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.     

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.     

Update on the telavancin activity tested against European staphylococcal clinical isolates (2009-2010)

This study evaluated telavancin activity against 3868 Staphylococcus aureus and 1003 coagulase-negative staphylococci (CoNS) collected from 33 European hospitals (2009-2010). Studies of telavancin potency included analysis of strains with decreased susceptibility to glycopeptides. Telavancin (MIC_50/90, 0.12/0.25 μg/mL) showed high activity against S. aureus and CoNS, regardless of the stratification analysis performed (year sampled, infection source, or methicillin susceptibility). In addition, telavancin (MIC_50/90, 0.25/0.5 μg/mL) retained activity against S. aureus isolates with higher vancomycin (MIC, 2 μg/mL) or teicoplanin (MIC, 2-8 μg/mL) MIC results. Overall, telavancin exhibited higher potency (at least 2-fold greater) than tested comparators (vancomycin, daptomycin, and linezolid) against European staphylococci. Alongside published clinical data, the telavancin in vitro activity observed against these pathogens supports this drug as an option for treating S. aureus infections in Europe, including those infections caused by strains with decreased susceptibility to vancomycin and/or teicoplanin.     

Surveillance of JNJ-Q2 activity tested against Staphylococcus aureus and beta-hemolytic streptococci as a component of the 2010 SENTRY Antimicrobial Surveillance Program

JNJ-Q2 is a novel broad-spectrum bactericidal fluorinated 4-quinolone with potent activity against Gram-positive and -negative pathogens with a balanced potency against both DNA gyrase and topoisomerase IV targets. JNJ-Q2 is in clinical development for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) and community-acquired bacterial pneumonia. With the use of reference broth microdilution methods in a central reference laboratory design, MIC values were obtained for 3650 pathogens (44.4% were from patients diagnosed with ABSSSI) obtained during the 2010 SENTRY antimicrobial surveillance program. Isolates were collected from patients in 96 medical centers in 26 countries in North America, Europe, Latin America, and Asia Pacific. JNJ-Q2 demonstrated good activity overall (MIC(50/90), 0.015/0.5 μg/mL) and against 3081 Staphylococcus aureus with >95% of the isolates inhibited at a MIC of ≤0.5 μg/mL; against 1410 levofloxacin-resistant Staphylococcus aureus isolates, >90% were inhibited by MIC ≤0.5 μg/mL. All isolates were inhibited at a MIC of ≤2 μg/mL. In addition, JNJ-Q2 demonstrated excellent activity (MIC(90), 0.015 μg/mL) against 569 isolates of beta-hemolytic streptococci (including 278 Streptococcus pyogenes and 161 Streptococcus agalactiae). JNJ-Q2 was the most potent fluoroquinolone tested overall and against all pathogens when compared directly to moxifloxacin, levofloxacin, and ciprofloxacin.     

Worldwide appraisal and update (2010) of telavancin activity tested against a collection of Gram-positive clinical pathogens from five continents

A total of 15,480 Gram-positive pathogens were collected from 89 sites in the United States, Europe, the Asia-Pacific region, and Latin America in 2010. Telavancin was active against indicated Staphylococcus aureus (MIC(50/90), 0.12/0.25 μg/ml), vancomycin-susceptible Enterococcus faecalis (MIC(50/90), 0.5/0.5 μg/ml), and beta-hemolytic (MIC(50/90), 0.06/0.12 μg/ml) and viridans group streptococcus (MIC(50/90), 0.03/0.06 μg/ml) isolates. These MIC results showed potency for telavancin equal to or greater than that of comparators. These in vitro data confirm a continued potent activity of telavancin when tested against contemporary Gram-positive clinical isolates.     

