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Surveying aminoglycoside resistance mechanisms: a tool for the development of neoglycosides

Abstract number: P643

Armstrong E., Biedenbach D., Jones R., Miller G.

Objectives: To support the development of neoglycosides, the next generation of aminoglycosides (AG) with an improved antibacterial spectrum, we conducted a survey of AG resistance mechanisms (AGRM) among selected clinical isolates. These data will be used to determine the spectrum of activity required of new compounds to overcome these mechanisms.

Methods: AGRM were surveyed using isolates of diverse geographic origin from the SENTRY 2005 and 2007 collections. Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii from Europe and North/South America were chosen from the 2005 SENTRY Program collection based on established amikacin (A), gentamicin (G) and tobramycin (T) MICs. They were selected such that resistance rates to these AGs in the test population matched those in the entire collection. MICs of 9 AGs were determined for 406 strains and the resulting antibiogram was used to characterise the AGRM. Phenotypes for 6 common AGRM were confirmed by PCR (89 strains). Our study of the 2007 SENTRY Program collection focused on multidrug resistant (MDR) Gram-negatives from Europe, North/South America, and Asia. MDR was defined by resistance to representatives of 3 drug classes; an aminoglycoside (A, G, or T), a fluoroquinolone (ciprofloxacin), and a third generation cephalosporin (ceftazidime or ceftriaxone). The strains selected for study were again representative of resistance rates to A, G, and T within this population. MICs of 9 AGs were determined for 302 strains and the resulting antibiogram used for AGRM characterisation. AGRM findings were compared to a published survey conducted between 1988 and 1993 (CID 1997;24:S46).

Results: The incidence of combined AGRM remained high and consisted of G and T modifying enzymes (AAC(3)-I, AAC(3)-II and ANT(2")-I) occurring with the T-, netilmicin- (N) and A-modifying enzyme AAC(6')-I. The GTNA-resistance phenotype that results from these combinations also continues to occur as a result of permeability/efflux and now due to ribosomal methyltransferases (RMT). In all 3 studies the kanamycin-/neomycin-resistance phenotype caused by APH(3')-I/II was not evaluated.

Conclusions: These results demonstrate that while the overall prevalence may be increasing (companion abstract by Biedenbach et al), the distribution of AGRM amongst AG-resistant isolates worldwide remained stable during the past 20 years. New agents that evade these AGRM, such as neoglycosides, are needed.

AGRMPhenotypePercentage of AG-R isolates with given AGRMa
  CID 1988–1993
n = 10,181
SENTRY 2005
n = 406
SENTRY 2007
n = 302
  AloneComb.AloneComb.AloneComb.
AAC(3)-IG1.28.30.712.10.36.3
AAC(3)-IIGTN20.917.512.323.723.215.2
AAC(3)-IVGTN1.700.72.00.31.0
AAC(2')-IGTN2.11.10000
AAC(6')-ITNA10.421.88.625.99.619.2
AAC(6')-IIGT3.63.07.42.71.74.0
ANT(2")-IGT7.24.315.07.42.74.6
APH(3')-VIA0.13.41.04.71.09.3
Perm/EffluxGTNA7.67.42.06.412.911.3
RMTGTNA005.20.215.6NDb
 Total54.866.852.985.167.370.9
aComb. = AGRM present in combination with one other or more AGRM.
bND = No data.

Session Details

Date: 16/05/2009
Time: 00:00-00:00
Session name: 19th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Helsinki, Finland, 16 - 19 May 2009
Presentation type:
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