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.     

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.     

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.     

Ceftobiprole Activity against over 60,000 Clinical Bacterial Pathogens Isolated in Europe,Turkey, and Israel from 2005 to 2010

Ceftobiprole medocaril is a newly approved drug in Europe for the treatment of hospital-acquired pneumonia (HAP) (excluding patients with ventilator-associated pneumonia but including ventilated HAP patients) and community-acquired pneumonia in adults. The aim of this study was to evaluate the in vitro antimicrobial activity of ceftobiprole against prevalent Gram-positive and -negative pathogens isolated in Europe, Turkey, and Israel during 2005 through 2010. A total of 60,084 consecutive, nonduplicate isolates from a wide variety of infections were collected from 33 medical centers. Species identification was confirmed, and all isolates were susceptibility tested using reference broth microdilution methods. Ceftobiprole had high activity against methicillin-susceptible Staphylococcus aureus (MSSA) (100.0% susceptible), methicillin-susceptible coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci, and Streptococcus pneumoniae (99.3% susceptible), with MIC₉₀ values of 0.25, 0.12, ≤0.06, and 0.5 μg/ml, respectively. Ceftobiprole was active against methicillin-resistant S. aureus (MRSA) (98.3% susceptible) and methicillin-resistant CoNS, having a MIC₉₀ of 2 μg/ml. Ceftobiprole was active against Enterococcus faecalis (MIC_50/90, 0.5/4 μg/ml) but not against most Enterococcus faecium isolates. Ceftobiprole was very potent against the majority of Enterobacteriaceae (87.3% susceptible), with >80% inhibited at ≤0.12 μg/ml. The potency of ceftobiprole against Pseudomonas aeruginosa (MIC_50/90, 2/>8 μg/ml; 64.6% at MIC values of ≤4 μg/ml) was similar to that of ceftazidime (MIC_50/90, 2/>16 μg/ml; 75.4% susceptible), but limited activity was observed against Acinetobacter spp. and Stenotrophomonas maltophilia. High activity was also observed against all Haemophilus influenzae (MIC₉₀, ≤0.06 μg/ml) and Moraxella catarrhalis (MIC_50/90, ≤0.06/0.25 μg/ml) isolates. Ceftobiprole demonstrated a wide spectrum of antimicrobial activity against this very large longitudinal sample of contemporary pathogens.     

Comparative In Vitro Activities of SMT19969, a New Antimicrobial Agent,against Clostridium difficile and 350 Gram-Positive and Gram-Negative Aerobic and Anaerobic Intestinal Flora Isolates

The comparative in vitro activity of SMT19969, a novel, narrow-spectrum, nonabsorbable agent, was studied against 50 ribotype-defined Clostridium difficile strains, 174 Gram-positive and 136 Gram-negative intestinal anaerobes, and 40 Gram-positive aerobes. SMT19969 was one dilution more active against C. difficile isolates (MIC range, 0.125 to 0.5 μg/ml; MIC₉₀, 0.25 μg/ml), including ribotype 027 strains, than fidaxomicin (range, 0.06 to 1 μg/ml; MIC₉₀, 0.5 μg/ml) and two to six dilutions lower than either vancomycin or metronidazole. SMT19969 and fidaxomicin were generally less active against Gram-negative anaerobes, especially the Bacteroides fragilis group species, than vancomycin and metronidazole, suggesting that SMT19969 has a lesser impact on the normal intestinal microbiota that maintain colonization resistance. SMT19969 showed limited activity against other Gram-positive anaerobes, including Bifidobacteria species, Eggerthella lenta, Finegoldia magna, and Peptostreptococcus anaerobius, with MIC₉₀s of >512, >512, 64, and 64 μg/ml, respectively. Clostridium species showed various levels of susceptibility, with C. innocuum being susceptible (MIC₉₀, 1 μg/ml) and C. ramosum and C. perfringens being nonsusceptible (MIC₉₀, >512 μg/ml). Activity against Lactobacillus spp. (range, 0.06 to >512 μg/ml; MIC₉₀, >512 μg/ml) was comparable to that of fidaxomicin and varied by species and strain. Gram-positive aerobic cocci (Staphylococcus aureus, Enterococcus faecalis, E. faecium, and streptococci) showed high SMT19969 MIC₉₀ values (128 to >512 μg/ml).     

