Antimicrobial activity of daptomycin tested against Gram-positive pathogens collected in Europe,Latin America,and selected countries in the Asia-Pacific Region (2011)

We report the results of the international daptomycin surveillance programs for Europe, Latin America, and selected Asia-Pacific nations. A total of 7948 consecutive Gram-positive organisms of clinical significance were collected in 2011 and susceptibility tested against daptomycin and various comparator agents by Clinical and Laboratory Standards Institute (Clinical and Laboratory Standards Institute. M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition Wayne, PA: CLSI. 2012.; Cubicin Package Insert 2012. Cubist Pharmaceuticals, Inc, Lexington, MA. Available at http://www.cubicin.com/pdf/PrescribingInformation.pdf. Accessed January 1, 2012.) broth microdilution methods. The test medium was adjusted to contain physiological levels of calcium (50 mg/L) when testing daptomycin. Daptomycin exhibited potent activity against methicillin-susceptible and -resistant Staphylococcus aureus overall and for each region (MIC_50/90, 0.25–0.5/0.5 μg/mL), with susceptibility rates at 100.0% in Latin America, Australia/New Zealand, and India, and at 99.9% in Europe. The daptomycin MIC_50/90 for coagulase-negative staphylococci was also at 0.25–0.5/0.5 μg/mL, and only 1 isolate was considered nonsusceptible with a MIC value at 2 μg/mL. Daptomycin was also highly active against Enterococcus faecalis (MIC_50/90, 1/1–2 μg/mL) and E. faecium (MIC_50/90, 2/2 μg/mL for both vancomycin-susceptible and -resistant isolates). All enterococcal isolates were susceptible to daptomycin (MIC, ≤4 μg/mL) and tigecycline. Susceptibility to linezolid for E. faecalis was at 100.0%, while for E. faecium regional susceptibility rates were at 100.0% except in Europe (99.0%). Viridans group streptococci (MIC_50/90, 0.25/1 μg/mL) and β-haemolytic streptococci (MIC_50/90, ≤0.06/0.25 μg/mL) continue to be very susceptible to daptomycin. In summary, the results of this investigation document the high potency and wide spectrum of daptomycin when tested against a large resistance-surveillance collection of Gram-positive pathogens and indicate that daptomycin nonsusceptibility remains rare among indicated species after many years of clinical use worldwide.     

In vitro activity of daptomycin against Staphylococcus aureus and vancomycin-resistant Enterococcus faecium isolates associated with skin and soft tissue infections: first results from India

The in vitro activity of daptomycin and selected comparator agents against Staphylococcus aureus and vancomycin-resistant Enterococcus faecium (VREF) isolates recovered from hospitalized patients with skin and soft tissue infection's was evaluated by Clinical and Laboratory Standards Institute broth microdilution method. Daptomycin was the most active agent against both S. aureus (MIC₉₀, 1 μg/mL; 100% susceptible) and VREF (MIC₉₀, 4 μg/mL; 100% susceptible), making it an excellent therapeutic option.     

Update of dalbavancin spectrum and potency in the USA: report from the SENTRY Antimicrobial Surveillance Program (2011)

Dalbavancin (DAL) is an investigational lipoglycopeptide with a prolonged serum half-life allowing once weekly dosing. DAL potency was assessed in the 2011 SENTRY Antimicrobial Surveillance Program among 1555 isolates sampled from all 9 US Census regions. Monitored Gram-positive cocci included Staphylococcus aureus (SA; 1,036/50.4% MRSA), coagulase-negative staphylococci (CoNS; 115), Enterococcus faecalis (25), E. faecium (31), Streptococcus pyogenes (155), Streptococcus agalactiae (153), and viridans group streptococci (VGS; 40). All susceptibility (S) testing used Clinical and Laboratory Standards Institute reference broth microdilution methods and interpretations. DAL (MIC_50/90, 0.06/0.06 μg/mL) was 8- and 16-fold more active than daptomycin (DAP) and vancomycin (VAN), respectively against SA, with MSSA and MRSA having the same MIC₉₀ results. CoNS was slightly more DAL-S (MIC₅₀, ≤0.03μg/mL). The highest staphylococcal DAL MIC was only 0.25 μg/mL. β-Haemolytic streptococci (βHS) and VGS had DAL MIC results ranging from ≤0.03 to 0.25 μg/mL (MIC₉₀, 0.06–0.12 μg/mL), and only enterococci showed elevated DAL MIC results. VanA phenotype–resistant E. faecalis or E. faecium had DAL MIC values at ≥1 μg/mL; VanB strains were DAL-S (MIC, ≤0.25 μg/mL). All cited DAL quantitative values were consistent with earlier surveillance data (2006–2009), without evidence of MIC creep. In conclusion, year 2011 SENTRY Program data for DAL documents sustained potent activity against SA, CoNS, βHS, VGS, and VAN-S enterococci, which averaged 4- to 32-fold greater than VAN, DAP, or linezolid.     

