In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Aspergillus spp. determined by CLSI and EUCAST broth microdilution methods.

E1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents against Aspergillus spp. by using the methods of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to test wild-type (WT) as well as amphotericin B (AMB)-resistant (-R) and azole-R strains (as determined by CLSI methods). Seventy-eight clinical isolates of Aspergillus were tested including 20 isolates of Aspergillus flavus species complex (SC), 22 of A. fumigatus SC, 13 of A. niger SC, and 23 of A. terreus SC. The collection included 15 AMB-R (MIC, ≥ 2 µg/ml) isolates of A. terreus SC and 10 itraconazole-R (MIC, ≥ 4 µg/ml) isolates of A. fumigatus SC (7 isolates), A. niger SC (2 isolates), and A. terreus SC (1 isolate). Comparator antifungal agents included anidulafungin, caspofungin, amphotericin B, itraconazole, posaconzole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparators. The essential agreement (EA; ± 2 log(2) dilution steps) was 100% for all comparisons with the exception of posaconazole versus A. terreus SC (EA = 91.3%). The minimum effective concentration (MEC)/MIC(90) values (µg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, and voriconazole, respectively, were as follows for each species: for A. flavus SC, 0.03, ≤ 0.008, 0.12, 1, 1, and 1; for A. fumigatus SC, 0.06, 0.015, 0.12, >8, 1, and 4; for A. niger SC, 0.015, 0.03, 0.12, 4, 1, and 2; and for A. terreus SC, 0.06, 0.015, 0.12, 1, 0.5, and 1. E1210 was very active against AMB-R strains of A. terreus SC (MEC range, 0.015 to 0.06 µg/ml) and itraconazole-R strains of A. fumigatus SC (MEC range, 0.03 to 0.12 µg/ml), A. niger SC (MEC, 0.008 µg/ml), and A. terreus SC (MEC, 0.015 µg/ml). In conclusion, E1210 was a very potent and broad-spectrum antifungal agent regardless of in vitro method applied, with excellent activity against AMB-R and itraconazole-R strains of Aspergillus spp.

In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Candida spp. as determined by CLSI broth microdilution method.

The in vitro activity of the novel antifungal agent E1210 and four comparators (caspofungin, fluconazole, posaconazole, and voriconazole) was determined against 90 clinical isolates of Candida using Clinical and Laboratory Standards Institute methods. The collection was composed of 21 Candida albicans, 20 C. glabrata, 25 C. parapsilosis, and 24 C. tropicals, and also included 21 fluconazole-resistant and 15 caspofungin-resistant strains. E1210 was highly active against all the species tested and was more potent than all comparators. The MIC(90) results (µg/mL) for E1210, caspofungin, fluconazole, posaconazole, and voriconazole, respectively, were as follows by species: C. albicans (0.06, 4, ≥64, 0.5, 0.5), C. glabrata (0.06, 2, 32, 1, 1), C. parapsilosis (0.06, 4, 16, 0.12, 0.25), and C. tropicalis (0.06, 4, ≥64, 0.5, 2). E1210 was also the most active agent against fluconazole-resistant strains of C. albicans (MIC range, 0.015-0.12 µg/mL), C. glabrata (0.06 µg/mL), C. parapsilosis (MIC range, 0.06-0.05 µg/mL), and C. tropicalis (MIC range, 0.008-0.06 µg/mL), and was the most potent agent tested against caspofungin-resistant strains of C. albicans (MIC range, 0.008-0.12 µg/mL), C. glabrata (MIC range, 0.03-0.06 µg/mL), and C. tropicalis (MIC range, 0.015-0.06 µg/mL).

Antimicrobial susceptibility of daptomycin and comparator agents tested against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: trend analysis of a 6-year period in US medical centers (2005-2010).

