JAC Advance Access originally published online on April 19, 2008
Journal of Antimicrobial Chemotherapy 2008 62(2):422-423; doi:10.1093/jac/dkn172
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Research letters |
In vitro activity of tigecycline against multidrug-resistant Acinetobacter baumannii
1 National Institute for Infectious Diseases ‘Lazzaro Spallanzani’, Via Portuense 292, 00149 Rome, Italy 2 Department of Biology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy
* Correspondence address. Molecular Microbiology Unit, National Institute for Infectious Diseases ‘Lazzaro Spallanzani’, Via Portuense 292, 00149 Rome, Italy. Tel: +39-0655176347; Fax: +39-0655176321; E-mail: visca{at}uniroma3.it
Keywords: antibiotics , GAR-936 , glycylcyclines , tetracyclines
Acinetobacter baumannii has emerged as a leading nosocomial pathogen, particularly in intensive care units (ICUs), where several outbreaks have been described.1
Treatment of severe A. baumannii infection represents a difficult clinical challenge due to the propensity of this organism to acquire antimicrobial resistance, resulting in the emergence of multi- and pan-resistant clones.1 There are few therapeutic options to combat multidrug-resistant (MDR) A. baumannii.1
Tigecycline, a new semi-synthetic tetracycline, has provided hope for the treatment of bacterial infections.2 Literature data on the in vitro activity of tigecycline against MDR A. baumannii shows variable susceptibility,3–7 likely resulting from different susceptibility testing methods and high clonal correlation among epidemic strains. Indeed, early studies have reported excellent in vitro activity of tigecycline against isolates of the A. baumannii complex (MIC90 2 mg/L).3 However, A. baumannii isolates showing reduced susceptibility to tigecycline (MIC90 32 mg/L) have recently been identified,4 posing the risk for selection and spreading of resistance in this notoriously adaptable species. Therefore, we investigated the in vitro activity of tigecycline against a collection of 80 presumed MDR A. baumannii isolates and compared the activity between tigecycline and 17 other antimicrobials, including three tetracyclines.
A. baumannii primary isolates were obtained between January 2004 and June 2005 from ICU patients cared for in six general hospitals of the Rome (Italy) urban area. None of the patients had undergone previous treatment with tigecycline. Bacteria were identified by the Vitek II system (bioMérieux, Marcy l’Étoile, France) and Amplified Ribosomal DNA Restriction Analysis.1 Although all isolates had been provided as MDR by collaborating centres, antimicrobial susceptibility testing was re-assessed using ampicillin/sulbactam, piperacillin, piperacillin/tazobactam, cefepime, ceftazidime, aztreonam, imipenem, meropenem, amikacin, gentamicin, ciprofloxacin, levofloxacin, trimethoprim/sulfamethoxazole, colistin, tetracycline, doxycycline, minocycline and tigecycline. For all drugs, except colistin, doxycycline, minocycline and tigecycline, susceptibility tests were performed by the Vitek II ID-GNB and AST-GN09 cards. Doxycycline and minocycline susceptibility was determined by the disc diffusion method. Tigecycline and colistin susceptibility was determined by the broth microdilution method, according to the CLSI guidelines. The US FDA breakpoints approved for Enterobacteriaceae were applied to define tigecycline susceptibility (
2 mg/L susceptibility; 
8 mg/L resistance). Colistin susceptibility was interpreted according to Gales et al.8 The MDR phenotype was defined as diminished susceptibility to more than one of the following five drug classes: antipseudomonal cephalosporins, antipseudomonal carbapenems, β-lactam/β-lactamase inhibitor combinations, antipseudomonal fluoroquinolones and aminoglycosides.9
The in vitro activity of individual antimicrobial agents against A. baumannii clinical isolates is summarized in Table 1. Seventy-eight isolates were definitively defined as MDR. The most common phenotype (90% of the isolates) was resistant to piperacillin, piperacillin/tazobactam, cefepime, ceftazidime, aztreonam, ciprofloxacin and levofloxacin. Individual resistance to imipenem, amikacin, trimethoprim/sulfamethoxazole and tetracycline was observed in 70% to 86.2% of the isolates. Approximately 50% of the A. baumannii isolates were resistant to gentamicin and 22.5% to ampicillin/sulbactam. A high level of carbapenem resistance was observed, with 77.5% and 81.3% of isolates resistant to imipenem and meropenem, respectively.