Antimicrobial susceptibility of Gram-positive bacteria isolated from US medical centers: results of the Daptomycin Surveillance Program (2007–2008)

Gram-positive bacterial strains (12?443) consecutively collected during 2007 to 2008 in hospitals located in the United States were tested by reference broth microdilution methods against daptomycin and comparison agents. Methicillin (oxacillin) resistance rates were 55.9% and 74.0% for Staphylococcus aureus and coagulase-negative staphylococci, respectively, and the vancomycin resistance rate among Enterococcus faecalis and Enterococcus faecium were 5.4% and 75.4%, respectively. Daptomycin was very active against all Gram-positive species with MIC₉₀ values of 0.5, 0.25, 0.5, and 2 μg/mL for staphylococci, β-hemolytic streptococci, viridans group streptococci, and enterococci, respectively. Overall, 99.9% of S. aureus, 100.0% of E. faecalis, and 99.5% of E. faecium were susceptible to daptomycin. In addition, daptomycin MIC distributions for S. aureus and enterococci from 2007 to 2008 were very similar to those from 2002 to 2003. In summary, high rates of methicillin-resistant staphylococci and vancomycin-resistant enterococci were observed in US hospitals, but daptomycin remains active against these clinically important Gram-positive organisms with no evidence of potency loss since its approval for clinical use in late 2003.     

Telavancin activity tested against a contemporary collection of Gram-positive pathogens from USA Hospitals (2007-2009)

This study updates the activity of telavancin against Gram-positive pathogens collected from USA hospitals (2007-2009). Telavancin (MIC_50/90, 0.12/0.25 μg/mL) was active against coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus (100% susceptible), for which only daptomycin (MIC_50/90, 0.25/0.5 μg/mL; 99% susceptible) and quinupristin/dalfopristin (MIC_50/90, ≤0.25-0.5/0.5 μg/mL; 99% susceptible) exhibited similar activity. Telavancin (MIC_50/90, 0.25/0.5 μg/mL) inhibited 96.5% of Enterococcus faecalis at the Food and Drug Administration breakpoint (MIC, ≤1 μg/mL), where ampicillin (99.9% susceptible), daptomycin (99.9% susceptible), and linezolid (100% susceptible) also demonstrated high-level coverage. Telavancin inhibited, respectively, 100.0% and 91.7% of VanB-phenotype E. faecalis and E. faecium at ≤1 μg/mL, whereas it was less active against VanA strains. Telavancin was uniformly active against Streptococcus pneumoniae and resistant subsets, and demonstrated good potency (MIC₉₀, 0.06-0.12 μg/mL) against other streptococci, regardless of resistance to other drugs. This assessment reveals potent activity of telavancin against Gram-positive isolates collected from USA hospitals with no evidence of emergence of resistance.     

Efficacy of vancomycin and daptomycin against Staphylococcus aureus isolates collected over 29 years

We investigated vancomycin and daptomycin efficacy for Staphylococcus aureus isolates at our institution by testing 221 methicillin-sensitive and 299 methicillin-resistant isolates recovered from serious infections between 1979 and 2007 using a microdilution method. The MIC₉₀'s for vancomycin remained constant at 2 μg/mL for methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA). For MSSA, the geometric mean vancomycin MICs remained at 1.1 μg/mL but varied from 1.1 to 1.7 for MRSA. Tolerance to vancomycin was seen in 6.5% of MRSA and 10.5% of MSSA. Daptomycin MIC₉₀'s remained at ≤1 μg/mL, and the daptomycin concentration at which 90% of the strains were killed (MBC₉₀) remained at 2 μg/ml. Over 29 years, no trend was detected in vancomycin or daptomycin susceptibilities. Daptomycin had excellent inhibitory and bactericidal activities against all strains throughout the years. Although vancomycin's inhibitory activity was consistent over time, vancomycin-tolerant strains whose presence was not predicted by their MIC were found.     

