JAC Advance Access originally published online on March 12, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):772-774; doi:10.1093/jac/dkm018
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High tigecycline resistance in multidrug-resistant Acinetobacter baumannii
1 The Laboratory for Molecular Epidemiology and Antibiotic Research, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2 Division of Epidemiology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
* Correspondence address. Department of Epidemiology, Tel Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv 64239, Israel. Tel: +972-3-692-5644; Fax: +972-3-697-4623; E-mail: shiri_nv{at}tasmc.health.gov.il
Received 5 December 2006; returned 20 December 2006; revised 10 January 2007; accepted 10 January 2007
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Abstract |
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Objectives: Multidrug-resistant (MDR) Acinetobacter baumannii is increasing in our hospital and worldwide, raising the necessity of finding effective therapies. We aimed to evaluate the in vitro activity of tigecycline against MDR A. baumannii clones isolated before tigecycline was used in our institution.
Methods: Eighty-two unique patient clinical isolates of multidrug-resistant A. baumannii collected in 2003 were studied. Species identification and antibiotic susceptibilities were determined by Vitek-2. Tigecycline MIC was determined by Etest. Clonal relatedness was determined by PFGE.
Results: MDR A. baumannii possessed 19 different pulsotypes. Sixty-six percent of the isolates were resistant to tigecycline, 12% were intermediate and 22% were susceptible. The MIC50 and MIC90 of tigecycline were 16 and 32 mg/L, respectively, with a wide MIC range of 1–128 mg/L. Variability in MIC of tigecycline was evident between and within the same pulsotype.
Conclusions: We report here high resistance rates to tigecycline, and higher than previously described MICs, in multiple clones of MDR A. baumannii. As tigecycline represents a new treatment choice for infections caused by A. baumannii, these findings are worrisome.
Keywords: antibiotic resistance , glycylcyclines , MDR multiple clones , Etest
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Introduction |
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The emergence of multidrug-resistant (MDR) Acinetobacter baumannii clones worldwide and the high morbidity and mortality associated with infections caused by these strains present a challenge to clinicians. Carbapenems have been an effective treatment for these infections but resistance to this class is emerging, leading to the evolution of pan-resistant strains1,2 and to the need for new therapeutic options. Tigecycline is a novel broad-spectrum glycylcycline. Vast in vitro studies, analysing cumulatively several thousand A. baumannii isolates, show excellent inhibitory activity with low MIC50 values of 0.5 to 2.0 mg/L and MIC90s of up to 2 mg/L, with percentage susceptibility ranging from 93% to 99%.3–6 This drug has been approved for treatment of complicated skin, skin structure and intra-abdominal infections,7 and according to a recent report this drug is the only compound in the pipeline for treatment of MDR A. baumannii infections.8
In our institution, MDR A. baumannii isolates cause polyclonal outbreaks.9 The aim of this study was to assess the in vitro activity of tigecycline against a collection of MDR A. baumannii isolates in our hospital, before tigecycline was used, to provide data to guide an appropriate antimicrobial therapy for this organism.