In vitro activity of dalbavancin and telavancin against staphylococci and streptococci isolated from patients in Canadian hospitals: results of the CANWARD 2007-2009 study

Two novel lipoglycopeptides, dalbavancin and telavancin, and relevant comparative agents were tested for in vitro activity against clinical isolates of staphylococci and streptococci collected in the cross-Canada surveillance study, CANWARD, in 2007-2009. The rank order of potency (based on MIC(90) [μg/mL], i.e., the concentration of antimicrobial agent required to inhibit the growth of 90% of isolates tested) of glycopeptides against both Staphylococcus aureus and Staphylococcus epidermidis was dalbavancin (0.06 μg/mL) >telavancin (0.5 μg/mL) > vancomycin (1-2 μg/mL); concurrent susceptibility or resistance to oxacillin in staphylococci did not affect potency of glycopeptides. Dalbavancin and telavancin also demonstrated potent activity against Streptococcus pneumoniae, including penicillin-resistant isolates (MIC(90), ≤ 0.03 μg/mL; ≤ 0.06 μg/mL), and Streptococcus pyogenes (≤ 0.03 μg/mL; 0.06 μg/mL). Based on their robust in vitro activities, dalbavancin and telavancin have the potential to treat Gram-positive infections caused by methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae.     

Antimicrobial resistance trends among 5608 clinical Gram-positive isolates in China: results from the Gram-Positive Cocci Resistance Surveillance program (2005-2010)

A total of 5608 clinical isolates of Gram-positive bacteria were collected from 12 teaching hospitals across China from 2005 to 2010. The minimum inhibitory concentrations (MICs) of 19 antimicrobial agents were determined by the agar dilution method at the central laboratory. Overall, the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRSCoN) were 46.8% and 81.5%, respectively. Isolates from inpatients exhibited a higher rate of MRSA than that from outpatients (52.3% versus 26.2%, P < 0.001). The prevalence of MRSA in respiratory infections (67.5%) was higher than in other sources of infections (P < 0.001). A shift in vancomycin MICs from <0.5 to 1.0 μg/mL was observed during the 6-year period. In 2005, 70.5% of S. aureus isolates were inhibited at the vancomycin MIC of 0.5 μg/mL, while in 2010, 89% of the isolates were inhibited at the vancomycin MIC of 1 μg/mL. With the use of penicillin oral breakpoints, penicillin-resistant Streptococcus pneumoniae (PRSP) increased from 28.6% in 2005 to 59.5% in 2010 and varied among different age groups, with an average rate of 70.6% for children under 5 years old. Importantly, an obvious penicillin MIC right shift was observed from 0.032 to 4 μg/mL during the study period. Serotyping for the isolates from 2005 and 2010 indicated that the high rate of PRSP could be due to the increased prevalence of serogroup 19. The prevalence of vancomycin-resistant enterococci (VRE) increased from 0 in 2005 to 4.9% in 2010. Of the 27 VRE isolates, vanA gene was the most prevalent gene. During the study period, 97.9-100% of different species tested were susceptible to teicoplanin. Linezolid and tigecycline showed potent activities, and no resistant isolate was identified. In conclusion, although the prevalence of MRSA and MRSCoN remained stable over the 6 years, a sharp increase in the prevalence of PRSP was identified. In addition, MIC shifts, including the MICs of penicillin against S. pneumoniae and vancomycin against S. aureus, were observed. Continuous surveillance is warranted to evaluate the resistance trend of clinically important Gram-positive organisms in the future.     

In vitro activity of ceftobiprole against frequently encountered aerobic and facultative Gram-positive and Gram-negative bacterial pathogens: results of the CANWARD 2007-2009 study

The in vitro activity of ceftobiprole was evaluated against 15 011 clinical isolates obtained from patients in Canadian hospitals between 2007 and 2009. All Staphylococcus aureus were susceptible to ceftobiprole (MIC(90)'s for methicillin-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus of ≤ 1 μg/mL and 2 μg/mL, respectively). Ceftobiprole was active against penicillin-susceptible Streptococcus pneumoniae (MIC(90), ≤ 0.06 μg/mL), penicillin-resistant Streptococcus pneumoniae (MIC(90), 0.5 μg/mL), Streptococcus pyogenes (MIC(90), ≤ 0.06 μg/mL), Staphylococcus epidermidis (MIC(90), ≤ 1 μg/mL), and Enterococcus faecalis (MIC(90), ≤ 1 μg/mL). Over 90% of Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter freundii, Proteus mirabilis, and Serratia marcescens isolates were inhibited by a ceftobiprole concentration of ≤ 1 μg/mL. Ceftobiprole was not active against extended-spectrum β-lactamase-producing Escherichia coli and K. pneumoniae. The in vitro activity of ceftobiprole versus Pseudomonas aeruginosa was similar to that of cefepime (MIC(90), 16 μg/mL). The broad spectrum of activity by ceftobiprole would support further study of this agent in the treatment of hospital-acquired infections.     