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 μg/mL; 100.0% susceptible), CoNS (MIC_50/90, 0.12/0.25 μg/mL), vancomycin-susceptible Enterococcus faecalis (MIC_50/90, 0.25/0.5 μg/mL; 100.0% susceptible), Enterococcus faecium (MIC_50/90, 0.06/0.12 μg/mL), Streptococcus pneumoniae (MIC_50/90, ≤0.015/0.03 μg/mL), viridans group Streptococcus spp. (MIC_50/90, 0.03/0.06 μg/mL; 100.0% susceptible), and β-hemolytic Streptococcus spp. (MIC_50/90, 0.03/0.12 μg/mL; 99.8% susceptible). Telavancin had potent activity against vancomycin-nonsusceptible, teicoplanin-susceptible (VanB) E. faecalis (MIC_50/90, 0.25/0.5 μg/mL) and E. faecium (MIC_50/90, 0.06/0.25 μg/mL). These in vitro results show continued activity for telavancin, which represents an important alternative available for treating cSSSI.     

Antimicrobial activity of daptomycin tested against Staphylococcus aureus with vancomycin MIC of 2 μg/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 μg/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 μg/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 (MIC₉₀, 0.5 μg/mL). Daptomycin exhibited potent bactericidal activity with MBC values at the MIC concentration (74.2%) or 1 log₂ dilution above the MIC (25.8%). In contrast, vancomycin MBC was ≥32 μg/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 μg/mL showed high rates of hVISA and vancomycin tolerance. Daptomycin retained potent bactericidal activity against S. aureus with decreased susceptibility to vancomycin.     

Baseline Activity of Telavancin against Gram-Positive Clinical Isolates Responsible for Documented Infections in U.S. Hospitals (2011-2012) as Determined by the Revised Susceptibility Testing Method

Telavancin had MIC₅₀ and MIC₉₀ values of 0.03 and 0.06 μg/ml (100.0% susceptible), respectively, against methicillin-resistant and -susceptible Staphylococcus aureus. Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC_50/90, 0.12/0.12 μg/ml; 100% susceptible) and Enterococcus faecium (MIC_50/90, 0.03/0.06 μg/ml), while higher MIC values were obtained against vancomycin-resistant E. faecium (MIC_50/90, 1/2 μg/ml) and E. faecalis (MIC_50/90, >2/>2 μg/ml). Streptococci showed telavancin modal MIC results of ≤0.015 μg/ml, except against Streptococcus agalactiae (i.e., 0.03 μg/ml). This study reestablishes the telavancin spectrum of activity against isolates recovered from the United States (2011-2012) using the revised broth microdilution method.     

Molecular characterization of vancomycin-resistant Enterococcus spp. clinical isolates recovered from hospitalized patients among several medical institutions in China

The epidemiology and molecular characteristics of vancomycin-resistant enterococci (VRE) from China deserve further investigation. This study reports on the molecular characterization of 101 unique VRE (96 E. faecium and 5 E. faecalis strains) recovered from diverse samples of 12 hospitals in China. MIC results were obtained by reference broth microdilution methods, and vancomycin resistance and virulence genes were screened by polymerase chain reaction. All strains were subjected to pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. E. faecalis exhibited vancomycin and teicoplanin MIC results at ≥256 μg/mL and harbored vanA, except for 1 vanB-carrying strain (MIC, 32 and 1 μg/mL, respectively). This strain had a unique PFGE pattern and was associated with ST410 (clonal complex [CC]4). E. faecium displayed vancomycin MIC values of ≥256 μg/mL with variable results for teicoplanin (1–256 μg/mL). One E. faecium had a teicoplanin MIC value of 1 μg/mL and carried a vanB, while the other 2 strains had teicoplanin MIC values of 4 and 8 μg/mL and harbored vanA. E. faecalis strains were susceptible to ampicillin, and all VRE displayed a susceptible phenotype to daptomycin, linezolid, and tigecycline. Four E. faecalis from a particular hospital were grouped within a single PFGE type and were associated with ST470 and ST471 (CC4), which are double- and triple-locus variants of ST410 and ST4, respectively. Overall, E. faecium displayed genetic variability, but clonal dissemination was noted within and among hospitals. All E. faecium belonged to STs associated with CC17, except for 1 strain (ST362; CC362). A total of 77.2% and 29.7% of all strains carried esp and hyl, respectively. In conclusion, these results show that vanA-carrying isolates predominated in strains from China, and E. faecium strains are usually associated with a common and human-adapted lineage (CC17). Unlike the majority of clinical E. faecalis (CC2 and CC9), strains included in this study showed ST profiles similar to ST4 (CC4), which has been associated with human infections in other Asia-Pacific countries.     