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Materials and methods |
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The in vitro activity of tigecycline was evaluated against 82 MDR A. baumannii clinical isolates. Isolates were collected consecutively in Tel Aviv Medical Center, a tertiary hospital, during a period of 6 months in 2003, and were isolated from wound (n = 36), respiratory tract (n = 32), blood (n = 7), urine (n = 6) and CSF (n = 1). Only one isolate per patient was included in the study. Identification of strains was performed using the Vitek 2 automatic system (bioMérieux, Marcy l'Étoile, France), with the AST-GN09 card for the identification of Gram-negative bacilli. Isolates identified as A. baumannii were further classified as belonging to genomic species 2 (A. baumannii) by sequence analysis of the 16S-23S rRNA gene intergenic spacer sequences. Isolates were all identified as having an MDR phenotype based on the definition that all of them exhibited resistance to three or more groups of antibiotics (including resistance to piperacillin/tazobactam, cefepime and ciprofloxacin). A disc diffusion test was used to verify susceptibilities to carbapenems and minocycline (Oxoid, Hampshire, UK), and to determine susceptibility to tigecycline (15 µg, Remel, kindly provided by Neopharm Ltd, Israel). An inhibition zone diameter of
19 mm was used as the breakpoint for minocycline and tigecycline. Tigecycline MIC testing was performed with the Etest using a standardized 0.5 McFarland standard inoculum on Mueller–Hinton agar plates (HyLabs, Rehovot, Israel), and the MIC values read at the point of 80% inhibition protocol according to the instructions for a bacteriostatic antimicrobial that appear in the package insert supplement provided by the manufacturer (AB Biodisk, Solna, Sweden). A. baumannii strain ATCC 19606 and Escherichia coli strain ATCC 25922 were used as quality control strains for the Etests. Interpretive criteria for tigecycline MICs were defined based on the United States Food and Drug Administration breakpoint criteria for tigecycline when testing Enterobacteriaceae (susceptibility at 
2 mg/L, intermediate at 4 mg/L and resistance at 8 mg/L). Etest MICs in half-log dilutions were rounded up and MIC50 and MIC90 were calculated using MIC values adjusted upwards. |
Results and discussion |
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All MDR A. baumannii isolates were resistant to aminoglycosides, cephalosporins and fluoroquinolones. Susceptibility to imipenem varied; 60 of the 82 isolates were susceptible (73.2%), 2 were intermediate (2.4%) and 20 (24.4%) were imipenem-resistant. PFGE classified the isolates into 19 different genetic clones based on the criteria of Tenover (Table 1).
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MIC testing of tigecycline using Etest showed higher MIC values for various clones than previously reported; 54 of 82 (66%) of the MDR A. baumannii isolates were resistant (MIC 8 mg/L or higher), 10 of 82 (12%) were intermediate (MIC 4–6 mg/L) and only 18 of 82 (22%) were susceptible to tigecycline. The MIC50 and MIC90 were 16 and 32 mg/L, respectively, with a wide range of 1.0–128 mg/L. Only five clones were uniformly susceptible to tigecycline (Table 1). All the Etest MIC values measured in the resistance range correlated 100% with inhibition zone diameters using the disc diffusion method with tigecycline discs.
Almost all the 22 imipenem-non-susceptible isolates were also resistant to tigecycline (95%). Among imipenem-susceptible isolates, a high proportion were tigecycline-resistant (60%), but this proportion was lower than among imipenem-non-susceptible isolates (P = 0.0038). These results suggest that tigecycline may be of limited clinical utility for the treatment of infections involving these pan-resistant strains.
Fifty-two of 82 (63%) of the isolates were susceptible to minocycline. Resistance to tigecycline was observed in minocycline-susceptible and -resistant isolates (Figure 1), although susceptibility was more common among minocycline-susceptible isolates (30.8% versus 6.7%, P = 0.011). The mechanism or mechanisms of resistance to tigecycline in A. baumannii should be elucidated; our data suggest either clustering of two mechanisms of resistance or, more likely, the occurrence of different but presumably additive resistance mechanisms. A recent description of a tigecycline-non-susceptible MDR A. baumannii isolate emerging during tigecycline therapy10 proves, at least partly, the involvement of an efflux pump mechanism as known from other Gram-negative bacteria where decreased susceptibility to tigecycline correlates with increased levels of AcrAB.
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The high MICs of tigecycline observed in our study differ substantially from previous reports in which Acinetobacter isolates were almost uniformly susceptible to tigecycline. Even studies that tested MDR Acinetobacter isolates with high imipenem resistance rates5,6 found significantly lower MIC90s of 2–8 mg/L; in our study with 24% resistance to imipenem the MIC90 was 32 mg/L.