Antimicrobial activity of DC-159a, a new fluoroquinolone, against 1,149 recently collected clinical isolates

The activity of DC-159a, a novel orally administered fluorinated quinolone, was evaluated by reference broth microdilution or agar dilution methods against 1,149 recently collected clinical isolates from five continents. Against pathogens associated with community-acquired respiratory tract infections (CA-RTIs), the MIC₉₀s were 0.12 μg/ml for Streptococcus pneumoniae, 0.015 to 0.03 μg/ml for Haemophilus influenzae, 0.03 μg/ml for Moraxella catarrhalis, and 0.12 μg/ml for beta-hemolytic streptococci. Similarly, DC-159a was potent against various types of staphylococci (MIC₉₀ range, 0.03 to 2 μg/ml), Enterococcus faecalis (MIC₉₀, 4 μg/ml), wild-type isolates of the family Enterobacteriaceae (MIC₉₀ range, 0.06 to 2 μg/ml), wild-type Pseudomonas aeruginosa (MIC₉₀, 2 μg/ml), and Acinetobacter spp. (MIC₉₀, 0.12 μg/ml). Fluoroquinolone-nonsusceptible organism subsets usually had elevated DC-159a MICs, but the MICs were often two- to fourfold lower than those of levofloxacin and moxifloxacin. In conclusion, DC-159a appears to possess a balanced broad spectrum of activity that exceeds the activities of the currently marketed fluoroquinolones, especially against pathogens that cause CA-RTIs.     

Update on Linezolid In Vitro Activity through the Zyvox Annual Appraisal of Potency and Spectrum Program, 2013

Linezolid showed MIC₅₀s and MIC₉₀s of 1 μg/ml (for both) against Staphylococcus aureus. Two S. aureus strains exhibited higher MICs (4 to 8 μg/ml) caused by cfr and/or target site mutations, including the first detection of cfr in Poland. Linezolid (MIC₅₀ and MIC₉₀, 0.5 and 1 μg/ml) had potent MICs against coagulase-negative staphylococci (CoNS). Four CoNS had MICs of 16 to 128 μg/ml due to alterations in 23S rRNA and/or L3/L4. Linezolid inhibited all enterococci and streptococci at ≤2 μg/ml, except for one Enterococcus faecium strain (MIC, 8 μg/ml; G2576T [Escherichia coli numbering] mutation).     

Activity of HMR 3647 Compared to Those of Six Compounds against 235 Strains of Enterococcus faecalis

Agar dilution was used to test the activities of HMR 3647, erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, and quinupristin-dalfopristin against 235 strains of Enterococcus faecalis. HMR 3647 was the most active compound (MICs at which 50 and 90% of the isolates are inhibited [MIC₅₀ and MIC₉₀, respectively] of 0.06 and 4.0 μg/ml, respectively). The MIC₅₀ and MIC₉₀ (with the MIC₅₀ given first and the MIC₉₀ given second; both in micrograms per milliliter) for other compounds were as follows: 4.0 and >32.0 for erythromycin A, 16.0 and >32.0 for azithromycin, 2.0 and >32 for clarithromycin, 32.0 and >32.0 for roxithromycin, 32.0 and >32.0 for clindamycin, and 8.0 and 16.0 for quinupristin-dalfopristin. All compounds were only bacteriostatic.     

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.     

