Rn Jones

In vitro antimicrobial activity of CP-99,219, a novel azabicyclo-naphthyridone.

CP-99,219 is a trifluoronaphthyridone with significant antibacterial activity that includes the family Enterobacteriaceae (MICs for 90% of the strains tested [MIC90s], < or = 0.015 to 0.5 micrograms/ml), Moraxella catarrhalis, Haemophilus influenzae, and gonococci (MICs, < or = 0.015 micrograms/ml). Legionella spp. were also CP-99,219 susceptible, with MICs of 0.008 to 0.12 micrograms/ml. CP-99,219 demonstrated activity greater than that of ciprofloxacin, ofloxacin, or enoxacin against Pseudomonas aeruginosa (MIC90, 1 microgram/ml), Xanthomonas maltophilia (MIC90, 2 micrograms/ml), Staphylococcus haemolyticus (MIC90, 0.5 micrograms/ml), Enterococcus faecalis (MIC90, 1 microgram/ml), and pneumococci (MIC90, 0.12 micrograms/ml). Numerous ciprofloxacin-resistant isolates were susceptible to CP-99,219, a new compound showing potential value for further in vivo trials.

In Vitro evaluation of BI 397, a novel glycopeptide antimicrobial agent

Abstract BI 397, a semi-synthetic amide derivative of the experimental glycopeptide, MDL 62,476 (A40926), has excellent In Vitro activity against a wide range of Gram-positive organisms. In this extensive study, 630 contemporary (1998-2000) Gram-positive isolates were selected from various resistance surveillance studies for their resistance patterns to fluoroquinolones, macrolides-lin-cosamides-streptogramins, β-lactams and glycopeptide agents. The BI 397 spectrum of activity was similar to that of other glycopeptides with a MIC90 of <0.5 μg/ml for all tested isolates with the exception of vancomycin-resistant enterococci Van A; (MIC90, 32 μg/ml). BI 397 was more potent than van-comycin and teicoplanin against Staphylococcus aureus (2- to 8-fold), β-haemolytic streptococci (equal to > 16-fold), viridans group streptococci (equal to >32-fold), and Corynebacterium spp. including C. jeikeium (8- to >16-fold). BI 397 was also more active than quinupristin/dalfopristin against all Gram-positive organisms tested with the exception of oxacillin-susceptible S. aureus, against which it had equal activity. BI 397 has little activity against Haemophilus influenzae (MIC90, 64 μg/ml) or other Gram-negative bacilli (MIC90, >64 μg/ml). BI 397 exhibited bacteriostatic activity (like the van-comycin control) versus most species, but was bactericidal against tested Streptococcus pneumoniae. In vitro testing conditions with blood supplemented or free protein containing media elevated BI 397 MIC results, and the 30-mg disk seems acceptable for further disk diffusion test development. Animal pharmacokinetic data published elsewhere suggest that BI 397 may be dosed less frequently than teicoplanin and the results of early studies in humans are awaited with interest, especially when treating teicoplanin-refracto-ry coagulase-negative staphylococci.

Eight-year (2002-2009) Summary of the Linezolid (Zyvox® Annual Appraisal of potency and Spectrum; ZAAPS) Program in European Countries

Abstract The linezolid surveillance network (ZAAPS program) has been monitoring linezolid activity and susceptibility rates for eight years (2002-2009) in European medical centers. Samples from 12-24 sites annually in 11 countries were monitored by a central laboratory design using reference MIC methods with international and regional interpretations (EUCAST). A total of 13,404 Gram-positive pathogens were tested from 6 pathogen groups. Linezolid remained without documented resistance from 2002 through 2005, but beginning in 2006 resistant strains emerged at very low rates among Staphylococcus aureus (G2576T mutant in ireland, 2007), coagulase-negative staphylococci (CoNS; usually Staphylococcus epidermidis, France and italy in 2006-2009) and enterococci (Enterococcus faecium in Germany [2006, 2008, 2009] and E. faecalis in Sweden [2008], United Kingdom [2008] and Germany [2009]); all but one strain having a target mutation. A mobile cfr was detected in an italian CoNS strain (2008 and 2009), and clonal spread was noted for linezolid-resistant strains (pfGe results). Overall the linezolid susceptibility rates were >99.9, 99.7 and 99.6% for S. aureus, CoNS and enterococci, respectively; and all streptococcal strains were susceptible (MIC90, 1 mg/L). In conclusion, the ZAAPS program surveillance confirmed high, sustained levels of linezolid activity from 2002-2009 and without evidence of MIC creep or escalating resistance in Gram-positive pathogens across monitored European nations.

