JAC Advance Access originally published online on October 25, 2007
Journal of Antimicrobial Chemotherapy 2007 60(6):1406-1407; doi:10.1093/jac/dkm391
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Correspondence |
In vitro activity of tigecycline against metallo-ß-lactamase-producing Enterobacteriaceae
Department of Microbiology, Hippokration G. Hospital, Thessaloniki, Greece
* Corresponding author. Tel: +30-2310934087; Fax: +30-2310892050; E-mail: vasoulapl{at}yahoo.gr
Keywords: glycylcyclines , carbapenemases , susceptibility
Tigecycline is a new semi-synthetic derivative of minocycline and the first in the glycylcycline class of antibiotics. Its mechanism of action involves inhibition of bacterial protein synthesis by binding to the 30S ribosomal subunit and blocking the entry of tRNA into the A site of the ribosome, thereby preventing the elongation of peptide chains. Pre-clinical studies have demonstrated the potent in vitro activity of tigecycline against a wide range of aerobic Gram-positive and Gram-negative bacteria, including multidrug-resistant strains, anaerobic and atypical pathogens.1,2 Tigecycline circumvents the two most frequent mechanisms of tetracycline resistance, which are the active efflux of drug from the bacterial cell and ribosomal protection. In addition, it is not affected by ß-lactamase production [extended-spectrum ß-lactamase (ESBL) production and AmpC hyperproduction] or DNA gyrase alterations, defence mechanisms that are used by many microorganisms.1,2
Even though many studies have demonstrated the activity of tigecycline against ESBL-producing Enterobacteriaceae, its activity is not well defined against microorganisms producing metallo-ß-lactamases (MBLs) as there are only a few reports and the number of isolates tested is limited.3 The aim of the present study was to evaluate the activity of tigecycline against 109 MBL-producing Enterobacteriaceae.
A total of 109 non-duplicate MBL-producing isolates of the family Enterobacteriaceae collected from hospitalized patients from January 2004 to June 2007 were studied. The identification of microorganisms and susceptibility testing were performed using the Vitek 2 automated system (bioMérieux, France). The isolates included 4 Escherichia coli, 13 Enterobacter spp. (11 Enterobacter cloacae and 2 Enterobacter aerogenes), 4 Serratia marcescens and 88 Klebsiella pneumoniae. The isolates were recovered from the following sources: blood (34%), wounds (28%), urine (21%), central venous catheters (9%), sputum (7%) and cerebrospinal fluid (1%). All isolates were characterized as resistant or intermediate to imipenem and meropenem and gave positive results for the double-disc synergy test between imipenem and EDTA.4 The production of VIM-type MBL was confirmed by PCR using specific primers. PFGE of XbaI-digested genomic DNA indicated that most of the isolates were unrelated (data not shown). MICs of tigecycline were determined using the Etest, according to manufacturer's guidelines. All isolates with tigecycline MICs of 
1 mg/L were tested by the broth microdilution method using panels purchased from Microscan (Dade Behring, Sacramento, LA, USA). E. coli ATCC 25922 was used as quality control. MIC50 and MIC90 values were calculated for Enterobacter spp. and K. pneumoniae strains.
Our results are demonstrated in Table 1. E. coli, S. marcescens and Enterobacter spp. isolates were inhibited at MIC values of 
1, 2 and 2 mg/L, respectively. For K. pneumoniae, MIC50 and MIC90 values of tigecycline were 0.25 and 2 mg/L, respectively. The Etest results were confirmed by the broth microdilution method. According to US Food and Drug Administration recommendation for tigecycline (susceptible 2 mg/L and resistant 8 mg/L), all isolates were susceptible and only one (1%) K. pneumoniae strain displayed an intermediate MIC of 4 mg/L. When the European Committee on Antimicrobial Susceptibility Testing breakpoint criteria (susceptible 1 mg/L and resistant >2 mg/L) were used, the percentage of tigecycline susceptibility decreased. Only 4 (31%) Enterobacter spp. and 78 (89%) K. pneumoniae isolates tested were susceptible. Furthermore, all S. marcescens were characterized as intermediate.1,2 The isolates collected in this study were broadly resistant to ß-lactams, fluoroquinolones and variably to aminoglycosides.
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Currently, multidrug-resistant Gram-negative bacteria remain the most problematic pathogens worldwide, especially in intensive care units. Carbapenem antibiotics were important agents for the management of those infections. Over the past few years, the progressive increase in carbapenem-resistant Gram-negative non-fermentative bacilli as well as the spread of genes encoding carbapenem-hydrolysing enzymes in enterobacterial species is of great concern, leaving limited choices for therapeutic regimens.5
Tigecycline was active against MBL-producing members of the family Enterobacteriaceae, inhibiting 99% of them at a concentration of 2 mg/L. A recent study demonstrated that tigecycline was effective against multiresistant K. pneumoniae strains producing Klebsiella pneumoniae carbapenemase (KPC), an ESBL belonging to molecular class A enzymes with activity against carbapenems.6 In addition, it was active against clinical isolates possessing blaVIM, but the number of MBL producers tested was small.3 Our results confirm the in vitro activity of tigecycline against Enterobacteriaceae possessing carbapenemases. Its broad-spectrum activity combined with its stability against common resistance mechanisms and the lack of cross-resistance with other classes of antibiotics1,2 make tigecycline a therapeutic agent for the treatment of infection caused by multiresistant microorganisms. However, the in vitro results require support from clinical studies.
None to declare.
Acknowledgements
We thank Wyeth Pharmaceuticals Inc. for providing us with the Etests and microdilution panels.
References
1 Townsend ML, Pound MW, Drew RH. Tigecycline: a new glycylcycline antimicrobial. Int J Clin Pract (2006) 60:1662–72.[CrossRef][Web of Science][Medline]
2
Morosini MI, García-Castillo M, Coque TM, et al. Antibiotic coresistance in extended-spectrum-ß-lactamase-producing Enterobacteriaceae and in vitro activity of tigecycline. Antimicrob Agents Chemother (2006) 50:2695–9.
3
Souli M, Kontopidou FV, Koratzanis E, et al. 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 (2006) 50:3166–9.
4
Arakawa Y, Shibata N, Shibayama K, et al. Convenient test for screening metallo-ß-lactamase-producing Gram-negative bacteria by using thiol compounds. J Clin Microbiol (2000) 38:40–3.
5
Walsh TR, Toleman MA, Poirel L, et al. Metallo-ß-lactamases: the quiet before the storm? Clin Microbiol Rev (2005) 18:306–25.
6
Bratu S, Tolaney P, Karumudi U, et al. Carbapenemase-producing Klebsliella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents. J Antimicrob Chemother (2005) 56:128–32.
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