We evaluated daptomycin activity trends against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE; MIC, ≥8 µg/mL) in a 6-year period (2005-2010) following US regulatory release for clinical use. Consecutive, unique patient strains of clinical significance were collected in 32 US medical centers and susceptibility tested in a central laboratory against daptomycin and various comparator agents by reference broth microdilution methods. A total of 22 858 S. aureus (12 181 [53.3%] MRSA), 4312 Enterococcus faecalis (195 [4.5%] VRE), and 2462 Enterococcus faecium (1867 [75.8%] VRE) were evaluated. Daptomycin susceptibility rates were 99.94%, 99.98%, and 99.68% for S. aureus, E. faecalis, and E. faecium, respectively. Among MRSA (daptomycin MIC50/90, 0.25/0.5 µg/mL), only 13 (0.11%) daptomycin-non-susceptible (MIC, ≥ 2 µg/mL) isolates were observed with no MIC creep over the study interval. Daptomycin was very active against vancomycin-resistant E. faecalis (MIC50/90, 1/2 µg/mL) and E. faecium (MIC50/90, 2/2 µg/mL). Among VRE, only 4 daptomycin-non-susceptible isolates (all E. faecium) were detected. In conclusion, daptomycin demonstrated sustained activity against an extensive collection of clinical isolates of MRSA and VRE from numerous US medical centers over the last 6 monitored years.

Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and azole antifungal agents in Intensive Care Unit (ICU) and non-ICU settings in the SENTRY Antimicrobial Surveillance Program (2008-2009).

Minimum inhibitory concentration (MIC) data from the SENTRY Antimicrobial Surveillance Program generated by reference methods were analysed to compare the antifungal resistance profiles and species distribution of Candida bloodstream infection (BSI) isolates obtained from patients in the Intensive Care Unit (ICU) and those from non-ICU locations. Results from 79 medical centres between 2008 and 2009 were tabulated. MIC values were obtained for anidulafungin, caspofungin, micafungin, fluconazole, posaconazole and voriconazole. Recently revised Clinical and Laboratory Standards Institute breakpoints for resistance were employed. A total of 1752 isolates of Candida spp. were obtained from ICU (779; 44.5%) and non-ICU (973; 55.5%) settings. The frequency of ICU-associated Candida BSI was higher in Latin America (56.5%) compared with Europe (44.4%) and North America (39.6%). The frequency of candidaemia in the ICU decreased both in Latin America and North America over the 2-year study period. Approximately 96% of isolates both in ICU and non-ICU settings were caused by only five species (Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei). Resistance both to azoles and echinocandins was uncommon in ICU and non-ICU settings. Overall, fluconazole resistance was detected in 5.0% of ICU isolates and 4.4% of non-ICU isolates. Candida glabrata was the only species in which resistance to azoles and echinocandins was noted, and this multidrug-resistant phenotype was found in both settings. In conclusion, the findings from this global survey indicate that invasive candidiasis can no longer be considered to be just an ICU-related infection, and efforts to design preventive and diagnostic strategies must be expanded to include other at-risk populations and hospital environments. Concern regarding C. glabrata must now include resistance to echinocandins as well as azole antifungal agents.

Candida bloodstream infections: comparison of species distributions and antifungal resistance patterns in community-onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, 2008-2009.

Community-onset (CO) candidemia, defined as a positive blood culture taken at or within 2 days of hospital admission, represents a distinct clinical entity associated with substantial morbidity and mortality. Reference MIC results from the SENTRY Antimicrobial Surveillance Program (2008-2009) were analyzed to compare the antifungal resistance patterns and species distributions from patients with CO and nosocomial bloodstream infections (BSI) in 79 medical centers. Among 1,354 episodes of BSI, 494 (36.5%) were classified as CO and 860 (63.5%) as nosocomial in origin. More than 95% of the isolates from both BSI types were contributed by Candida albicans (48.4%), C. glabrata (18.2%), C. parapsilosis (17.1%), C. tropicalis (10.6%), and C. krusei (2.0%). C. albicans was more common in CO BSI (51.0%) than nosocomial BSI (46.9%), whereas C. parapsilosis and C. krusei were more common in nosocomial BSIs (18.1 and 2.7%, respectively) than in CO BSIs (15.4 and 0.8%, respectively). C. glabrata and C. tropicalis were comparable in both CO (18.4 and 10.5%, respectively) and nosocomial (18.1 and 10.6%, respectively) episodes. Resistance to azoles (fluconazole, posaconazole, and voriconazole) and echinocandins (anidulafungin, caspofungin, and micafungin) was uncommon (<5%) in CO BSI using recently established Clinical and Laboratory Standards Institute breakpoint criteria. Resistance to echinocandins (anidulafungin [3.8%], caspofungin [5.1%], and micafungin [3.2%]) and azoles (fluconazole [7.7%], posaconazole [5.1%], and voriconazole [6.4%]) was most prevalent among nosocomial BSI isolates of C. glabrata. CO candidemia is not uncommon and appears to be increasing worldwide due to changing health care practices. Although resistance to the azoles and echinocandins remains uncommon among CO isolates, we demonstrate the emergence of nosocomial occurrences of C. glabrata expressing resistance to both monitored classes of antifungal agents.