Antimicrobial activity of daptomycin in comparison to glycopeptides and other antimicrobials when tested against numerous species of coagulase-negative Staphylococcus

Coagulase-negative Staphylococcus spp. (CoNS) represent a major cause of bloodstream infections, especially in patients with prosthetic devices and intravenous catheters. We evaluated the activity of daptomycin in comparison to vancomycin and teicoplanin against a large collection of 22,024 CoNS isolates causing clinically significant infections from 283 medical centers over 9 years (2002-2010) and tested for susceptibility by broth microdilution methods against daptomycin and numerous comparators. Overall, daptomycin (MIC(50/90), 0.25/0.5 μg/mL) inhibited 99.8% of CoNS at the susceptible breakpoint of ≤1 μg/mL and was 4- to 16-fold more active than vancomycin (MIC(50/90), 1/2 μg/mL; >99.9% susceptible). All species showed ≥99.6% susceptibility to daptomycin, except Staphylococcus auricularis (95.1%), S. capitis (99.0%), S. warneri (98.8%), and S. sciuri. S.sciuri represented only 0.2% of the collection (46 strains) and exhibited decreased susceptibility to daptomycin (MIC(50/90), 1/2 μg/mL; 71.7% susceptible). In contrast, S. sciuri exhibited high susceptibility to vancomycin and teicoplanin (highest MIC at 2 μg/mL for both drugs). In summary, daptomycin exhibited species-specific activity among CoNS, especially versus S. sciuri. No correlation between decreased susceptibility to daptomycin and the glycopeptides tested was observed.     

Comparative surveillance study of telavancin activity against recently collected gram-positive clinical isolates from across the United States

Telavancin is an investigational, rapidly bactericidal lipoglycopeptide antibiotic that is being developed to treat serious infections caused by gram-positive bacteria. A baseline prospective surveillance study was conducted to assess telavancin activity, in comparison with other agents, against contemporary clinical isolates collected from 2004 to 2005 from across the United States. Nearly 4,000 isolates were collected, including staphylococci, enterococci, and streptococci (pneumococci, beta-hemolytic, and viridans). Telavancin had potent activity against Staphylococcus aureus and coagulase-negative staphylococci (MIC range, 0.03 to 1.0 microg/ml), independent of resistance to methicillin or to multiple agents. Telavancin activity was particularly potent against all streptococcal groups (MIC(90)s, 0.03 to 0.12 microg/ml). Telavancin had excellent activity against vancomycin-susceptible enterococci (MIC(90), 1 microg/ml) and was active against VanB strains of vancomycin-resistant enterococci (MIC(90), 2 microg/ml) but less active against VanA strains (MIC(90), 8 to 16 microg/ml). Telavancin also demonstrated activity against vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus strains (MICs, 0.5 microg/ml to 1.0 microg/ml and 1.0 microg/ml to 4.0 microg/ml, respectively). These data may support the efficacy of telavancin for treatment of serious infections with a wide range of gram-positive organisms.     