Dalbavancin is active in vitro against biofilms formed by dalbavancin-susceptible enterococci

We tested the in vitro activity of dalbavancin, vancomycin and daptomycin against 83 enterococcal isolates in planktonic and biofilm states. The MIC₉₀ for vancomycin-susceptible Enterococcus faecalis was 0.125 and 4 μg/mL for dalbavancin and daptomycin, respectively. For vancomycin-resistant Enterococcus faecium, the MIC₉₀ was >16 and 2 μg/mL for dalbavancin and daptomycin, respectively. Dalbavancin minimum biofilm inhibitory concentrations (MBICs) for vancomycin-susceptible and -resistant isolates were ≤0.25 and >16 μg/mL, respectively. The daptomycin MBIC₉₀ for all isolates was 4 μg/mL. For E. faecalis and E. faecium, dalbavancin minimum biofilm bactericidal concentrations (MBBCs) for vancomycin-susceptible and -resistant isolates were ≤4 and >16 μg/mL, respectively, whereas vancomycin MBBCs were >128 μg/mL for all isolates, and daptomycin MBBC₉₀ values for both species were 128 μg/mL. In summary, dalbavancin exhibited in vitro activity against all tested isolates of vancomycin-susceptible, but not against vancomycin-resistant enterococci; activity was observed in both the planktonic and biofilm states.     

In Vitro Activities of Tedizolid and Linezolid against Gram-Positive Cocci Associated with Acute Bacterial Skin and Skin Structure Infections and Pneumonia

Tedizolid is a novel, expanded-spectrum oxazolidinone with potent activity against a wide range of Gram-positive pathogens. A total of 425 isolates of Gram-positive bacteria were obtained consecutively from patients with acute bacterial skin and skin structure infections (ABSSSIs) or pneumonia. These isolates included methicillin-susceptible Staphylococcus aureus (MSSA) (n = 100), methicillin-resistant Staphylococcus aureus (MRSA) (n = 100), Streptococcus pyogenes (n = 50), Streptococcus agalactiae (n = 50), Streptococcus anginosus group (n = 75), Enterococcus faecalis (n = 50), and vancomycin-resistant enterococci (VRE) (Enterococcus faecium) (n = 50). The MICs of tedizolid and linezolid were determined by the agar dilution method. Tedizolid exhibited better in vitro activities than linezolid against MSSA (MIC₉₀s, 0.5 versus 2 μg/ml), MRSA (MIC₉₀s, 0.5 versus 2 μg/ml), S. pyogenes (MIC₉₀s, 0.5 versus 2 μg/ml), S. agalactiae (MIC₉₀s, 0.5 versus 2 μg/ml), Streptococcus anginosus group (MIC₉₀s, 0.5 versus 2 μg/ml), E. faecalis (MIC₉₀s, 0.5 versus 2 μg/ml), and VRE (MIC₉₀s, 0.5 versus 2 μg/ml). The tedizolid MICs against E. faecalis (n = 3) and VRE (n = 2) intermediate to linezolid (MICs, 4 μg/ml) were 1 μg/ml and 0.5 μg/ml, respectively. The tedizolid MIC₉₀s against S. anginosus, S. constellatus, and S. intermedius were 0.5, 1, and 0.5 μg/ml, respectively, and the rates of susceptibility based on the U.S. FDA MIC interpretive breakpoints to the isolates were 16%, 28%, and 72%, respectively. Tedizolid exhibited 2- to 4-fold better in vitro activities than linezolid against a variety of Gram-positive cocci associated with ABSSSIs and pneumonia. The lower susceptibilities of tedizolid against isolates of S. anginosus and S. constellatus than against those of S. intermedius in Taiwan were noted.     