Echinocandin and triazole antifungal susceptibility profiles for Candida spp., Cryptococcus neoformans, and Aspergillus fumigatus: application of new CLSI clinical breakpoints and epidemiologic cutoff values to characterize resistance in the SENTRY Antimicrobial Surveillance Program (2009).

The SENTRY Antimicrobial Surveillance Program monitors global susceptibility and resistance rates for newer and established antifungal agents. The echinocandins displayed excellent potency against both Candida spp. and Aspergillus fumigatus in 2009 samples. Using the new Clinical and Laboratory Standards Institute breakpoint values for the echinocandins when testing Candida spp., we demonstrate low but measurable rates of resistance to all 3 echinocandins (anidulafungin, caspofungin, and micafungin) when tested against Candida glabrata. Three of the 8 isolates demonstrating in vitro echinocandin resistance harbored fks resistance mutations, including 1 C. glabrata. The triazoles, with the exception of itraconazole, also exhibited excellent potency and low levels of resistance when tested against clinical isolates of Candida spp., Cryptococcus neoformans, and A. fumigatus. Overall, echinocandin and triazole resistance rates were minimal; however, the distinct increase in echinocandin resistance observed among C. glabrata strains warrants further surveillance associated with molecular support.

Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the SENTRY Antimicrobial Surveillance Program (2008 to 2009).

Antifungal testing results from the SENTRY Antimicrobial Surveillance Program (2008 to 2009) were analyzed for regional variations of invasive Candida species infections. Among 2,085 cases from the Asian-Pacific (APAC) (51 cases), Latin American (LAM) (348 cases), European (EU) (750 cases), and North American (NAM) (936 cases) regions, Candida albicans predominated (48.4%), followed by C. glabrata (18.0%), C. parapsilosis (17.2%), C. tropicalis (10.5%), and C. krusei (1.9%). Resistance to echinocandins (anidulafungin [2.4%] and micafungin [1.9%]) and azoles (3.5 to 5.6%) was most prevalent among C. glabrata isolates, as determined using recently established CLSI breakpoint criteria. C. glabrata isolates were more common in NAM (23.5%), and C. albicans isolates were more common in APAC (56.9%), with C. parapsilosis (25.6%) and C. tropicalis (17.0%) being more prominent in LAM. Emerging resistance patterns among C. glabrata cases in NAM require focused surveillance.

Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program (2008-2009).

