JAC Advance Access originally published online on March 12, 2007
Journal of Antimicrobial Chemotherapy 2007 59(5):1025-1030; doi:10.1093/jac/dkm063
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Activity of faropenem against cephalosporin-resistant Enterobacteriaceae
Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, London NW9 5EQ, UK
* Corresponding author. Tel +44-208-327-7227; Fax: +44-208-327-6264; E-mail: david.livermore{at}hpa.org.uk
Received 6 December 2006; returned 29 January 2007; revised 8 February 2007; accepted 8 February 2007
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Abstract |
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Background: There is a need for new oral agents active against extended-spectrum ß-lactamase (ESBL) producers, as these increasingly cause community-onset infections. We therefore evaluated faropenem, a penem in Phase III development, against recently collected oxyimino-cephalosporin-resistant bacteria.
Methods: We tested 847 consecutive cephalosporin-resistant Enterobacteriaceae collected at 16 centres in South-East England in 2004, 501 of them with CTX-M enzymes; we also tested reference strains and transconjugants with acquired ß-lactamases and various modes of AmpC expression. MICs were determined by the BSAC agar dilution method.
Results: Modal MICs of faropenem for Escherichia coli or Klebsiella spp. with CTX-M or non-CTX-M ESBLs or high-level AmpC enzyme were 0.5–1 mg/L, with over 95% of producers susceptible to 
2 mg/L. Modal MICs for Enterobacter and Citrobacter spp. with ESBLs or derepressed AmpC were 2–4 mg/L, although around 5% of AmpC-derepressed Enterobacter spp. required faropenem MICs of 16 mg/L. MICs of 8–16 mg/L were seen also for most AmpC-derepressed Serratia spp. isolates. Derepression of AmpC in isogenic mutant series typically raised faropenem MICs by one doubling dilution; among the ß-lactamases introduced into E. coli, only NMC-A (Class A) and IMP (Class B) carbapenemases caused substantive rises in faropenem MICs.
Conclusions: Faropenem has good activity against E. coli and Klebsiella spp. with ESBLs, including the CTX-M types now proliferating in Europe, but was less active against AmpC-derepressed and ESBL-producing Enterobacter spp. Its clinical utility will depend on levels achieved in the urinary tract, the site of most of the community infections caused by ESBL producers, and more work is needed in this area.
Keywords: penems , ESBLs , AmpC ß-lactamases
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Introduction |
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Resistance to oxyimino-cephalosporins among Enterobacteriaceae is changing in nature and increasing in prevalence.1 More importantly, CTX-M extended-spectrum ß-lactamases (ESBLs) have become widespread in Europe since around year 2000. CTX-M-15 is predominant in most countries, but CTX-M-9 and M-14 are more common in Spain.1 Whereas the longer-established TEM and SHV ESBLs occur mostly in nosocomial isolates, often Klebsiella spp., CTX-M enzymes are often found in Escherichia coli from urinary infections in ‘community’ patients, typically those who are elderly, with underlying disease and recent hospitalization or antibiotics.1
Community-onset infections with ESBL producers present therapeutic challenges, especially if the patient's condition would not ordinarily warrant hospitalization. Most CTX-M-positive E. coli isolates are multiresistant to trimethoprim, fluoroquinolones and amoxicillin/clavulanate, as well as to oral cephalosporins and penicillins.1 Nitrofurantoin and fosfomycin generally remain active and can be given orally, but nitrofurantoin requires lengthy courses and is unpalatable, whereas fosfomycin is not universally available – neither drug is suitable for ascending infections. There is a consequent need for new oral options, both for community-onset infections and as follow-on treatment of infections initially managed with intravenous (iv) carbapenems. Oral penems and carbapenems potentially meet this need, and we evaluated the in vitro activity of faropenem, an oral penem, versus recently collected Enterobacteriaceae with ESBLs and other potent cephalosporinases, also against reference strains and transconjugants varying in ß-lactamase type or expression.
