Activity of ACHN-490 against meticillin-resistant Staphylococcus aureus (MRSA) isolates from patients in US hospitals.

The activity of ACHN-490 was evaluated against 493 meticillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2009-2010 from 23 US hospitals. The MIC(50) and MIC(90) values (minimal inhibitory concentrations for 50% and 90% of the organisms, respectively) for ACHN-490 were 1 and 2 µg/mL compared with 8 and 32 µg/mL for amikacin, 0.5 and 1 µg/mL for gentamicin and 2 and >16 µg/mL for tobramycin. The gene encoding the aminoglycoside-modifying enzyme APH(2″)-Ia/AAC(6')-Ie was present in 12% of the subset of 84 isolates examined by polymerase chain reaction (PCR), whilst the gene encoding ANT(4')-Ia was present in 89% of isolates. ACHN-490 activity was not affected by either enzyme.

Combating evolution with intelligent design: the neoglycoside ACHN-490.

The challenge posed by increasing levels of drug-resistant bacteria world-wide is manifest, and must be dealt with both by new approaches to the use of existing antibiotics and by the introduction of novel drugs. ACHN-490 is the first neoglycoside, or next-generation aminoglycoside, to begin clinical development. ACHN-490 was designed to target key pathogens, particularly gram-negative organisms and those resistant to older antibiotics. ACHN-490 demonstrates promising in vitro activity against wild-type and resistant bacteria while retaining the favorable bactericidal and synergistic properties of the aminoglycoside class. These attributes, along with the results of Phase 1 studies of ACHN-490 injection, suggest that ACHN-490 may help to fill the growing unmet need for new antibacterial agents.

Synthesis and spectrum of the neoglycoside ACHN-490.

ACHN-490 is a neoglycoside, or "next-generation" aminoglycoside (AG), that has been identified as a potentially useful agent to combat drug-resistant bacteria emerging in hospitals and health care facilities around the world. A focused medicinal chemistry campaign produced a collection of over 400 sisomicin analogs from which ACHN-490 was selected. We tested ACHN-490 against two panels of Gram-negative and Gram-positive pathogens, many of which harbored AG resistance mechanisms. Unlike legacy AGs, ACHN-490 was active against strains expressing known AG-modifying enzymes, including the three most common such enzymes found in Enterobacteriaceae. ACHN-490 inhibited the growth of AG-resistant Enterobacteriaceae (MIC(90), ≤4 µg/ml), with the exception of Proteus mirabilis and indole-positive Proteae (MIC(90), 8 µg/ml and 16 µg/ml, respectively). ACHN-490 was more active alone in vitro against Pseudomonas aeruginosa and Acinetobacter baumannii isolates with AG-modifying enzymes than against those with altered permeability/efflux. The MIC(90) of ACHN-490 against AG-resistant staphylococci was 2 µg/ml. Due to its promising in vitro and in vivo profiles, ACHN-490 has been advanced into clinical development as a new antibacterial agent.

In vitro activity of the aminoglycoside antibiotic arbekacin against Acinetobacter baumannii-calcoaceticus isolated from war-wounded patients at Walter Reed Army Medical Center.

We determined the in vitro MIC of arbekacin against 200 Acinetobacter isolates recovered from wounded soldiers. The median MIC was 2 microg/ml (range, 0.5 to > 64 microg/ml). A total of 97.5% of the isolates had arbekacin MICs of < 8 microg/ml and 86.5% had MICs of < or = 4 microg/ml. There was no association between the arbekacin MIC and susceptibility to 16 other antibiotics or the specimen source (P = 0.7239). Synergy testing suggested an enhanced effect of arbekacin-carbapenem combinations.

Temporal appearance of plasmid-mediated quinolone resistance genes.

One hundred fifty AAC(6')-Ib-positive gram-negative isolates collected between 1981 and 1991 were examined by PCR for the presence of the aac(6')-Ib-cr variant and other plasmid-mediated quinolone resistance (PMQR) genes. None had the aac(6')-Ib-cr variant, qnrA, qnrS, qnrC, or qepA, but two strains collected in 1988 had qnrB alleles, making these the earliest known PMQR genes.

Detection of methyltransferases conferring high-level resistance to aminoglycosides in enterobacteriaceae from Europe, North America, and Latin America.

The alteration of ribosomal targets by recently described 16S rRNA methyltransferases confers resistance to most aminoglycosides, including arbekacin. Enterobacteriaceae and nonfermentative bacilli acquired through global surveillance programs were screened for the presence of these enzymes on the basis of phenotypes that were resistant to nine tested aminoglycosides. Subsequent molecular studies determined that 20 of 21 (95.2%) methyltransferase-positive isolates consisted of novel species records or geographic occurrences (North America [armA and rmtB], Latin America [rmtD], and Europe [armA]; rmtA, rmtC, and npmA were not detected). The global emergence of high-level aminoglycoside resistance has become a rapidly changing event requiring careful monitoring.