The variation in Candida spp. causing bloodstream infection (BSI) and the frequency of resistance to fluconazole by patient age have been previously described. However, similar data have been shown for neither the echinocandins nor the newer triazoles. We analyzed the 24-h reference MIC data from the SENTRY Antimicrobial Surveillance Program to compare the antifungal resistance profiles and species distribution of Candida BSI isolates according to patient age. MIC results were obtained for anidulafungin, caspofungin, micafungin, fluconazole, posaconazole, and voriconazole, and recently revised Clinical and Laboratory Standards Institute breakpoints were applied. A total of 1239 Candida BSI isolates were obtained from 79 medical centers in 2008 to 2009: 50.0%, 17.4%, 17.4%, 9.8%, and 1.8% were Candida albicans (Ca), Candida glabrata (Cg), Candida parapsilosis (Cp), Candida tropicalis (Ct), and Candida krusei (Ck), respectively. Ca was most common in the 60- to 79-year age group (52.3%) and least common in the 80- to 99-year age group (46.7%), whereas Cg was most common in the 80- to 99-year age group (28.6%) and least common in the 0- to 19-year age group (2.0%). Cp and Ct were most common in the 0- to 19-year age group (28.5% and 12.9%, respectively), and Ck was most common among the patients in the 20- to 39-year age group (3.5%). No resistance to echinocandins was detected among isolates of Ca, Cp, and Ct from all age groups. Likewise, no resistance to posaconazole or voriconazole was observed in isolates of Ca, Cp, or Ck from all age groups. Resistance to both azoles and echinocandins was most prominent among isolates of Cg with the highest resistance rates to echinocandins (16.7%), fluconazole (16.7%), posaconazole (5.0%), and voriconazole (11.1%) among isolates from the 20- to 39-year age group. Both species distribution and antifungal resistance patterns vary markedly with patient age. Cg BSI isolates may show lower susceptibility rates to both azoles and echinocandins with the highest rates of resistance detected in 20- to 59-year-old patients.

Worldwide summary of telavancin spectrum and potency against Gram-positive pathogens: 2007 to 2008 surveillance results.

Telavancin was approved in the United States and Canada for the treatment of adult patients with complicated skin and skin-structure infections (cSSSI) caused by susceptible Gram-positive isolates. In this study, telavancin and comparator antimicrobial activities were determined against a total of 24,017 clinical isolates, including Staphylococcus aureus, coagulase-negative Staphylococcus spp. (CoNS), Enterococcus spp., and various Streptococcus spp. Overall, telavancin was highly active across all geographic regions for S. aureus (MIC(50/90), 0.12/0.25 microg/mL; 100.0% susceptible), CoNS (MIC(50/90), 0.12/0.25 microg/mL), vancomycin-susceptible Enterococcus faecalis (MIC(50/90), 0.25/0.5 microg/mL; 100.0% susceptible), Enterococcus faecium (MIC(50/90), 0.06/0.12 microg/mL), Streptococcus pneumoniae (MIC(50/90), < or =0.015/0.03 microg/mL), viridans group Streptococcus spp. (MIC(50/90), 0.03/0.06 microg/mL; 100.0% susceptible), and beta-hemolytic Streptococcus spp. (MIC(50/90), 0.03/0.12 microg/mL; 99.8% susceptible). Telavancin had potent activity against vancomycin-nonsusceptible, teicoplanin-susceptible (VanB) E. faecalis (MIC(50/90), 0.25/0.5 microg/mL) and E. faecium (MIC(50/90), 0.06/0.25 microg/mL). These in vitro results show continued activity for telavancin, which represents an important alternative available for treating cSSSI.

Potency of anidulafungin compared to nine other antifungal agents tested against Candida spp., Cryptococcus spp., and Aspergillus spp.: results from the global SENTRY Antimicrobial Surveillance Program (2008).

The SENTRY Antimicrobial Surveillance Program regularly monitors global susceptibility rates for a spectrum of both novel and established antifungal agents. Anidulafungin and the other echinocandins displayed sustained, excellent activity against Candida spp. and Aspergillus fumigatus, with >or=98% of MIC results at or=0.5 microg/ml were further analyzed for potential fks hot spot (HS) mutations; three isolates had confirmed mutations in the fks1 HS1 region (S645P), and three exhibited mutations in the fks2 HS1 region (S645F and S645P).

In vitro activity of telavancin against a contemporary worldwide collection of Staphylococcus aureus isolates.