Comparative Antimicrobial Potency of Meropenem Tested Against Gram-Negative Bacilli: Report from the MYSTIC Surveillance Program in the United States (2004)

Abstract The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is a longitudinal resistance surveillance network of more than 100 medical centers worldwide monitoring the susceptibility of bacterial pathogens to carbapenems and other broad-spectrum agents. In 2004 (year six), the antimicrobial activity of 12 broad-spectrum agents was assessed against 2,799 Gram-negative bacterial isolates submitted from 15 United States (USA) medical centers using Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) recommended methods. Meropenem continued to demonstrate a high potency with MIC90 values 4- to 32- fold lower than imipenem against the Enterobacteriaceae. The wide spectrum of activity for meropenem against all Gram-negative isolates was demonstrated by the overall rank order of percentage susceptibility at CLSI breakpoints: amikacin (96.5%) > meropenem (96.0%) > imipenem (95.8%) > piperacillin/tazobactam (91.5%) > tobramycin (91.4%) > cefepime (91.2%) > ceftazidime (89.0%) > gentamicin (88.0%) > aztreonam (81.5%) > levofloxacin (80.5%) > ciprofloxacin (80.2%) > ceftriaxone (69.1%). Only the aminoglycosides (84.5%) and carbapenems (76.1 - 83.8%) exhibited acceptable levels of susceptibility against the Acinetobacter spp. isolates as this species group became more resistant to all antimicrobial classes. A continued increase in the resistance rate for both ciprofloxacin and levofloxacin over the six years was observed, most alarming among Escherichia coli (20.2 - 20.7%) and indole-positive Proteus species (34.4 - 42.2%) isolates, some documented as clonal. Continued surveillance of these broad-spectrum antimicrobial agents appears warranted to monitor the potency and spectrum of activity against Gram-negative pathogens causing serious infections and the emergence of new or novel resistance mechanisms that could compromise carbapenem therapy.

Antimicrobial Resistance among Gram-Positive Bacteria Isolated in Latin American Hospitals

Abstract Antimicrobial resistance patterns of the most frequently isolated Gram-positive bacteria in selected latin American hospitals were evaluated under the auspices of the SENTRY Antimicrobial Surveillance program. The strains were consecutively collected (one per patient) between January 2003 and December 2008 and tested by reference broth microdilution methods at the monitoring central laboratory (JMI laboratories, North Liberty, Iowa, USA). A total of 12,324 Gram-positive cocci were analyzed. The organisms were isolated from bloodstream (53.2%) and skin and skin structure infections (16.4%). Resistance to oxacillin (MRSA) was observed in 40.0% of Staphylococcus aureus, varying from 32.7% in Brazil to 49.7% in Chile. Resistance to erythromycin (90.1%), clindamycin (84.4%), and levofloxacin (86.8%) was very high in MRSA. Vancomycin, linezolid and daptomycin were all very active against S. aureus strains tested (>99.9-100.0% susceptible), but daptomycin (MIC50/90, 0.25/0.5 μg/ml) was four- to eight-fold more potent than three comparators. Vancomycin resistance increased from 5.0% in 2003 to 15.5% in 2008 among enterococci (VRE); the most significant increase occurred among isolates from brazilian medical centers (from 6.9 to 31.1%). Daptomycin was the most active antimicrobial tested against enterococci in general (MIC50/90, 1/2 μg/ml; 100.0% susceptible), followed by linezolid (MIC50/90, 1/2 μg/ml; 99.9% susceptible), teicoplanin (MIC50 and MIC90 of ≤2 μg/ml; 91.3% susceptible), vancomycin (MIC50/90, 1/8 μg/ml; 89.6% susceptible). In summary, daptomycin and linezolid showed excellent in vitro activity against Gram-positive organisms (12,324) collected in latin American hospitals, including MRSA, VRE and other multidrug- resistant organisms.

Antimicrobial Activity of Daptomycin Tested Against Gram-Positive Strains Collected in European Hospitals: Results from 7 Years of Resistance Surveillance (2003-2009)

Abstract Daptomycin is a cyclic lipopeptide approved by the European medicines Agency (EMEA) for the treatment of complicated skin and soft tissue infections (cSSTI) and Staphylococcus aureus bacteremia and endocarditis. We evaluated the in vitro activity of daptomycin and comparators tested against clinical isolates from European hospitals over a 7-year period (2003-2009). A total of 36,769 consecutive isolates were collected in 34 medical centers located in 13 European countries, turkey and Israel. the collection included S. aureus (18,352; 27.2% oxacillin-resistant [MRSA]); coagulase-negative staphylo-cocci (CoNS; 6,874), Enterococcus spp. (7,241; 9.4% vancomycin-resistant),β-hemolytic (3,009), viridans group streptococci (1,176), and Streptococcus bovis/gallolyticus (107). The organisms were isolated mainly from patients with bloodstream infection (56%) or cSSTI (23%). Daptomycin was very active against S. aureus and CoNS (MIC50/90, 0.25/0.5 mg/L for both organisms), and its activity was not adversely influenced by oxacillin resistance. All Enterococcus faecalis strains were susceptible to daptomycin (MIC50/90, 1/1 mg/L). Daptomycin (MIC50/90, 2/2 mg/L; 100.0% susceptible) and linezolid (MIC50/90, 1/2 mg/L; 99.7% susceptible) were the most active agents tested against vancomycin-resistant E. faecium. Vancomycin-resistant and -susceptible enterococcal strains were equally susceptible to daptomycin. Daptomycin was also active against β-hemolytic streptococci (MIC50/90, 0.06/0.25 mg/L; 100.0% susceptible), viridans group streptococci (MIC50/90, 0.25/0.5 mg/L; 99.8% susceptible) and S. bovis (MIC50/90, 0.06/0.12 mg/L; 100.0% susceptible). In summary, daptomycin was very potent against this large collection (36,769) of Gram-positive organisms isolated in European hospitals, and its activity remained stable across the 7-year period evaluated (2003-2009), using reference methods and interpretive criteria. Decreases in daptomycin potency were not observed since EMEA approval and widespread clinical use, and emerging resistance to other compounds did not adversely influence daptomycin activity against contemporary Gram-positive species.