Antimicrobial Activity of Quinupristin-Dalfopristin (RP 59500, Synercid®) Tested against Over 28,000 Recent Clinical Isolates from 200 Medical Centers in the United States and Canada

A total of 200 medical center laboratories in the USA and Canada contributed results of testing quinupristin-dalfopristin, a streptogramin combination (formerly RP 59500 or Synercid®), against 28,029 Gram-positive cocci. Standardized tests [disk diffusion, broth microdilution, Etest (AB BIODISK, Solna, Sweden)] were utilized and validated by concurrent quality control tests. Remarkable agreement was obtained between test method results for characterizing the collection by the important emerging resistances: 1) oxacillin resistance among Staphylococcus aureus (41.0 to 43.7%); 2) vancomycin resistance among Enterococcus faecium (50.0 to 52.0%); and 3) the penicillin nonsusceptible rate for pneumococci (31.1% overall, with 10.6% at MICs of ≥2 μg/mL). The quinupristin-dalfopristin MIC₉₀ for oxacillin-susceptible and -resistant S. aureus was 0.5 μg/mL and 1 μg/mL, respectively. The quinupristin-dalfopristin MIC₉₀ for vancomycin-resistant E. faecium was 1 μg/mL, and only 0.2% of isolates were resistant. Other Enterococcus species were generally not susceptible to the streptogramin combination but were usually inhibited by ampicillin (86 to 97% susceptible; MIC₅₀, 1.0 μg/mL) or vancomycin (86 to 95%; MIC₅₀, 1.0 μg/mL). Among all tested enterococci, the rate of vancomycin resistance was 16.2%. The quinupristin-dalfopristin MIC₉₀ (0.75 μg/mL) for 4,626 tested Streptococcus pneumoniae strains was not influenced by the penicillin or macrolide susceptibility patterns. When five regions in the USA and Canada were analyzed for significant streptogramin and other antimicrobial spectrum differences, only the Farwest region had lower numbers of streptogramin-susceptible E. faecium. Canadian strains were generally more susceptible to all drugs except chloramphenicol and doxycycline when tested against E. faecalis (73% and 89% susceptible, respectively). The U.S. Southeast region had S. pneumoniae strains less susceptible to macrolides (73%) but had more susceptibility among E. faecium isolates tested against vancomycin and ampicillin. The Northeast region of the USA had the greatest rate of vancomycin resistance among enterococci. Strains retested by the monitor because of quinupristin-dalfopristin resistance (MICs, ≥4 μg/mL) were generally not confirmed (2.2% validation), and only 0.2% of E. faecium isolates were identified as truly resistant. The most common errors were: 1) species misidentification (28.0%); 2) incorrect susceptibility results (65.6%); and 3) mixed cultures (4.3%) tested by participants. Overall, quinupristin-dalfopristin was consistently active (≥90% susceptible) against major Gram-positive pathogens in North America, regardless of resistance patterns to other drug classes and geographic location of their isolation.     

In vitro antimicrobial activity and MIC quality control guidelines of RPR 106972 (RPR 112808/RPR106950): A novel orally administered streptogramin combination

