JAC Advance Access originally published online on January 17, 2007
Journal of Antimicrobial Chemotherapy 2007 59(3):582-583; doi:10.1093/jac/dkl514
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Correspondence |
In vitro activity of tigecycline against carbapenem-susceptible and -resistant isolates of Klebsiella spp. and Enterobacter spp.
Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, London NW9 5EQ, UK
* Corresponding author. Tel: +44-20-8327-7255; Fax: +44-20-8327-6264; E-mail: neil.woodford{at}hpa.org.uk
Keywords: glycylcyclines , ESBLs , Enterobacteriaceae , ertapenem
Carbapenems are often the last active antibiotics for serious infections caused by Gram-negative opportunist pathogens. Resistance is still extremely rare among Enterobacteriaceae, but is increasingly detected in isolates of Klebsiella and Enterobacter in the UK.1 In a few cases it is mediated by class A or B carbapenemases, but more often results from combinations of a ß-lactamase [often a CTX-M extended-spectrum ß-lactamase (ESBL) in Klebsiella or an AmpC enzyme in Enterobacter] acting together with impermeability and/or increased efflux.1 Among the three available carbapenems, ertapenem is most affected and, hence, is also the best indicator. The public health importance of this resistance type, which prompted the UK's first National Resistance Alert in December 2005 (http://www.hpa.org.uk/infections/topics_az/antimicrobial_resistance/alert.htm), reflects the limited options for treating serious infections caused by such multiresistant isolates: many of which are susceptible only to polymyxins among established antibiotics.
Tigecycline is a new glycylcycline with broad-spectrum activity, including against most Enterobacteriaceae except Proteeae. Previously, we noted a trend toward decreased susceptibility to tigecycline among ESBL-producing Klebsiella spp. and AmpC-producing Enterobacter spp. collected in a survey of cephalosporin-resistant isolates from south-east England, with a raised modal MIC for the Klebsiella spp. and with increased ‘trails’ of resistant isolates among both genera.2 Here we investigated whether this pattern was general for ESBL and AmpC-producing isolates of Klebsiella and Enterobacter submitted from across the UK; we also assessed whether the in vitro activity of tigecycline was further reduced against those isolates with the permeability and efflux changes that, acting in concert with an ESBL or AmpC enzyme, can confer carbapenem resistance.
Eight hundred and sixty-nine clinical isolates of Klebsiella spp. (n = 540) and Enterobacter spp. (n = 329) were included. These had been referred to the Antibiotic Resistance Monitoring and Reference Laboratory from UK clinical laboratories between June 2004 and July 2006 on the basis of resistance, mainly to cephalosporins. The isolates included 89 Klebsiella spp. and 65 Enterobacter spp. that were resistant to ertapenem (MIC >2 mg/L). Among ertapenem-resistant isolates, 7 Klebsiella spp. and 21 Enterobacter spp. were also resistant to imipenem; 19 Klebsiella spp. and 15 Enterobacter spp. also to meropenem. Even when not considered resistant, MICs of the latter carbapenems for these ertapenem-resistant isolates were above the modal values for the genera. Among referred carbapenem-susceptible isolates, 240 (91%) Enterobacter spp. and 380 (84%) Klebsiella spp. were resistant to cephalosporins, defined here as cefotaxime MIC >1 mg/L.
Tigecycline was supplied as powder of known potency by the manufacturer (Wyeth Pharmaceuticals, Taplow, UK). MICs were determined and interpreted in accordance with BSAC and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints; values 
1 mg/L indicate susceptibility for Enterobacteriaceae and those >2 mg/L indicate resistance (http://www.bsac.org.uk). Statistical comparisons were performed using Fisher's exact test (http://www.graphpad.com/quickcalcs/contingency2.cfm).
MIC distributions of tigecycline for referred carbapenem-susceptible and -resistant isolates are shown in Table 1, together with EUCAST data for susceptible wild-type populations (http://www.srga.org/eucastwt/WT_EUCAST.htm) and data from the BSAC Bacteraemia Surveillance for 2002–2004 (http://www.bsacsurv.org.uk). Among Klebsiella spp., the modal MIC was 0.5 mg/L for referred carbapenem-resistant isolates and for the BSAC and EUCAST datasets, but was raised to 1 mg/L for referred carbapenem-susceptible isolates; the reason for this requires further investigation. The modal MIC for all groups of Enterobacter spp. was 0.5 mg/L (Table 1).