Antimicrobial activities of two investigational fluoroquinolones (CI-960 and E4695) against over 100 Legionella sp. isolates.

The antimicrobial activities of two investigational fluoroquinolones (CI-960 and E4695) were compared with those of five similar compounds and four comparison drugs against 103 strains of Legionella pneumophila and five other Legionella species type strains. When concentrations inhibiting 90% of strains tested (MIC90s) for L. pneumophila were determined, CI-960 and temafloxacin emerged as the most active (0.015 microgram/ml) and were followed in potency by E4695 (0.03 microgram/ml). This activity was two- to fourfold greater than that of the reference drug, ciprofloxacin, and approached that of rifampin (MIC90, 0.008 microgram/ml). All fluoroquinolones studied were more active than erythromycin (MIC90, 0.5 microgram/ml). These two investigational fluoroquinolones appear well suited for further in vivo study of legionellosis therapy.

Antimicrobial Activity of Solithromycin against Serotyped Macrolide-Resistant Streptococcus pneumoniae Isolates Collected from U.S. Medical Centers in 2012

ABSTRACT Solithromycin, a next-generation macrolide and novel fluoroketolide, was tested against a 2012 collection of serotyped U.S. macrolide-resistant Streptococcus pneumoniae isolates associated with community-acquired bacterial pneumonia (CABP). Against all 272 isolates, solithromycin demonstrated high potency (MIC50/90, 0.06/0.25 μg/ml), and it inhibited all strains at MICs of ≤0.5 μg/ml, including the two most prevalent macrolide-resistant serotypes (19A and 35B). These data support the continued clinical development of solithromycin for the treatment of multidrug-resistant CABP.

Update on the In Vitro Activity of Daptomycin Tested against 17,193 Gram-positive Bacteria Isolated from European Medical Centers (2005-2007)

Abstract The antimicrobial susceptibility patterns of 17,193 Gram-positive isolates consecutively collected from 28 medical centers in 12 countries in Europe and Israel in 2005-2007 were evaluated by Clinical and laboratory Standards institute (CLSI) broth microdilution methods supplemented with calcium to 50 mg/L for testing daptomycin. Overall, the rate of methicillin-re-sistant Staphylococcus aureus(MRSA) was 28.3%, varying from 32.3% in 2005 to 27.1% in 2006 and 28.5% in 2007. Vancomycin resistance rates were 0.8% and 21.5% among Enterococcus faecalis and E. faecium, respectively. Among E. faecium, vancomycin resistance increased from 17.9% in 2005 to 26.3% in 2007, and varied from 0.0% in Spain, Sweden and Switzerland to as high as 54.6% in ireland for 2007. All isolates tested, except for seven CoNS(0.2%; 3,234 tested) were considered susceptible to daptomycin using breakpoints establishedby the United States food and Drug Administration, the CLSI and the EUCAST. Daptomycin wasvery active against all Gram-positive species with the highest minimum inhibitory concentration(MIC) results being 1, 4, 2 and 4 mg/L for S. aureus, coagulase-negative staphylococci, E. faecalis and E. faecium, respectively. Daptomycin activity was not adversely influenced by resistanceto oxacillin among staphylococci or to vancomycin among enterococci.

Daptomycin In Vitro Activity Tested Against Gram-Positive Strains Collected from European and Latin American Medical Centers in 2003

Abstract Daptomycin, a cyclic lipopeptide, was susceptibility tested against clinical bacterial isolates consecutively collected in hospitals located in Europe (4,731 strains) and Latin America (1,007 strains) in 2003 as part of a continuing surveillance program. The bacterial isolates tested were Gram-positive pathogens that included staphylococci, streptococci and enterococci. The isolates were tested for susceptibility using broth microdilution methods (broth with 50 mg/L Ca++ for testing daptomycin). All isolates, except two Enterococcus faecium strains from Europe, were inhibited at daptomycin MIC of ≤4 mg/L. In addition, 99.4 and 97.3% of isolates were inhibited at daptomycin MIC of ≤2 and ≤1 mg/L, respectively. Except for one Staphylococcus aureus and one viridans group streptococci from Europe and one coagulase-negative staphylococci from Latin America, all staphylococcal and streptococcal isolates were inhibited by 1 mg/L of daptomycin. Resistance to other compounds (vancomycin, oxacillin, and penicillin) did not influence daptomycin activity. The activity of daptomycin was very similar in both geographic regions evaluated and demonstrated the same MIC distribution as isolates evaluated in studies in the United States. The results of this study showed that daptomycin continues to be very active against clinical isolates of Gram-positive cocci isolated in Europe and Latin America.