolates of Acinetobacter calcoaceticus–Acinetobacter baumannii complex. Microb Drug Resist 2010;16:87–9. [82] Hornsey M, Ellington MJ, Doumith M, Hudson S, Livermore DM, Woodford N. Tigecycline resistance in Serratia marcescens associated with up-regulation of the SdeXY–HasF efflux system also active against ciprofloxacin and cefpirome. J Antimicrob Chemother 2010;65:479–82. [83] Moore IF, Hughes DW, Wright GD. Tigecycline is modified by the flavin-dependent monooxygenase TetX. Biochemistry 2005;44: 11829–35. [84] Bartha NA, Sóki J, Urbán E, Nagy E. Investigation of the prevalence of tetQ, tetX and tetX1 genes in Bacteroides strains with elevated tigecycline minimum inhibitory concentrations. Int J Antimicrob Agents 2011;38: 522–5. [85] Volkers G, Palm GJ, Weiss MS, Wright GD, Hinrichs W. Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase. FEBS Lett 2011;585:1061–6. [86] McAleese F, Petersen P, Ruzin A, Dunman PM, Murphy E, Projan SJ, et al. A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline. Antimicrob Agents Chemother 2005;49:1865–71.