It should be pointed out that our susceptibility testing was based on the Etest method where previous studies used mostly broth-based methods. A recent study compared broth and Etest MIC testing and showed that Acinetobacter spp. indeed displayed the greatest change in tigecycline susceptibility,11 but the MIC90 differed only by a factor of two and thus the methodology differences in MIC testing do not explain the high MIC90 we found.
Recently, non-susceptibility to tigecycline was reported in a single clone of MDR A. baumannii in the Chicago area.12 This report is the first in vitro description of a high resistance rate to tigecycline in multiple clones of MDR A. baumannii. Although this phenomenon may be unique to our geographical region, with the increasing incidence of Acinetobacter infections and increasing rates of multidrug resistance, this phenomenon is worrisome and should be further investigated.
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Transparency declarations |
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None to declare.
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Acknowledgements |
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The study was presented in part at the Interscience Conference on Antimicrobial Agents Chemotherapy, San Francisco, CA, USA, 2006.
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References |
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1 Quale J, Bratu S, Landman D, et al. (2003) Molecular epidemiology and mechanisms of carbapenem resistance in Acinetobacter baumannii endemic in New-York City. Clin Infect Dis 37:214–20.[CrossRef][Web of Science][Medline]
2 Van Looveren M and Goossens H. ARPAC Steering Group. (2004) Antimicrobial resistance of Acinetobacter spp. in Europe. Clin Microbiol Infect 10:684–704.[CrossRef][Web of Science][Medline]
3 Gales AC and Jones RN. (2000) Antimicrobial activity and spectrum of the new glycylcycline, GAR-936 tested against 1,203 recent clinical bacterial isolates. Diagn Microbiol Infect Dis 36:19–36.[CrossRef][Web of Science][Medline]
4 Bouchillon SK, Hoban DJ, Johnson BM, et al. (2005) In vitro activity of tigecycline against 3989 Gram-negative and Gram-positive clinical isolates from the United States. Tigecycline Evaluation and Surveillance Trial (TEST Program; 2004). Diagn Microbiol Infect Dis 52:173–9.[CrossRef][Web of Science][Medline]
5 Pachón-Ibáñez ME, Jiménez-Mejías ME, Pichardo C, et al. (2002) Activity of tigecycline (GAR-936) against Acinetobacter baumannii strains, including those resistant to imipenem. Antimicrob Agents Chemother 48:4479–81.
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Souli M, Kontopidou FV, Koratzanis E, et al. (2006) In vitro activity of tigecycline against multiple-drug-resistant, including pan-resistant, Gram-negative and Gram-positive clinical isolates from Greek hospitals. Antimicrob Agents Chemother 50:3166–69.
7 Bradford PA, Weaver-Sands DT, Petersen PJ. (2005) In vitro activity of tigecycline against isolates from patients enrolled in phase 3 clinical trials of treatment for complicated skin and skin structure infection and complicated intra-abdominal infections. Clin Infect Dis 41:Suppl 5, s315–32.
8 Talbot GH, Bradley J, Edwards JE Jr, et al. (2006) Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 42:657–68.[CrossRef][Web of Science][Medline]
9 Abbo A, Navon-Venezia S, Hammer-Muntz O, et al. (2005) Multidrug-resistant. Acinetobacter baumannii. Emerg Infect Dis 11:22–9.
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Peleg AY, Potoski BA, Rea R, et al. (2007) Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report. J Antimicrob Chemother 59:128–31.
11 Sahm DF, Dowzicky MJ, Draghi DC, et al. Surveillance of tigecycline activity; discordance between national profiles associated with testing protocols and methods. Abstracts of the Forty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy2006San Francisco, CA(American Society for Microbiology, Washington, DC, USA) Abstract D-701.
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Lolans K, Rice TW, Munoz-Price S, et al. (2006) Multicity outbreak of carbapenem-resistant Acinetobacter baumannii isolates producing the carbapenemase OXA-40. Antimicrob Agents Chemother 50:2941–45.
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