The activity of telavancin and comparators was assessed against a contemporary (2007 and 2008) global collection of 10,000 isolates of Staphylococcus aureus. Telavancin was very active against methicillin-susceptible and -resistant S. aureus (MSSA and MRSA, respectively; MIC(50/90) for both, 0.12/0.25 microg/ml; 100.0% susceptible). This agent was 2-, 4-, and 8-fold more potent than daptomycin (MIC(90), 0.5 microg/ml), vancomycin or quinupristin-dalfopristin (MIC(90), 1 microg/ml), and linezolid (MIC(90), 2 microg/ml) against MRSA, respectively. These data show a potent activity of telavancin tested against a current global collection of S. aureus.

Antimicrobial activity of daptomycin tested against Staphylococcus aureus with vancomycin MIC of 2 microg/mL isolated in the United States and European hospitals (2006-2008).

We evaluated the activity of daptomycin (minimum inhibitory [MIC] and bactericidal [MBC] concentration) against Staphylococcus aureus strains with elevated (2 microg/mL) vancomycin MIC values. A total of 410 contemporary clinical S. aureus isolates (282 from the United States and 128 from Europe) with vancomycin MIC values of 2 microg/mL were tested by reference broth microdilution method. Vancomycin MBC and the presence of vancomycin-heteroresistant population (heterogeneous vancomycin-intermediate S. aureus [hVISA]) were evaluated in 31 randomly selected strains. Overall, 97.3% of isolates were susceptible to daptomycin (MIC(90), 0.5 microg/mL). Daptomycin exhibited potent bactericidal activity with MBC values at the MIC concentration (74.2%) or 1 log(2) dilution above the MIC (25.8%). In contrast, vancomycin MBC was > or = 32 microg/mL in 12.9% of strains tolerance, and 25.8% of strains tested positive for hVISA (AB BIODISK GRD Etest, Solna, Sweden). In conclusion, S. aureus strains with vancomycin MIC of 2 microg/mL showed high rates of hVISA and vancomycin tolerance. Daptomycin retained potent bactericidal activity against S. aureus with decreased susceptibility to vancomycin.

CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria.

CEM-101 is a novel fluoroketolide with reported high potency against diverse groups of Gram-positive (Micrococcus spp., viridans group streptococci, Corynebacterium spp. Listeria monocytogenes, Clostridium spp., etc.) and Gram-negative bacteria (Neisseria gonorrhoeae, Campylobacter jejuni, Helicobacter pylori, Bacteroides fragilis, Shigella spp., etc.), including mycoplasma and ureaplasma, as well as bacteria commonly associated with community-acquired respiratory tract infections and skin and skin structure infections. In this study, CEM-101 and comparator antimicrobials were tested against a collection of very low prevalence aerobic and anaerobic bacteria collected via the SENTRY Antimicrobial Surveillance Program platform. CEM-101 was highly active against all Gram-positive organisms (MIC(50), 0.015 microg/mL) as compared with telithromycin (MIC(50), 0.06 microg/mL), clarithromycin (MIC(50), 0.12 microg/mL), and erythromycin (MIC(50), 0.25 microg/mL). Among Gram-negative pathogens, CEM-101 also displayed a high potency against most strains (MIC(50), 4 microg/mL) but was found to be equivalent or less active when compared with other antimicrobials tested with MIC(50) values ranging from < or =0.12 microg/mL for levofloxacin to 8 microg/mL for telithromycin. Among the strict anaerobic species, CEM-101 activity mirrored that of the aerobic species: high activity against the Gram-positive anaerobes (MIC(50) results ranging from < or =0.03 microg/mL to 0.12 microg/mL) and equivalent or less susceptible against Gram-negative anaerobes. Our in vitro antimicrobial susceptibility results for CEM-101 demonstrate better activity compared with other MLS(B) class agents among a diverse group of uncommonly isolated bacterial pathogens; these results provide an impetus for possible expanded indications during Phase 2 and 3 clinical trials.

Expanded studies of piperacillin/tazobactam formulations: variations among branded product lots and assessment of 46 generic lots.