RPR 106972 is a novel oral streptogramin combination with reported therapeutic potency against Gram-positive and certain respiratory tract pathogens. MICs for RPR 106972, quinupristin/dalfopristin, and seven comparison drugs were determined by the reference methods against 337 strains selected to define spectrum and potency. RPR 106972 demonstrated antimicrobial activity against oxacillin-susceptible and -resistant Staphylococcus aureus (MIC ranges of 0.12 to 2 μg/ml and 0.5 to 2 μg/ml, respectively), and coagulase-negative staphylococci were also inhibited by RPR 106972 (MIC_90′, ≤ 0.5 μg/ml) and quinupristin/dalfopristin (MIC_90′, ≤ 0.25 μg/ml). Against all streptococcal strains tested (including penicillin-resistant pneumococcus), RPR 106972 was highly active with MIC results at ≤ 1 μg/ml. RPR 106972 inhibited Corynebacterium jeikeium (MIC_90′ 0.5 μg/ml), Moraxella catarrhalis (MIC_90′, 0.25 μg/ml), and some Haemophilus influenzae (MIC_50′, 2 μg/ml). RPR 106972 and quinupristin/dalfopristin demonstrated little activity against Enterococcus faecalis (MIC₉₀s, 4 to 32 μg/ml) as compared to Enterococcus faecium (MIC₉₀s, 0.5 to 1 μg/ml) and other Enterococcus ssp. (MIC₉₀s, 1 μg/ml). Studies to establish MIC quality-control guidelines indicated the following ranges: for E. faecalis ATCC 29212, 0.5 to 4 μg/ml; for S. aureus ATCC 29213, 0.25 to 1 μg/ml; and for Streptococcus pneumoniae ATCC 49619, 0.06 to 0.5 μg/ml. The results of this study indicate that the in vitro activity of RPR 106972 against Gram-positive bacteria and selected Gram-negative respiratory organisms is promising and warrants additional studies of pharmacokinetics, and in vivo infection model dynamics.     

Telavancin In Vitro Activity against a Collection of Methicillin-Resistant Staphylococcus aureus Isolates,Including Resistant Subsets,from the United States

Telavancin had MIC₅₀, MIC₉₀, and MIC₁₀₀ values of 0.03, 0.06, and 0.12 μg/ml, respectively, against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and non-multidrug-resistant (non-MDR) and MDR subsets. MRSA with elevated MIC values for vancomycin (2 to 4 μg/ml) or daptomycin (1 to 2 μg/ml) had telavancin MIC₅₀ (0.06 μg/ml) values 2-fold higher than those of isolates with lower MIC results (MIC₅₀, 0.03 μg/ml). However, telavancin had MIC₉₀ and MIC₁₀₀ results of 0.06 and 0.12 μg/ml (100% susceptible), respectively, regardless of the MRSA subset.     

Antimicrobial activity of ceftaroline combined with avibactam tested against bacterial organisms isolated from acute bacterial skin and skin structure infections in United States medical centers (2010–2012)

Ceftaroline-avibactam and comparator agents were tested against clinical isolates collected at 174 medical centers from patients with acute bacterial skin and skin structure infection (ABSSSI) in the United States (USA) during 2010–2012. Isolates were processed at the medical centers and forwarded to a central laboratory for confirmatory identification and susceptibility testing using reference methods. Ceftaroline-avibactam was highly active against methicillin-susceptible (MIC_50/90, 0.25/0.25 μg/mL) and methicillin-resistant Staphylococcus aureus (MRSA; MIC_50/90, 0.5/1 μg/mL). Vancomycin, tigecycline, daptomycin, and linezolid were also active (>99.9% susceptible) against MRSA (51.4% of S. aureus), but activity against MRSA was decreased for erythromycin, levofloxacin, and clindamycin (10.8, 40.3, and 81.9% susceptible, respectively). β-Hemolytic streptococci were highly susceptible to β-lactam antimicrobials, including ceftaroline-avibactam (MIC_50/90, ≤0.03/≤0.03 μg/mL). Ceftaroline-avibactam was very active against Escherichia coli and Klebsiella pneumoniae (MIC_50/90, 0.03/0.06 and 0.06/0.25 μg/mL, respectively) including extended-spectrum β-lactamase (ESBL) screen–positive phenotypes (MIC_50/90, 0.06/0.12 and 0.12/1 μg/mL, respectively). Susceptibility of ESBL screen–positive E. coli and K. pneumoniae was 100.0/97.9% for tigecycline and 99.2/56.1% for meropenem, respectively. Susceptibility to other agents for ESBL screen–positive E. coli and K. pneumoniae was decreased. Ceftaroline-avibactam exhibited a broad-spectrum of in vitro activity against isolates from patients in the USA with ABSSSI including MRSA, β-hemolytic streptococci, E. coli, and K. pneumoniae as well as ESBL screen–positive phenotype isolates and merits further study in clinical indications where these resistant organisms may be a concern.     