European glycopeptide susceptibility survey of Gram-positive bacteria for 1995

In the European Glycopeptide Susceptibility Survey 7078 Gram-positive isolates collected in 1995 from 70 centers in 9 countries of Western Europe were examined, using a standardized, quantitative susceptibility testing method. Of the 7078 isolates, 6824 (96.4%) were tested by the national coordinating centers. Teicoplanin (mode MIC 0.5 μg/mL) was generally twice as active as vancomycin (mode MIC 1 μg/mL) against Staphylococcus aureus (n = 2852). All isolates were susceptible to vancomycin (MIC ≤4 μg/mL) and all but four to teicoplanin (MIC ≤8 μg/mL); these four isolates were of intermediate susceptibility (MIC 16 μg/mL). With coagulase-negative staphylococci (n = 1444), the distribution of MIC of teicoplanin was wider than for vancomycin. Two and two-tenths percent of coagulase-negative staphylococci excluding Staphylococcus haemolyticus required 16 μg/mL teicoplanin for inhibition (intermediate) and 0.4% ≥32 μg/mL (resistant). Among isolates of S. haemolyticus, 4.4% were of intermediate susceptibility (MIC 16 μg/mL) and 3.3% were resistant (MIC ≥32 μg/mL) to teicoplanin. However, this species represented only 6.3% of the isolates of coagulase-negative Staphylococcus spp. Generally, teicoplanin (mode MIC ≤0.12 μg/mL) was four to eight times more active than vancomycin (mode MIC ≤0.5 μg/mL) against the 770 streptococcal isolates. Glycopeptide-susceptible Enterococcus spp. (n = 1695) were generally four times more susceptible to teicoplanin (mode MIC 0.25 μg/mL) than to vancomycin (mode MIC 1 μg/mL). Combined vancomycin and teicoplanin (VanA phenotype) resistance was observed more frequently (9.3%) in isolates of Enterococcus faecium than in Enterococcus faecalis (0.8%). Four isolates of unspeciated enterococci (1.4%) also expressed this resistance phenotype. Four isolates of E. faecium and four of E. faecalis expressed the VanB-type (low-level, vancomycin only) resistance. Spain was the only country not to submit resistant E. faecium strains while resistant E. faecalis isolates came only from Spain and Italy.     

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.     

Activity of JNJ-Q2 against Staphylococcus aureus isolated from patients with acute bacterial skin and skin-structure infection obtained during a Phase 2 clinical trial

JNJ-Q2, a fluorinated 4-quinolone, was very active against both methicillin-susceptible Staphylococcus aureus (n = 42; MIC(50/90), 0.008/0.12 μg/mL) and methicillin-resistant S. aureus (n = 69; MIC(50/90), 0.12/0.12 μg/mL) obtained from patients with acute bacterial skin and skin-structure infection (ABSSSI). Overall moxifloxacin and levofloxacin resistance rates were 31.5% and 46.9%, respectively. These favorable results support the continued clinical development of JNJ-Q2 to treat ABSSSI.     

Comparison of the Sensititre YeastOne colorimetric antifungal panel with CLSI microdilution for antifungal susceptibility testing of the echinocandins against Candida spp., using new clinical breakpoints and epidemiological cutoff values

A commercially prepared dried colorimetric microdilution panel (Sensititre Yeast One, TREK Diagnostic Systems, Cleveland, OH, USA) was compared in 3 different laboratories with the Clinical and Laboratory Standards Institute (CLSI) reference microdilution method by testing 2 quality control strains, 25 reproducibility strains, and 404 isolates of Candida spp. against anidulafungin, caspofungin, and micafungin. Reference CLSI BMD MIC end points and YeastOne colorimetric end points were read after 24 h of incubation. Excellent (100%) essential agreement (within 2 dilutions) between the reference and colorimetric MICs was observed. Categorical agreement (CA) between the 2 methods was assessed using the new species-specific clinical breakpoints (CBPs): susceptible (S), ≤0.25 μg/mL; intermediate (I), 0.5 μg/mL; and resistant (R), ≥1 μg/mL, for C. albicans, C. tropicalis, and C. krusei, and ≤2 μg/mL (S), 4 μg/mL (I), and ≥8 μg/mL (R) for C. parapsilosis and all 3 echinocandins. The new CBPs for anidulafungin and caspofungin and C. glabrata are ≤0.12 μg/mL (S), 0.25 μg/mL (I), and ≥0.5 μg/mL (R), whereas those for micafungin are ≤0.06 μg/mL (S), 0.12 μg/mL (I), and ≥0.25 μg/mL (R). Due to the lack of CBPs for any of the echinocandins and C. lusitaniae, the epidemiological cutoff values (ECVs) were used for this species to categorize the isolates as wild-type (WT; MIC ≤ECV) and non-WT (MIC >ECV), respectively, for anidulafungin (≤2 μg/mL/>2 μg/mL), caspofungin (≤1 μg/mL/>1 μg/mL), and micafungin (≤0.5 μg/mL/>0.5 μg/mL). CA ranged from 93.6% (caspofungin) to 99.6% (micafungin) with less than 1% very major or major errors. The YeastOne colorimetric method remains comparable to the CLSI BMD reference method for testing the susceptibility of Candida spp. to the echinocandins when using the new (lower) CBPs and ECVs. Further study using defined fks mutant strains of Candida is warranted.     