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Concerning tigecycline, 27.5% of the isolates were non-susceptible, including 23.7% intermediate and 3.7% fully resistant isolates. The MIC50 and MIC90 values were 2 and 4 mg/L, respectively, with a unimodal distribution of tigecycline MICs in the 0.125–8 mg/L range. These findings are in the middle-upper range of previously reported tigecycline resistance data.3–7 Notably, the only isolate resistant to colistin was susceptible to tigecycline.
Recent data on the activity of tetracyclines against A. baumannii are conflicting. In large surveys from the UK, the USA, Germany and Italy, the frequency of A. baumannii isolates resistant to tigecycline, minocycline and doxycycline varied in the ranges 4% to 6%, 0% to 18% and 6% to 44%, respectively, in association with high overall rates of resistance to tetracycline.3,5–7 Conversely, a study conducted in Israel showed that 66% and 37% of the MDR A. baumannii isolates were resistant to tigecycline and minocycline, respectively.4 Here, we report that 3 (3.8%), 13 (16.3%) and 69 (86.3%) out of the 80 presumed MDR A. baumannii isolates were resistant to minocycline, doxycycline and tetracycline, respectively. Taking into account non-susceptible isolates (intermediate and fully resistant), the relative activities of tetracyclines were minocycline > tigecycline 
doxycycline > tetracycline, with an overall decreased susceptibility to tigecycline among A. baumannii isolates resistant to other tetracyclines. In fact, all isolates susceptible to minocycline, doxycycline and tetracycline were highly susceptible to tigecycline (MIC range 0.125–1 mg/L), whereas only 6 of 16 (37.5%) isolates non-susceptible to the three tetracyclines were susceptible to tigecycline (MIC range 0.125–2 mg/L). It should be pointed out, however, that the in vitro superiority of minocycline among tetracyclines has limited clinical implications due to the unavailability of intravenous minocycline formulations.
In conclusion, tigecycline resistance among MDR A. baumannii isolates that had not previously been exposed to the drug is worrying, given the paucity of antibiotic options available to clinicians to combat these bacteria. When treating patients with severe infections caused by MDR A. baumannii, in vitro susceptibility to tigecycline should be assessed preventively.
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Funding |
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 Top Funding Transparency declarationsReferences |
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Wyeth-Ayerst (Collegeville, PA, USA) kindly provided laboratory-grade tigecycline. This research was supported by the INMI ‘L. Spallanzani’—Ricerca Corrente 2006 grant to P. V.
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Transparency declarations |
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TopFundingTransparency declarationsReferences |
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None to declare.
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Footnotes |
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All authors equally contributed to this work. 
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Acknowledgements |
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We thank Gruppo Romano Acinetobacter baumannii (M. Ballardini, S. Bartolini, E. Bordi, M. Galiè, R. Minniti, M. Meledandri, L. Pacciani, G. Parisi, G. Prignano, C. Santini, M. Valmarin and S. Ziantoni) for providing A. baumannii isolates.
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References |
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TopFundingTransparency declarationsReferences |
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1 Dijkshoorn L, Nemec A, Seifert H. An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii. Nat Rev Microbiol (2007) 5:939–51.[CrossRef][Web of Science][Medline]
2
Livermore DM. Tigecycline: what is it, and where should it be used? J Antimicrob Chemother (2005) 56:611–4.
3
Henwood CJ, Gatward T, Warner M, et al. Antibiotic resistance among clinical isolates of Acinetobacter in the UK, and in vitro evaluation of tigecycline (GAR-936). J Antimicrob Chemother (2002) 49:479–87.
4
Navon-Venezia S, Leavitt A, Carmeli Y. High tigecycline resistance in multidrug-resistant Acinetobacter baumannii. J Antimicrob Chemother (2007) 59:772–4.
5
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.
6
Scheetz MH, Qi C, Warren JR, 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.
7 Mezzatesta ML, Trovato G, Gona F, et al. In vitro activity of tigecycline and comparators against carbapenem-susceptible and resistant Acinetobacter baumannii clinical isolates in Italy. Ann Clin Microbiol Antimicrob (2008) 7:4.[CrossRef][Medline]
8
Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol (2001) 39:183–90.
9 Paterson DL. The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis (2006) 43(Suppl_2):s43–8.[CrossRef][Web of Science][Medline]
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