Antimicrobial Activity of Ceftaroline Tested against Staphylococci with Reduced Susceptibility to Linezolid,Daptomycin, or Vancomycin from U.S. Hospitals, 2008 to 2011

Vancomycin, linezolid, and daptomycin are very active against staphylococci, but isolates with decreased susceptibility to these antimicrobial agents are isolated sporadically. A total of 19,350 Staphylococcus aureus isolates (51% methicillin resistant [MRSA]) and 3,270 coagulase-negative staphylococci (CoNS) were collected consecutively from 82 U.S. medical centers from January 2008 to December 2011 and tested for susceptibility against ceftaroline and comparator agents by the reference broth microdilution method. Among S. aureus strains, 14 isolates (0.07%) exhibited decreased susceptibility to linezolid (MIC, ≥8 μg/ml), 18 (0.09%) to daptomycin (MIC, ≥2 μg/ml), and 369 (1.9%) to vancomycin (MIC, ≥2 μg/ml; 368 isolates at 2 μg/ml and 1 at 4 μg/ml). Fifty-one (1.6%) CoNS were linezolid resistant (MIC, ≥8 μg/ml), and four (0.12%) were daptomycin nonsusceptible (MIC, ≥2 μg/ml). Ceftaroline was very active against S. aureus overall (MIC_50/90, 0.5/1 μg/ml; 98.5% susceptible), including MRSA (MIC_50/90, 0.5/1 μg/ml; 97.2% susceptible). All daptomycin-nonsusceptible and 85.7% of linezolid-resistant S. aureus isolates were susceptible to ceftaroline. Against S. aureus isolates with a vancomycin MIC of ≥2 μg/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively. CoNS strains were susceptible to ceftaroline (MIC_50/90, 0.25/0.5 μg/ml; 99.1% inhibited at ≤1 μg/ml), including methicillin-resistant (MIC_50/90, 0.25/0.5 μg/ml), linezolid-resistant (MIC_50/90, 0.5/0.5 μg/ml), and daptomycin-nonsusceptible (4 isolates; MIC range, 0.03 to 0.12 μg/ml) strains. In conclusion, ceftaroline demonstrated potent in vitro activity against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin, and it may represent a valuable treatment option for infections caused by these multidrug-resistant staphylococci.     

Ceftaroline activity against organisms isolated from respiratory tract infections in USA hospitals: results from the AWARE program, 2009–2011

The Assessing Worldwide Antimicrobial Resistance Evaluation Program monitors the activity of ceftaroline and comparator agents tested against pathogens causing either respiratory or skin and soft tissue infections. A total of 7733 isolates from patients in 80 medical centers across the United States (USA) identified as respiratory tract pathogens by the infection type and/or specimen site recorded by the submitting laboratory during 2009–2011 were evaluated. There were 3360 isolates of Streptococcus pneumoniae, 1799 Haemophilus influenzae, 1087 Staphylococcus aureus, 678 Moraxella catarrhalis, 459 Klebsiella pneumoniae, 223 Escherichia coli, and 127 Klebsiella oxytoca. Annual penicillin resistance among S. pneumoniae ranged from 21.9 to 24.3%. All S. pneumoniae strains were inhibited at a ceftaroline MIC of ≤0.5 μg/mL with 100.0% of isolates categorized as susceptible. Ceftaroline was 16-fold more active than ceftriaxone and 32-fold more active than amoxicillin-clavulanate against penicillin-resistant pneumococci. Only 49.8% of the penicillin-resistant isolates were susceptible to ceftriaxone. There were a total of 1087 S. aureus (48.9% methicillin-resistant S. aureus [MRSA]) isolates, and the yearly MRSA rate ranged from 47.9 to 49.7%. The ceftaroline MIC_50/90 for S. aureus was at 0.25/1 μg/mL; 98.2% susceptible and no resistant strains (≥4 μg/mL). Ceftaroline activity against methicillin-susceptible S. aureus (MSSA) isolates (MIC₅₀ and MIC₉₀, 0.25 and 0.25 μg/mL, respectively; 100% susceptible) was 2- to 4-fold greater than for MRSA (MIC_50/90, 0.5/1 μg/mL; 96.2% susceptible). The ceftriaxone MIC₉₀ for MSSA was 4 μg/mL. Ceftaroline was active against H. influenzae (MIC_50/90 ≤0.015/0.03 μg/mL; 100.0% susceptible) and against M. catarrhalis (MIC_50/90, 0.06/0.12 μg/mL). Ceftaroline was active against non–extended spectrum β-lactamase (ESBL) phenotype strains of Enterobacteriaceae but not against ESBL-positive phenotype strains. In summary, ceftaroline was highly active against a large collection of bacterial pathogens isolated from patients with respiratory tract infections in the USA during 2009 through 2011.     