LEADER Surveillance program results for 2010: an activity and spectrum analysis of linezolid using 6801 clinical isolates from the United States (61 medical centers)

The LEADER program monitors the in vitro activity of linezolid and comparator agents across the United States using reference broth microdilution and supportive molecular susceptibility-based investigations. This report summarizes the data from the 2010 program, the seventh consecutive year. A total of 61 medical centers from the USA including 7 medical centers specializing in children's healthcare provided a total of 6801 Gram-positive pathogens. The medical centers represented all 9 US Bureau of Census geographic regions. The organisms tested by reference broth microdilution were 3105 Staphylococcus aureus, 944 coagulase-negative staphylococci (CoNS), 934 Enterococci, 803 Streptococcus pneumoniae, 604 β-haemolytic streptococci, and 411 viridans group and other streptococci. The MIC(90) value for each of the above 6 targeted groups of organisms was 1 μg/mL. The "all organism" linezolid-resistant and nonsusceptible rate was 0.38%, which has been constant at 0.34% (2009) to 0.45% (2006) for the last 4 years. For Staphylococcus aureus, only 0.06% of the isolates were linezolid-resistant (MIC, ≥8 μg/mL); however, 2 additional methicillin-resistant Staphylococcus aureus had a cfr and a MIC of only 4 μg/mL. Resistance to linezolid was detected in 7 enterococci (0.75%) and 14 CoNS isolates (1.48%). This also represents a stable rate of resistance noted since the 2006 LEADER program report. Of note, for the first time in the 7 years of the Leader Program a linezolid-resistant Streptococcus pneumoniae was encountered. Overall, the results of the LEADER program demonstrate that linezolid maintains excellent in vitro activity against target Gram-positive pathogens across the USA. The LEADER program continues to provide valuable reference and molecular-level monitoring of linezolid activity.     

In vitro activity against Staphylococcus aureus of a novel antimicrobial agent, PRF-119, a recombinant chimeric bacteriophage endolysin

Antistaphylococcal activity of the novel chimeric endolysin PRF-119 was evaluated with the microdilution method. The MIC(50) and MIC(90) of 398 methicillin-susceptible Staphylococcus aureus isolates were 0.098 μg/ml and 0.391 μg/ml, respectively (range, 0.024 to 0.780 μg/ml). Both the MIC(50) and MIC(90) values of 776 methicillin-resistant S. aureus isolates were 0.391 μg/ml (range, 0.024 to 1.563 μg/ml). All 192 clinical isolates of coagulase-negative staphylococci exhibited MIC values of >50 μg/ml. In conclusion, PRF-119 exhibited very good activity specifically against S. aureus.     

Evaluation of telavancin activity versus daptomycin and vancomycin against daptomycin-nonsusceptible Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model

Daptomycin-nonsusceptible (DNS) Staphylococcus aureus strains have been reported over the last several years. Telavancin is a lipoglycopeptide with a dual mechanism of action, as it inhibits peptidoglycan polymerization/cross-linking and disrupts the membrane potential. Three clinical DNS S. aureus strains, CB1814, R6212, and SA-684, were evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (starting inoculum, 10(8.5) CFU/g) for 120 h. Simulated regimens included telavancin at 10 mg/kg every 24 h (q24h; peak, 87.5 mg/liter; t(1/2), 7.5 h), daptomycin at 6 mg/kg q24h (peak, 95.7 mg/liter; t(1/2), 8 h), and vancomycin at 1 g q12h (peak, 30 mg/liter; t(1/2), 6 h). Differences in CFU/g between regimens at 24 through 120 h were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥3-log(10) CFU/g decrease in colony count from the initial inoculum. MIC values were 1, 0.25, and 0.5 mg/liter (telavancin), 4, 2, and 2 mg/liter (daptomycin), and 2, 2, and 2 mg/liter (vancomycin) for CB1814, R6212, and SA-684, respectively. Telavancin displayed bactericidal activities against R6212 (32 to 120 h; -4.31 log(10) CFU/g), SA-684 (56 to 120 h; -3.06 log(10) CFU/g), and CB1814 (48 to 120 h; -4.9 log(10) CFU/g). Daptomycin displayed initial bactericidal activity followed by regrowth with all three strains. Vancomycin did not exhibit sustained bactericidal activity against any strain. At 120 h, telavancin was significantly better at reducing colony counts than vancomycin against all three tested strains and better than daptomycin against CB1814 (P < 0.05). Telavancin displayed bactericidal activity in vitro against DNS S. aureus isolates.     