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Materials and methods |
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Cephalosporin-resistant Enterobacteriaceae isolates were collected in a 16 hospital survey, undertaken in South-East England in autumn 2004.2 The mechanisms present in these isolates (see Results) were deduced by interpretive reading, cephalosporin/inhibitor synergy tests, group-specific PCR for CTX-M enzymes and plasmid-mediated AmpC types2 and reverse-line hybridization.3 In addition, we tested E. coli transconjugants with various ß-lactamases, including ESBLs; also isogenic mutant series of Enterobacter cloacae, Citrobacter freundii, Serratia spp. and Morganella morganii varying in expression of AmpC ß-lactamases, and Proteus vulgaris mutants varying in expression of their chromosomal Class A ß-lactamase. The derivation of these organisms was described previously.4
MICs of faropenem (Replidyne, Louisville, CO, USA), imipenem (Merck, Hoddesdon, Herts, UK), cefpodoxime and cefixime (both from Sanofi-Aventis, Frankfurt Am Main, Germany) ceftazidime and amoxicillin/clavulanate (2:1) (GlaxoSmithKline, Stevenage, Herts, UK) were determined by the British Society for Antimicrobial Chemotherapy agar dilution method.5
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Results and discussion |
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MIC distributions for the survey collection, by species and resistance mechanism, are shown in Table 1. More than 77% (500/646) of the ESBL producers had CTX-M enzymes; over 97% (487/500) of these were Group 1 types, as shown by PCR, and over 90% of Group 1 types were CTX-M-15, as tested by the reverse line blot method. There was no evidence that the behaviour of faropenem varied in relation to ESBL type.
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Modal MICs of faropenem for E. coli isolates with CTX-M ESBLs, non-CTX-M ESBLs and hyperproduced AmpC enzymes were all 1 mg/L, with only
5% of the ESBL producers requiring MICs >2 mg/L and none requiring MICs >8 mg/L. Modal faropenem MICs for Klebsiella spp. with ESBLs (CTX-M or non-CTX-M) or hyperproduced K1 enzyme also were 0.5–1 mg/L. A few Klebsiella isolates required faropenem MICs up to 16 mg/L, but 94% of the ESBL producers were inhibited at 2 mg/L. These results compare with faropenem MICs of 0.25–0.5 mg/L for the ampicillin-susceptible E. coli NCTC 10418 and ATCC 29522 control strains and a modal MIC of 0.5 mg/L for 40 ESBL-negative Klebsiella spp. collected in 1994 (data not shown). Cephalosporin-resistant Enterobacter and Citrobacter spp. were less susceptible to faropenem than E. coli and Klebsiella spp., with modal MICs of 2–4 mg/L for both ESBL producers and AmpC-derepressed isolates. Around 5% of the AmpC-derepressed Enterobacter spp. isolates required faropenem MICs of 16 mg/L, though with no higher values recorded. AmpC-derepressed Serratia spp. were less susceptible, with the modal MIC of faropenem straddling 8–16 mg/L.
MIC modes and ranges for imipenem were two to three doubling dilutions below those of faropenem, with modal values of 0.12–0.25 mg/L for ESBL-producing E. coli and Klebsiella isolates and 0.25–0.5 mg/L for AmpC-hyperproducing and ESBL-producing Enterobacter, Citrobacter and Serratia spp. The differential in the activity between imipenem and faropenem was greater for AmpC-derepressed Serratia spp., with the modal MIC of imipenem 32–64-fold lower than that of faropenem. The reduced activity of faropenem against ESBL- and AmpC-producing Enterobacter and Serratia spp. is not surprising, since previous studies have shown that these species are less susceptible to faropenem, regardless of their ability to produce ß-lactamases.6 MICs of co-amoxiclav were high for most members of all the groups of isolates tested, with modal values at or above the breakpoint of 16 mg/L; the amoxicillin/clavulanate resistance of many CTX-M-15-positive E. coli isolates is because they also have OXA-1, an inhibitor-resistant penicillinase, not because of the CTX-M-15 enzyme.7
Faropenem was also tested against isogenic mutant series of Enterobacteriaceae, differing in expression of AmpC enzymes, and against E. coli transconjugants with various classical and ESBLs (Table 2). MICs for AmpC-derepressed C. freundii, E. cloacae and Serratia marcescens mostly were one dilution above those for the corresponding AmpC-inducible parent organisms, whereas no such differential was seen for imipenem. Faropenem retained equal activity against AmpC-inducible and -derepressed M. morganii and P. vulgaris, as did imipenem. AmpC-basal mutants were one to three dilutions more susceptible to faropenem than their AmpC-derepressed counterparts, as with imipenem, indicating that even inducible AmpC confers some slight protection.
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Among the various plasmid-mediated ß-lactamases introduced into E. coli recipients, the only ones to cause a significant (i.e. greater than one doubling dilution) rise in the faropenem MIC were the carbapenemases, NMC-A (Class A) and IMP-1 (Class B), both of which engendered 64-fold MIC increases. Neither of these two enzymes caused such significant MIC rises for imipenem itself, supporting the view that imipenem resistance requires some further factor, usually impermeability arising via porin loss.1 Neither CTX-M nor TEM/SHV-derived ß-lactamases conferred any protection against faropenem or imipenem in transconjugants, though they did, predictably, protect against oxyimino-cephalosporins, including cefixime, cefpodoxime and ceftazidime.