A correlation between reduced susceptibilities to vancomycin and daptomycin among the MRSA isolates selected in mutant selection window of both vancomycin and daptomycin

Guidelines for the treatment of MRSA infection, recently published by the IDSA and JSC, recommend daptomycin for sepsis and skin and soft tissue infections comparably to or more strongly than vancomycin. Meanwhile MIC creeping with an increased isolation frequency of MRSA isolates with vancomycin MIC of 2 μg/mL has become a problem. In the present study, the MIC creeping rate of MRSA strains in the Tohoku district, Japan in 2012 was 13%, a significantly higher value than 3.3% in 2008 (P < 0.01). Of these isolates, the MIC and mutant prevention concentration (MPC) values of daptomycin and vancomycin were determined for 30 clinical isolates of MRSA in 2012. The MIC₅₀/MIC₈₀ values of daptomycin and vancomycin were 0.125/0.5 μg/mL and 0.125/1 μg/mL, respectively. The MPC₅₀/MPC₈₀ values of daptomycin and vancomycin were both 32/64 μg/mL. In the present study, the mutant selection window (MSW) of daptomycin and vancomycin was ≥64 MIC. Of strains that selected in the MSW, daptomycin non-susceptible isolates accounted for 70.0%, while MRSA with vancomycin MIC of 2 μg/mL accounted for 26.7%. On the other hand, 50% of the strains that selected in the vancomycin MSW were daptomycin non-susceptible strain. The detection rate of MRSA with vancomycin MIC of 2 μg/mL that selected in the daptomycin MSW was 36.7%. These results showed that MRSA with vancomycin MIC of 2 μg/mL and daptomycin non-susceptible isolates were selected by exposure to both antibiotics. Therefore, though vancomycin is frequently used for treatment of MRSA infection, both antibiotics should be selected as a first-line drug appropriately.     

Activity of Daptomycin or Linezolid in Combination with Rifampin or Gentamicin against Biofilm-Forming Enterococcus faecalis or E. faecium in an In Vitro Pharmacodynamic Model Using Simulated Endocardial Vegetations and an In Vivo Survival Assay Using Galleria mellonella Larvae

Enterococci are the third most frequent cause of infective endocarditis. A high-inoculum stationary-phase in vitro pharmacodynamic model with simulated endocardial vegetations was used to simulate the human pharmacokinetics of daptomycin at 6 or 10 mg/kg of body weight/day or linezolid at 600 mg every 12 h (q12h), alone or in combination with gentamicin at 1.3 mg/kg q12h or rifampin at 300 mg q8h or 900 mg q24h. Biofilm-forming, vancomycin-susceptible Enterococcus faecalis and vancomycin-resistant Enterococcus faecium (vancomycin-resistant enterococcus [VRE]) strains were tested. At 24, 48, and 72 h, all daptomycin-containing regimens demonstrated significantly more activity (decline in CFU/g) than any linezolid-containing regimen against biofilm-forming E. faecalis. The addition of gentamicin to daptomycin (at 6 or 10 mg/kg) in the first 24 h significantly improved bactericidal activity. In contrast, the addition of rifampin delayed the bactericidal activity of daptomycin against E. faecalis, and the addition of rifampin antagonized the activities of all regimens against VRE at 24 h. Also, against VRE, the addition of gentamicin to linezolid at 72 h improved activity and was bactericidal. Rifampin significantly antagonized the activity of linezolid against VRE at 72 h. In in vivo Galleria mellonella survival assays, linezolid and daptomycin improved survival. Daptomycin at 10 mg/kg improved survival significantly over that with linezolid against E. faecalis. The addition of gentamicin improved the efficacy of daptomycin against E. faecalis and those of linezolid and daptomycin against VRE. We conclude that in enterococcal infection models, daptomycin has more activity than linezolid alone. Against biofilm-forming E. faecalis, the addition of gentamicin in the first 24 h causes the most rapid decline in CFU/g. Of interest, the addition of rifampin decreased the activity of daptomycin against both E. faecalis and VRE.