The experience with analyzing the potency of piperacillin/tazobactam generic formulations by a precise multiorganism in vitro assay was expanded to 46 lots (29 manufacturers, 17 countries). Across all generic lots, the range of activity compared with a reference branded lot (RLOT; Zosyn; Wyeth Pharmaceuticals, Philadelphia, PA) was +10% to -42% (average, -16%). Eight lots of Zosyn were also tested with a range of +7 to -19 (average, only -6%), and the reproducibility (13 replicates) of the RLOT assay was confirmed (+/-3%). This ongoing quality assurance project demonstrated wide activity variations in piperacillin/tazobactam generic lots with a consistent trend toward subpotent performance (-16%) compared with the branded product. Generic substitutions within hospital formularies should consider parameters of in vitro activity, in addition to applied chemical analyses and measures of bioavailability to avoid potential adverse clinical consequences.

Activity of contemporary antifungal agents, including the novel echinocandin anidulafungin, tested against Candida spp., Cryptococcus spp., and Aspergillus spp.: report from the SENTRY Antimicrobial Surveillance Program (2006 to 2007).

Results from the SENTRY international fungal surveillance program for 2006 to 2007 are presented. A total of 1,448 Candida sp., 49 Aspergillus fumigatus, and 33 Cryptococcus neoformans isolates were obtained from infected sterile-site sources in patients on five continents. Reference susceptibility was determined for anidulafungin, caspofungin, 5-flucytosine, fluconazole, itraconazole, posaconazole, voriconazole, and amphotericin B by CLSI methods.

TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens.

BACKGROUND: TR-700, the active component of the oxazolidinone prodrug TR-701, has demonstrated potent activity against numerous Gram-positive species. In this study, single-step mutation frequencies, passaging and the activity of TR-700 were tested against a worldwide collection of linezolid-non-susceptible organisms and matched controls. METHODS: One hundred and twenty linezolid-non-susceptible and 120 controls matched by genus/species, geographic origin, site of infection and time were susceptibility tested by reference broth microdilution methods. Species of isolates were: Enterococcus faecalis (16 linezolid non-susceptible/16 wild-type strains); Enterococcus faecium (55/55), Staphylococcus aureus (8/8); coagulase-negative staphylococci (at least 7 spp., 40/40) and viridans group streptococci (2 spp., 1/1). 23S rRNA target mutations or cfr genes were detected by PCR and sequencing. RESULTS: Among linezolid-non-susceptible strains, the resistance mechanisms were G2576T (109), cfr (4) and unknown (7), with strains originating from Europe, Far East and North and South America. Most strains were multidrug-resistant and cfr isolates exhibited co-resistance to phenicols, clindamycin, linezolid, pleuromutilins and streptogramin B. TR-700 MIC values, regardless of species, were 4-32-fold lower than those of linezolid. TR-700 MIC results were < or = 4, < or = 8 or < or = 16 mg/L for 88%, 96% and > 99% of linezolid-non-susceptible strains, respectively. Spontaneous single-step mutations were undetected (<1.1 x 10(-9)) and 14 day passaging studies produced modest TR-700 MIC elevations compared with linezolid controls. CONCLUSIONS: TR-700 exhibited enhanced activity against linezolid-non-susceptible and wild-type control strains of Gram-positive cocci. A significant number (nearly 90%) of linezolid-non-susceptible strains were inhibited by potentially achievable levels (< or = 4 mg/L) of TR-700. All strains with the emerging cfr-mediated resistance determinant had TR-700 MIC results at < or = 8 mg/L.

In vitro potency evaluations of various piperacillin/tazobactam generic products compared with the contemporary branded (Zosyn, Wyeth) formulation.

Twenty-three generic intravenous piperacillin/tazobactam products were compared for in vitro activity to the branded formulation (Zosyn, Wyeth, Philadelphia, PA) by disk diffusion and incremental broth microdilution assay methods. All but 1 lot demonstrated significantly decreased activity (-5 to -35%), necessitating further investigations regarding the chemical purity, potency, and therapeutic equivalence of these products worldwide. The average -16% activity across all generic lots was equivalent to underdosing piperacillin/tazobactam by 2.6 g daily for serious clinical infections (4.5 g Q6 h).