In Vitro Spectrum of Pexiganan Activity When Tested against Pathogens from Diabetic Foot Infections and with Selected Resistance Mechanisms

Pexiganan, a 22-amino-acid synthetic cationic peptide, is currently in phase 3 clinical trials as a topical antimicrobial agent for the treatment of mild infections associated with diabetic foot ulcers. Bacterial isolates from the 2013 SENTRY Antimicrobial Surveillance Program designated as pathogens from diabetic foot infections (DFI) and Gram-negative and -positive pathogens from various infection types that harbored selected resistance mechanisms/phenotypes were tested against pexiganan in reference cation-adjusted Mueller-Hinton broth. The MIC₅₀ and MIC₉₀ against all organisms tested from DFI were 16 and 32 μg/ml, respectively. Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter cloacae, Acinetobacter species, and Pseudomonas aeruginosa MIC values ranged from 8 to 16 μg/ml. Pexiganan MIC values among Staphylococcus aureus (methicillin-resistant S. aureus [MRSA] and methicillin-susceptible S. aureus [MSSA]), beta-hemolytic streptococci, and Enterococcus faecium ranged from 8 to 32 μg/ml. Pexiganan activity was not adversely affected for members of the family Enterobacteriaceae or P. aeruginosa that produced β-lactamases or resistance mechanisms to other commonly used antimicrobial agents. Decreased susceptibility to vancomycin did not affect pexiganan activity against S. aureus or E. faecium. Enterococcus faecalis appears to be intrinsically less susceptible to pexiganan (MIC, 32 to 256 μg/ml). The “all organism” MIC₉₀ of 32 μg/ml for pexiganan in this study was >250-fold below the pexiganan concentration in the cream/delivery vehicle being developed for topical use.     

Multicenter Prospective Observational Study of the Comparative Efficacy and Safety of Vancomycin versus Teicoplanin in Patients with Health Care-Associated Methicillin-Resistant Staphylococcus aureus Bacteremia

The purpose of this study was to compare the clinical efficacy and safety of vancomycin to those of teicoplanin for the treatment of adult patients with health care-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) bacteremia. A multicenter observational study was prospectively conducted in 15 teaching hospitals in Korea between February 2010 and July 2011. Adult patients (≥18 years old) with HA-MRSA bacteremia who were initially treated with vancomycin (VAN) (n = 134) or teicoplanin (TEC) (n = 56) were enrolled. Clinical and microbiological responses and drug-related adverse events were compared between the two treatment groups using univariate and multivariate logistic regression analyses. The vancomycin and teicoplanin MICs were determined by Etest. The MRSA-related mortality, duration of fever, and duration of MRSA bacteremia in the treatment groups were not significantly different. There was no significant difference in the occurrence of drug-related adverse events. Among the 190 MRSA isolates, the VAN MICs ranged from 0.5 to 2 μg/ml (MIC₅₀ and MIC₉₀, 1.5 μg/ml), and the TEC MIC ranged from 0.5 to 8 μg/ml (MIC₅₀, 3 μg/ml; MIC₉₀, 6 μg/ml). In multivariate analyses, the antibiotic type (vancomycin or teicoplanin) was not associated with treatment outcomes. This study indicates that teicoplanin is an effective and safe alternative to vancomycin for the treatment of HA-MRSA bacteremia.     

Linezolid Surveillance Results for the United States: LEADER Surveillance Program 2011

The LEADER surveillance program monitors the in vitro activity of linezolid and comparator agents against Gram-positive bacteria in the United States. In its eighth consecutive year (2011), a total of 60 medical centers from the United States, including seven medical centers specializing in children''s health care contributed a total of 7,303 Gram-positive pathogens. The MIC₉₀ value for Staphylococcus aureus was 2 μg/ml, and for coagulase-negative staphylococci, enterococci, Streptococcus pneumoniae, β-hemolytic streptococci, and viridans group streptococci, the MIC₉₀ was 1 μg/ml. The “all organism” linezolid-resistant and nonsusceptible rate was only 0.19%.     