The present data suggest that faropenem has potential to be useful against infections due to ESBL producers—which nowadays are mostly caused, in the UK at least, by E. coli and Klebsiella spp. with CTX-M-15 enzyme.1 It might be used in community-onset infections due to these organisms and as follow-on treatment for nosocomial infections initially managed with an iv carbapenem. Whether this potential is borne out in practice will depend very much on the levels achieved in the urinary tract, which is the site of more than three-quarters of the community infections due to ESBL producers.2 The MICs found here for ESBL producers and other cephalosporin-resistant organisms seem promising when set against published pharmacokinetics,8 which indicate a serum peak of 10–14 mg/L and a t1/2 of 0.9 h, based on a 300 mg oral dose, along with post-dose urine levels of 70 mg/L at 0–4 h and 12 mg/L at 4–8 h.
So far, there are few clinical data on faropenem's efficacy in urinary tract infections. Disappointingly, one Phase III trial found faropenem 300 mg twice daily less effective than co-trimoxazole in acute uncomplicated urinary tract infections;9 however, a small Japanese trial found faropenem 300 mg three times daily was equivalent to levofloxacin—given (somewhat unusually) as a 100 mg three times daily regimen—in complicated urinary infections.10 Perhaps the clearest conclusion is that faropenem has potential for treatment of urinary tract infections due to ESBL producers and other cephalosporin-resistant Enterobacteriaceae, but that further clinical work is needed to optimize regimens for this purpose.
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D. M. L. has received research grants and conference support from Replidyne and Merck. All authors work on antimicrobial resistance and could be construed to have interests in investment in the area, whether by governments, charities or industry.
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Acknowledgements |
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We are grateful to Replidyne for financial support and to all the hospitals that contributed to the 2004 survey.
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References |
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1 Livermore DM, Canton R, Gniadkowski M, et al. (2007) CTX-M: changing the face of ESBLs in Europe. J Antimicrob Chemother 59:165–74.
2
Potz NA, Hope R, Warner M, et al. (2006) Prevalence and mechanisms of cephalosporin resistance in Enterobacteriaceae in London and South-East England. J Antimicrob Chemother 58:320–6.
3
Ensor VM, Livermore DM, Hawkey PM. (2007) A novel reverse-line hybridization assay for identifying genotypes of CTX-M-type extended-spectrum ß-lactamases. J Antimicrob Chemother 59:387–95.
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Mushtaq S, Ge Y, Livermore DM. (2004) Comparative activities of doripenem versus isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp. with characterized ß-lactamases. Antimicrob Agents Chemother 48:1313–9.
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Andrews JM. (2005) BSAC standardized disc susceptibility testing method (version 4). J Antimicrob Chemother 56:60–76.
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Milatovic D, Schmitz FJ, Verhoef J, et al. (2002) In vitro activity of faropenem against 5460 clinical bacterial isolates from Europe. J Antimicrob Chemother 50:293–9.
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Karisik E, Ellington MJ, Pike R, et al. (2006) Molecular characterization of plasmids encoding CTX-M-15 ß-lactamases from Escherichia coli strains in the United Kingdom. J Antimicrob Chemother 58:665–8.
8 Voith B, Schuehly U, Voigt U, et al. Influence of food intake on the pharmacokinetics, safety and tolerability of a single dose of faropenem daloxate. Abstracts of the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy2000Toronto(American Society for Microbiology, Washington, USA) pp. 16 Abstract 496.
9 Richard G, Mazzone F, Drehobl M, et al. Prospective randomized double-blind study comparing faropenem daloxate 300 mg p.o. bid for 5 days with trimethoprim/sulfamethoxazole (TMP/SMX) 160/800 mg p.o. bid for 5 days in treatment of patients with acute, uncomplicated lower urinary tract infections (uUTI). Study 100286. Abstracts of the Forty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy2005Washington, DC(American Society for Microbiology, Washington, USA) pp. 411 Abstract L-2233.
10 Muratani T, Iihara K, Nishimura T, et al. (2002) Faropenem 300 mg 3 times daily versus levofloxacin 100 mg 3 times daily in the treatment of urinary tract infections in patients with neurogenic bladder and/or benign prostatic hypertrophy. Kansenshogaku Zasshi 76:928–38.[Medline]
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