Multistep resistance development studies of ceftaroline in gram-positive and -negative bacteria

Ceftaroline, the active component of the prodrug ceftaroline fosamil, is a novel broad-spectrum cephalosporin with bactericidal activity against Gram-positive and -negative isolates. This study evaluated the potential for ceftaroline and comparator antibiotics to select for clones of Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus aureus, and Enterococcus faecalis with elevated MICs. S. pneumoniae and S. pyogenes isolates in the present study were highly susceptible to ceftaroline (MIC range, 0.004 to 0.25 μg/ml). No streptococcal strains yielded ceftaroline clones with increased MICs (defined as an increase in MIC of >4-fold) after 50 daily passages. Ceftaroline MICs for H. influenzae and M. catarrhalis were 0.06 to 2 μg/ml for four strains and 8 μg/ml for a β-lactamase-positive, efflux-positive H. influenzae with a mutation in L22. One H. influenzae clone with an increased ceftaroline MIC (quinolone-resistant, β-lactamase-positive) was recovered after 20 days. The ceftaroline MIC for this isolate increased 16-fold, from 0.06 to 1 μg/ml. MICs for S. aureus ranged from 0.25 to 1 μg/ml. No S. aureus isolates tested with ceftaroline had clones with increased MIC (>4-fold) after 50 passages. Two E. faecalis isolates tested had ceftaroline MICs increased from 1 to 8 μg/ml after 38 days and from 4 to 32 μg/ml after 41 days, respectively. The parental ceftaroline MIC for the one K. pneumoniae extended-spectrum β-lactamase-negative isolate tested was 0.5 μg/ml and did not change after 50 daily passages.     

Enhancement of antistaphylococcal activities of six antimicrobials against sasG-negative methicillin-susceptible Staphylococcus aureus: an in vitro biofilm model

This study was designed to evaluate antimicrobial activities against methicillin-susceptible Staphylococcus aureus in both sessile and planktonic forms and to detect genes associated with this biofilm phenotype. Minimal biofilm inhibition and eradication concentrations (MBIC and MBEC, respectively) were determined by an in vitro biofilm model, and icaA, atlA, and sasG genes were detected by polymerase chain reaction. Vancomycin and tigecycline presented better biofilm inhibitory activity (MBIC range: 4-8 μg/mL) (P ≤ 0.05) and lower MBEC/MIC ratios (P ≤ 0.001) than other antimicrobials. All isolates harbored icaA and atlA, whereas sasG was present only in strong biofilm formers (P ≤ 0.05). Interestingly, antimicrobial activities against sasG- weak biofilm formers were significantly higher than those against sasG+ strong biofilm formers (P ≤ 0.05), demonstrating that number of cells in a biofilm matrix affected the antimicrobial activity, which was also variable, and might be associated with specific genetic determinants. To our knowledge, this was the first study reporting the presence of sasG in clinical isolates of S. aureus in South America.     

Antistaphylococcal activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic

TD-1792 is a new multivalent glycopeptide-cephalosporin antibiotic with potent activity against Gram-positive bacteria. The in vitro activity of TD-1792 was tested against 527 Staphylococcus aureus isolates, including multidrug-resistant isolates. TD-1792 was highly active against methicillin-susceptible S. aureus (MIC(90), 0.015 μg/ml), methicillin-resistant S. aureus, and heterogeneous vancomycin-intermediate S. aureus (MIC(90), 0.03 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of TD-1792 at concentrations of ≤ 0.12 μg/ml. A postantibiotic effect of >2 h was observed after exposure to TD-1792.