Characterization of Vancomycin-Resistant Enterococcus faecium Isolates from the United States and Their Susceptibility In Vitro to Dalfopristin-Quinupristin

In the course of clinical studies with the investigational streptogramin antimicrobial dalfopristin-quinupristin, isolates of vancomycin-resistant Enterococcus faecium were referred to our laboratory from across the United States. Seventy-two percent of the strains were of the VanA type, phenotypically and genotypically, while 28% were of the VanB type. High-level resistance to streptomycin or gentamicin was observed in 86 and 81%, respectively, of the VanA strains but in only 69 and 66%, respectively, of the VanB strains. These enterococci were resistant to ampicillin (MIC for 50% of the isolates tested [MIC₅₀] and MIC₉₀, 128 and 256 μg/ml, respectively) and to the other approved agents tested, with the exception of chloramphenicol (MIC₉₀, 8 μg/ml) and novobiocin (MIC₉₀, 1 μg/ml). Considering all of the isolates submitted, dalfopristin-quinupristin inhibited 86.4% of them at concentrations of ≤1 μg/ml and 95.1% of them at ≤2 μg/ml. However, for the data set comprised of only the first isolate submitted for each patient, 94.3% of the strains were inhibited at concentrations of ≤1 μg/ml and 98.9% were inhibited at concentrations of ≤2 μg/ml. Multiple drug resistance was very common among these isolates of vancomycin-resistant E. faecium, while dalfopristin-quinupristin inhibited the majority at concentrations that are likely to be clinically relevant.     

Dalbavancin Activity When Tested against Streptococcus pneumoniae Isolated in Medical Centers on Six Continents (2011 to 2014)

Dalbavancin, a novel lipoglycopeptide, was approved for use in 2014 by regulatory agencies in the United States and Europe for the treatment of skin and skin structure infections. The activity of dalbavancin was also widely assessed by determination of its activity against Streptococcus pneumoniae clinical isolates collected from patients on six continents monitored during two time intervals (2011 to 2013 and 2014). A total of 18,186 pneumococcal isolates were obtained from 49 nations and submitted to a monitoring laboratory as part of the SENTRY Antimicrobial Surveillance Program for reference susceptibility testing. The potency of dalbavancin against S. pneumoniae was consistent across the years that it was monitored, with the MIC₅₀ and MIC₉₀ being 0.015 and 0.03 μg/ml, respectively, and all isolates were inhibited by ≤0.12 μg/ml. The activity of dalbavancin was not adversely influenced by nonsusceptibility to β-lactams (ceftriaxone or penicillin), macrolides, clindamycin, fluoroquinolones, or tetracyclines or multidrug resistance (MDR). Regional variations in dalbavancin activity were not detected, but S. pneumoniae strains isolated in the Asia-Pacific region were more likely to be nonsusceptible to penicillin and ceftriaxone as well as to be MDR than strains isolated in North or South America and Europe. Direct comparisons of potency illustrated that dalbavancin (MIC₅₀ and MIC₉₀, 0.015 and 0.03 μg/ml, respectively) was 16-fold or more active than vancomycin (MIC₅₀, 0.25 μg/ml), linezolid (MIC₅₀, 1 μg/ml), levofloxacin (MIC₅₀, 1 μg/ml), ceftriaxone (MIC₉₀, 1 μg/ml), and penicillin (MIC₉₀, 2 μg/ml). In conclusion, dalbavancin had potent and consistent activity against this contemporary (2011 to 2014) collection of S. pneumoniae isolates.     