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Among referred carbapenem-susceptible Enterobacter spp. isolates, 205 (78%) were susceptible to tigecycline, 35 (13%) were fully resistant, and 24 (9%) had intermediate susceptibility. No differential was seen between the tigecycline susceptibility of these carbapenem-susceptible isolates and isolates in the BSAC dataset (P = 0.37). However, referred carbapenem-resistant Enterobacter spp. isolates were less often susceptible to tigecycline (32/65, 49%; P < 0.0001); with 20 (31%) fully resistant, and 13 (20%) intermediate. In contrast, there was no significant difference in the proportions of tigecycline-susceptible Klebsiella spp. isolates among referred carbapenem-susceptible (303/451; 67%) and carbapenem-resistant isolates (54/89; 60%) (P = 0.27). However, tigecycline non-susceptibility (MICs
2 mg/L) was more frequent in both groups when compared with BSAC bacteraemia isolates (P < 0.0001). Among new agents, tigecycline is unique in having good activity against Gram-negative bacteria in general. However, these data support the observation that many cephalosporin-resistant (i.e. mostly ESBL-producing) Klebsiella spp. isolates require slightly raised tigecycline MICs,2,3 but refute the hypothesis that further rises occur in this genus contingent on the uptake and efflux changes associated with carbapenem resistance. In contrast, carbapenem-resistant Enterobacter spp. isolates were more likely to show reduced tigecycline susceptibility than carbapenem-susceptible isolates, even when the latter were resistant to cephalosporins. These differences between Enterobacter spp. and Klebsiella spp. remain to be explained. Non-carbapenemase-mediated carbapenem resistance in Klebsiella spp. is associated with porin loss along with ESBLs; the mechanisms in Enterobacter spp. are less clear although AmpC enzyme activity has a role.1 Porin loss may arise via mutations in porin genes or via changes at global regulatory loci, with the latter also able to affect efflux pumps. Acquired resistance to tigecycline in the Enterobacteriaceae can also involve efflux through up-regulation of intrinsic pumps4 or mutations in acquired pumps,5,6 and has also been associated with changes at a regulatory locus.7 There is therefore potential for such mechanisms to confer reduced susceptibility to both carbapenems and tigecycline. The mechanisms of reduced tigecycline susceptibility and resistance in cephalosporin-resistant Klebsiella spp. and in carbapenem-resistant Enterobacter spp. are now under investigation.
D. M. L. and N. W. have received grants and speaking invites from Merck, AstraZeneca and Wyeth; D. M. L. holds shares in AstraZeneca.
Acknowledgements
We thank Dr Russell Hope for his assistance with analysis of the BSAC bacteraemia data.
References
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2
Hope R, Warner M, Potz N, et al. (2006) Activity of tigecycline against ESBL-producing and AmpC-hyperproducing Enterobacteriaceae from South-East England. J Antimicrob Chemother 58:1312–4.
3 Hoban DJ, Bouchillon SK, Johnson BM, et al. (2005) In vitro activity of tigecycline against 6792 Gram-negative and Gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST Program, 2004). Diagn Microbiol Infect Dis 52:215–27.[CrossRef][Web of Science][Medline]
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Hirata T, Saito A, Nishino K, et al. (2004) Effects of efflux transporter genes on susceptibility of Escherichia coli to tigecycline (GAR-936). Antimicrob Agents Chemother 48:2179–84.
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Guay GG, Tuckman M, Rothstein DM. (1994) Mutations in the tetA(B) gene that cause a change in substrate specificity of the tetracycline efflux pump. Antimicrob Agents Chemother 38:857–60.
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7
Ruzin A, Visalli MA, Keeney D, et al. (2005) Influence of transcriptional activator RamA on expression of multidrug efflux pump AcrAB and tigecycline susceptibility in Klebsiella pneumoniae. Antimicrob Agents Chemother 49:1017–22.
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