Antimicrobial resistance and molecular epidemiology of vancomycin-resistant enterococci from North America and Europe: a report from the SENTRY antimicrobial surveillance program.

Increases in prevalence of vancomycin-resistant enterococci (VRE) have been documented globally since its emergence in the 1980s. A SENTRY Antimicrobial Surveillance Program (2003) objective monitored VRE isolates with respect to antimicrobial susceptibility trends, geographic resistance variability, and clonal dissemination. In 2003, VRE isolates from North America (United States and Canada, n = 839, 26 sites) and Europe (n = 56, 10 sites) were susceptibility tested using Clinical and Laboratory Standards Institute (CLSI) reference methodologies. Based on resistance profiles, 155 isolates displayed similar multidrug-resistant (MDR) profiles and were temporally related; these were subsequently submitted for typing by pulsed-field gel electrophoresis (PFGE). Most of the submitted isolates were Enterococcus faecium (91.0%) and Enterococcus faecalis (7.8%). Among VRE, the VanA phenotype was more prevalent in North America (76%) than Europe (40%), and all isolates had elevated resistance rates to other antimicrobial classes including the following: 1) chloramphenicol resistance among E. faecalis being greater in North America than in Europe (28.6% versus 7.1%, respectively) but reversed among E. faecium (0.5% and 15.0%, the latter due to clonal occurrences); 2) ciprofloxacin resistance in North America >99% for both species and in Europe varying from 85.7% to 87.5%; 3) rare occurrences of linezolid resistance in North America (0.8% to 1.8%) due to G2576U ribosomal mutation; 4) higher quinupristin/dalfopristin resistance observed among European E. faecium strains (10.0% versus 0.6%); and 5) higher rifampin resistance rates among European E. faecalis (21.4% versus 5.4%). Thirty-five MDR epidemic clusters were identified by PFGE in 21 North American and 2 European medical centers including the following: 1) VanA (20 sites, 27 clonal occurrences) and VanB (1 site, 2 clonal occurrences); 2) elevated quinupristin/dalfopristin MIC results (not vatD/E, 3 sites); and 3) chloramphenicol resistance (chloramphenicol acetyltransferase-positive strains, 3 sites). The esp gene, part of the putative E. faecium pathogenicity island and a marker for the clonal complex-17 lineage, was detected in 76% of vancomycin-resistant E. faecium. Clonal spread appears to be a dominant factor of MDR VRE dissemination on both continents, and further monitoring is critical to assist in the control of these resistant pathogens.

Tigecycline (GAR-936) activity against Streptococcus gallolyticus (bovis) and viridans group streptococci.

Viridans group streptococci including Streptococcus gallolyticus (formerly S. bovis) represent serious invasive pathogens often associated with endocarditis or sepsis among immunocompromised or cancer patients. Tigecycline (GAR-936), the first clinically studied glycylcycline, has a potent gram-positive activity with a potential treatment option for these streptococcal infections. The studied collection (848 strains) included 100 isolates each of Streptococcus anginosus, Streptococcus constellatus, Streptococcus intermedius, Streptococcus mitis, Streptococcus oralis, Streptococcus salivarius, Streptococcus sanguis, and fewer strains of S. gallolyticus (98 strains) and Streptococcus mutans (50 strains). These strains were isolated from patients on 3 continents in the SENTRY Antimicrobial Surveillance Program and tested for susceptibility and interpreted by Clinical and Laboratory Standards Institute broth microdilution methods and criteria (< or = 0.25 microg/mL for tigecycline per US Food and Drug Administration). Penicillin susceptibility rates for the entire collection varied from 61% (S. sanguis) to 98% (S. constellatus), and macrolide susceptibility was also compromised (49-88%; average, 69%). Tigecycline was active against all isolates tested, in contrast to tetracycline resistance rates of 8-66%, and highest for S. gallolyticus. In conclusion tigecycline was quite active against bacteremic isolates of viridans group streptococci species and S. gallolyticus with an overall MIC90 at < or = 0.06 microg/mL; the highest MIC was only 0.25 microg/mL.