Activities of HMR 3004 (RU 64004) and HMR 3647 (RU 66647) Compared to Those of Erythromycin, Azithromycin, Clarithromycin, Roxithromycin, and Eight Other Antimicrobial Agents against Unusual Aerobic and Anaerobic Human and Animal Bite Pathogens Isolated from Skin and Soft Tissue Infections in Humans

The activities of HMR 3004 and HMR 3647 and comparator agents, especially macrolides, were determined by the agar dilution method against 262 aerobic and 120 anaerobic strains isolated from skin and soft tissue infections associated with human and animal bite wounds. HMR 3004 and HMR 3647 were active against almost all aerobic and fastidious facultative isolates (MIC at which 90% of the isolates are inhibited [MIC₉₀], ≤0.5 and 1 μg/ml, respectively) and against all anaerobes [Bacteroides tectum, Porphyromonas macacae (salivosa), Prevotella heparinolytica, Porphyromonas sp., Prevotella sp., and peptostreptococci] at ≤0.25 and ≤0.5 μg/ml, respectively, except Fusobacterium nucleatum (HMR 3004, MIC₉₀ = 16 μg/ml; HMR 3647, MIC₉₀ = 8 μg/ml) and other Fusobacterium species (MIC₉₀, 1 and 2 μg/ml, respectively). In general, HMR 3004 and HMR 3647 were more active than any of the macrolides tested. Azithromycin was more active than clarithromycin against all Pasteurella species, including Pasteurella multocida subsp. multocida, Eikenella corrodens, and Fusobacterium species, while clarithromycin was more active than azithromycin against Corynebacterium species, Weeksella zoohelcum, B. tectum, and P. heparinolytica.     

Telavancin Demonstrates Activity against Methicillin-Resistant Staphylococcus aureus Isolates with Reduced Susceptibility to Vancomycin,Daptomycin, and Linezolid in Broth Microdilution MIC and One-Compartment Pharmacokinetic/Pharmacodynamic Models

Methicillin-resistant Staphylococcus aureus (MRSA) isolates have arisen with reduced susceptibility to several anti-MRSA agents. Telavancin (TLV), a novel anti-MRSA agent, retains low MICs against these organisms. Our objective was to determine the MICs for TLV, daptomycin (DAP), vancomycin (VAN), and linezolid (LZD) against daptomycin-nonsusceptible (DNS) S. aureus, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and linezolid-resistant (LZD^r) S. aureus. We also evaluated these agents against each phenotype in pharmacokinetic/pharmacodynamic (PK/PD) models. Seventy DNS, 100 VISA, 180 hVISA, and 25 LZD^r MRSA isolates were randomly selected from our library and tested to determine their MICs against TLV, DAP, VAN, and LZD via broth microdilution and a Trek panel. Four isolates were randomly selected for 168-h in vitro models to evaluate treatment with TLV at 10 mg/kg of body weight/day, DAP at 10 mg/kg/day, VAN at 1 g every 12 h (q12h), and LZD at 600 mg q12h. The MIC_50/90 for TLV, DAP, VAN, and LZD against 70 DNS S. aureus isolates were 0.06/0.125 μg/ml, 2/4 μg/ml, 1/2 μg/ml, and 2/2 μg/ml, respectively. Against 100 VISA isolates, the MIC_50/90 were 0.06/0.125 μg/ml, 1/1 μg/ml, 4/8 μg/ml, and 1/2 μg/ml, respectively. Against 170 hVISA isolates, the MIC_50/90 were 0.06/0.125 μg/ml, 0.5/1 μg/ml, 1/2 μg/ml, and 1/2 μg/ml, respectively. Against 25 LZD^r isolates, the MIC_50/90 were 0.03/0.06 μg/ml, 1/1 μg/ml, 2/2 μg/ml, and 8/8 μg/ml, respectively. The TLV MIC was >0.125 μg/ml for 10/365 (2.7%) isolates. In PK/PD models, TLV was universally bactericidal at 168 h and statistically superior to all antibiotics against DNS S. aureus strain R2334. These data further establish the potency of TLV against resistant MRSA. The model data demonstrate in vitro bactericidal activity of TLV against hVISA, VISA, DNS S. aureus, and LZD^r S. aureus strains. Further clinical research is warranted.     

