JAC Advance Access originally published online on March 12, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):816-818; doi:10.1093/jac/dkm002
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Correspondence |
Tigecycline resistance in Australian antibiotic-resistant Gram-negative bacteria
Centre for Infectious Diseases and Microbiology, University of Sydney, Westmead Hospital, NSW 2145, Australia
* Corresponding author. Tel: +61-2-9845-6255; Fax: +61-2-9891-5317; E-mail: joni{at}icpmr.wsahs.nsw.gov.au
Keywords: glycylcycline , efflux , resistance , Acinetobacter baumannii
The new glycylcycline antibiotic, tigecycline, is reported to be highly active against all members of the Enterobacteriaceae and Acinetobacter spp., although MIC90s of 32 mg/L have been reported for Acinetobacter spp.1,2 We tested a selection of multiresistant Australian isolates (Table 1), including multiple isolates of Acinetobacter strains designated RB02 (n = 6) and PW01 (n = 2) to examine intra- and inter-strain variation. MICs were determined by Phoenix NMIC/ID-101 (Becton Dickinson, NJ, USA), by disc diffusion (15 µg tigecycline discs; BBL, Sparks, MD, USA) as previously described3 and by Etest (carbapenems, tigecycline; AB BIODISK, Solna, Sweden) on fresh Mueller–Hinton agar. A detailed characterization of these Acinetobacter strains has been previously reported,4 but important resistance phenotypes are included for reference. At least, three tigecycline disc diffusion assays were conducted on resistant isolates on separate occasions by separate observers (L. T., D. P. and E. M.). Unless there was no detectable disc zone, the mean zone sizes are given with 1 SD, and Etest-derived tigecycline MICs are presented without averaging (Table 1). In some strains, the edge of diffusion zones and/or resistant colonies growing inside the zone of clearing were subcultured aerobically on 5% horse blood agar (Columbia agar base) at 37°C without antibiotic selection for 24–48 h, and then retested as above.
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Overall, we found that the selected multidrug-resistant members of the Enterobacteriaceae were consistently susceptible to tigecycline (Table 1) and that diffusion disc and Etest zones were distinct and reproducible. However, some Serratia, Citrobacter and Enterobacter isolates were borderline susceptible or non-susceptible, and sampling from the edge of the tigecycline Etest zone of some of these strains yielded higher MICs even after antibiotic-free passage.
In contrast, several Acinetobacter baumannii isolates had very high MICs on first survey and several had heterogeneous Etest zones apparent after 16–20 h of incubation. Prolonged incubation resulted in increased numbers of colonies within the inhibition zone, consistent with a bacteriostatic effect, but occasional vigorous and apparently highly resistant colonies could be readily picked even at 16 h. Colonies growing inside the Etest zone remained highly resistant after further passage on blood agar or displayed similar heterogeneous Etest zones, and colony morphology and growth rates of resistant variants appeared identical with those of parent strains (not shown).
The recommended disc diffusion breakpoints are 
19 and 
15 mm (15 µg discs) for members of the Enterobacteriaceae corresponding to MICs of 2 and 8 mg/L, respectively, although a recent authoritative study has recommended that this should be set at 16 and 12 mm for Acinetobacter spp. to avoid over-reporting of resistance.3 Correlation with disc zone sizes interpreted by these criteria was excellent, results were highly reproducible and control strains yielded the expected results by both these methods. Prolonged incubation times may result in falsely elevated MICs for Acinetobacter spp., but resistant colonies were apparent even at 16 h in most strains that we tested.
None of the Australian carbapenem-resistant A. baumannii strains tested had an MIC low enough to suggest clinical utility for tigecycline. This is particularly disappointing because the isolates tested were those for which antibiotic choices are extremely limited and for which tigecycline would have been an attractive option. The propensity of A. baumannii to colonize the nosocomial environment and invasive medical devices, and be thereby exposed to antibiotic concentration gradients, raises concerns about whether tigecycline-resistant A. baumannii is likely to arise in vivo. This has been described in the Enterobacteriaceae5 and in A. baumannii,6 and our data further suggest that this will be the case. The phenomenon was consistent in multiple isolates of strains RB02 and PW01 (Table 1) and is unlikely to be unique to these isolates, as we have previously shown that strains WM96 and WM98 are closely related to the widespread A. baumannii EU clone II.4 Tigecycline is clearly a valuable addition to the formulary, but it should not be used against Gram-negative bacteria without prior susceptibility testing. Tigecycline resistance in A. baumannii appears to be stable and readily selected, pre-dates the use of the drug in this country and may be much more important than has been previously recognized. This may be especially true in strains exhibiting high-level resistance to multiple antibiotics, in which efflux systems may already be highly active.
None to declare.
Acknowledgements
For provision of strains, we are grateful to T. Gottlieb (Ec39381), J. Faoagali (RB-strains), J. Bell (ElN12282), J. Pham (Ko1156), C. Franklin and D. Spelman (Pa-206) and E. Mamizuka (KpBr1). Thanks to B. Espedido for review of the data and susceptibility testing of several strains. This study was supported by the Australian National Health and Medical Research Council (CCRE 264625) and NSW Health (CIDM Public Health).
References
1
Pachon-Ibanez ME, Jimenez-Mejias ME, Pichardo C, et al. (2004) Activity of tigecycline (GAR-936) against Acinetobacter baumannii strains, including those resistant to imipenem. Antimicrob Agents Chemother 48:4479–81.
2 Zhang YY, Zhou L, Zhu DM, et al. (2004) In vitro activities of tigecycline against clinical isolates from Shanghai, China. Diagn Microbiol Infect Dis 50:267–81.[CrossRef][Web of Science][Medline]
3
Jones RN, Ferraro MJ, Reller LB, et al. (2007) Multicenter studies of tigecycline disk diffusion susceptibility results for Acinetobacter spp. J Clin Microbiol 45:227–30.
4 Valenzuela J, Thomas L, Partridge S, et al. (2006) Horizontal gene transfer within a polyclonal outbreak of carbapenem-resistant Acinetobacter baumannii. J Clin Microbiol doi:10.1128/JCM.01971-06.
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Nord CE, Sillerstrom E, Wahlund E. (2006) Effect of tigecycline on normal oropharyngeal and intestinal microflora. Antimicrob Agents Chemother 50:3375–80.
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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.
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