Oritavancin Activity against Staphylococcus aureus Causing Invasive Infections in U.S. and European Hospitals: a 5-Year International Surveillance Program

In this study, oritavancin had modal MIC, MIC₅₀, and MIC₉₀ values of 0.03, 0.03, and 0.06 μg/ml, respectively, against Staphylococcus aureus. Similar results (MIC_50/90, 0.03/0.06 μg/ml) were observed against methicillin-resistant and -susceptible isolates and those demonstrating multidrug-resistant (MDR) and non-MDR phenotypes. When oritavancin (MIC_50/90, 0.06/0.12 mg/ml) was tested against S. aureus with elevated MIC values for daptomycin (i.e., 1 to 4 mg/ml) and vancomycin (i.e., 2 mg/ml), it showed MIC results 2-fold higher than those for the more susceptible vancomycin or daptomycin counterparts (MIC_50/90, 0.03/0.06 mg/ml), yet it inhibited these isolates at ≤0.25 mg/ml.     

In Vitro Susceptibilities of Bordetella pertussis and Bordetella parapertussis to Two Ketolides (HMR 3004 and HMR 3647), Four Macrolides (Azithromycin, Clarithromycin, Erythromycin A, and Roxithromycin), and Two Ansamycins (Rifampin and Rifapentine)

When tested by agar dilution on Mueller-Hinton agar supplemented with 5% horse blood, the ketolides HMR 3004 and HMR 3647 were slightly more active (MIC at which 90% of the isolates were inhibited [MIC₉₀], 0.03 μg/ml) against Bordetella pertussis than azithromycin, clarithromycin, erythromycin A, and roxithromycin. Azithromycin (MIC₉₀, 0.06 μg/ml) was the most active compound against B. parapertussis. Rifampin and rifapentine were considerably less active.     

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.     

Antimicrobial Activity of the Pleuromutilin Antibiotic BC-3781 against Bacterial Pathogens Isolated in the SENTRY Antimicrobial Surveillance Program in 2010

BC-3781 is a novel semisynthetic pleuromutilin antibiotic inhibiting bacterial protein synthesis. BC-3781 has completed a phase 2 clinical trial in acute bacterial skin and skin structure infections (ABSSSI). Its antibacterial spectrum additionally covers the predominant pathogens causing community-acquired bacterial pneumonia (CABP). In this study, the antibacterial activity of BC-3781 was evaluated against a contemporary collection of 10,035 bacterial isolates predominately causing ABSSSI and CABP, among other infections, collected within the SENTRY Antimicrobial Surveillance Program worldwide in 2010. BC-3781 exhibited potent activity against organisms commonly isolated from ABSSSI such as Staphylococcus aureus (MIC_50/90, 0.12/0.12 μg/ml; 99.8% inhibited at ≤0.5 μg/ml), beta-hemolytic streptococci (MIC_50/90, 0.03/0.03 μg/ml; 99.3% inhibited at ≤0.5 μg/ml), and coagulase-negative staphylococci (CoNS; MIC_50/90, 0.06/0.12 μg/ml; 97.8% inhibited at ≤1 μg/ml). BC-3781 displayed similar MIC distributions among methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) S. aureus strains. BC-3781 was also active against Enterococcus faecium, with 76.3% of vancomycin-susceptible and 97.0% of vancomycin-resistant isolates being inhibited at BC-3781 concentrations of ≤1 μg/ml. Beta-hemolytic and viridans group streptococci were highly susceptible to BC-3781, with 99.3% and 96.7% of isolates inhibited at ≤0.5 μg/ml, respectively. Further, activity of BC-3781 against Streptococcus pneumoniae (MIC_50/90, 0.12/0.25 μg/ml), Haemophilus influenzae (MIC_50/90, 1/2 μg/ml), and Moraxella catarrhalis (MIC_50/90, 0.12/0.25 μg/ml) was not negatively influenced by β-lactamase production or resistance to other antimicrobial classes tested. In all, BC-3781 displayed a very potent antibacterial profile including the most prevalent bacterial pathogens causing ABSSSI and CABP, thus warranting further clinical development of this antibiotic in these and possibly other indications.