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

The in vitro activity of the novel antifungal agent E1210 and four comparators (caspofungin, fluconazole, posaconazole, and voriconazole) was determined against 90 clinical isolates of Candida using Clinical and Laboratory Standards Institute methods. The collection was composed of 21 Candida albicans, 20 C. glabrata, 25 C. parapsilosis, and 24 C. tropicals, and also included 21 fluconazole-resistant and 15 caspofungin-resistant strains. E1210 was highly active against all the species tested and was more potent than all comparators. The MIC₉₀ results (μg/mL) for E1210, caspofungin, fluconazole, posaconazole, and voriconazole, respectively, were as follows by species: C. albicans (0.06, 4, ≥64, 0.5, 0.5), C. glabrata (0.06, 2, 32, 1, 1), C. parapsilosis (0.06, 4, 16, 0.12, 0.25), and C. tropicalis (0.06, 4, ≥64, 0.5, 2). E1210 was also the most active agent against fluconazole-resistant strains of C. albicans (MIC range, 0.015–0.12 μg/mL), C. glabrata (0.06 μg/mL), C. parapsilosis (MIC range, 0.06–0.05 μg/mL), and C. tropicalis (MIC range, 0.008–0.06 μg/mL), and was the most potent agent tested against caspofungin-resistant strains of C. albicans (MIC range, 0.008–0.12 μg/mL), C. glabrata (MIC range, 0.03–0.06 μg/mL), and C. tropicalis (MIC range, 0.015–0.06 μg/mL).     

Effects of fluoroquinolones on experimental pneumonia caused by penicillin-resistantStreptococcus pneumoniae in mice

The in vitro and in vivo activities of several fluoroquinolones, ampicillin and cefteram-pivoxil were investigated against penicillin-resistantStreptococcus pneumoniae (PRSP). The MIC₉₀s of sparfloxacin, levofloxacin, tosufloxacin, AM-1155, ampicillin, and cefteram-pivoxil for 13 PRSP strains were 0.78, 3.13, 0.39, 1.56, 3.13, and 3.13 μg/mL, respectively. An experimental fatal pneumonia was induced by intranasal inoculation of PRSP No. 65 in CBA/J mice. The fluoroquinolones were effective against the experimental pneumonia, but ampicillin and cefteram-pivoxil were not sufficiently effective. The oral 50% effective doses (ED₅₀) of sparfloxacin, levofloxacin, tosufloxacin, and AM-1155 on the experimental pneumonia were 6.09, 49.3, 5.07, and 8.59 mg/kg/dose, respectively, when treatment was initiated 3 hours after infection and were 30.0, >50, 17.7, and 45.9 mg/kg/dose, respectively, when treatment was initiated 24 hours after infection. These results suggest that some fluoroquinolones such as sparfloxacin, tosufloxacin and AM-1155 may be effective in the treatment of pneumonia due to PRSP in humans.     

Antifungal spectrum and fungicidal mechanism of an N-terminal peptide of bovine lactoferrin

The antifungal spectrum and fungicidal mechanism of an N-terminal peptide of bovine lactoferrin (lactoferricin B), an antimicrobial peptide produced by gastric pepsin digestion of bovine lactoferrin, were investigated. The susceptibility of pathogenic yeasts and dermatophytes to the peptide varied in a species-dependent and strain-dependent manner. Dematiaceous fungi and dimorphic fungi were susceptible to the peptide (range of MIC values: 0.63 to 10 μg/mL). In the case of nonpigmented hyphomycetes and zygomycetes, most strains exhibited resistance to the peptide (MIC:>80 μg/ mL). This peptide killedCandida albicans dose dependently without inducing a change in cell wall stability against osmotic stress. The peptide at 10 μg/ml immediately induced the release of K⁺ fromC. albicans cells and pH increases in cell suspensions. These pharmacological activities were more potent than those for miconazole nitrate, a well-known antifungal agent that interferes with membrane synthesis and function. These in vitro findings suggest that the lactoferrin oligopeptide has potent membrane disrupting activity against this yeast and suggests that in vivo LF-B studies would be useful to further understand host defenses and to develop improved therapeutic agents against yeast infections.     

Activity of JNJ-Q2, a novel fluoroquinolone,tested against Neisseria gonorrhoeae, including ciprofloxacin-resistant strains

JNJ-Q2 is a broad-spectrum fluoroquinolone with activity against Gram-positive and -negative pathogens. The in vitro activity of JNJ-Q2 was evaluated when tested against Neisseria gonorrhoeae isolates, including 31 ciprofloxacin-resistant strains with documented mutations in the quinolone resistance determining region. MIC values were determined using reference agar dilution methods using ciprofloxacin, penicillin, ceftriaxone, tetracycline, and azithromycin as comparators. All isolates were inhibited by ≤ 0.25 μg/mL of JNJ-Q2 (range, 0.004–0.25 μg/mL; MIC_50/90, 0.03/0.25 μg/mL) which was 8-fold (MIC₅₀) and 32-fold more potent (MIC₉₀) compared to ciprofloxacin. Few strains were susceptible to penicillin (3.0%) and tetracycline (6.1%), and with the use of the European Committee on Antimicrobial Susceptibility Testing interpretive criteria, 13.6% were resistant to azithromycin. All strains were susceptible to ceftriaxone, the most potent agent (MIC₉₀, 0.06 μg/mL) followed by JNJ-Q2 (MIC₉₀, 0.25 μg/mL). JNJ-Q2 appears to be a potent fluoroquinolone when tested against contemporary multidrug-resistant N. gonorrhoeae.     

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 ceftaroline and comparator agents tested against bacterial isolates causing skin and soft tissue infections and community-acquired respiratory tract infections isolated from the Asia-Pacific region and South Africa (2010)

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in vitro bactericidal activity against resistant Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant strains of Streptococcus pneumoniae, and common Gram-negative organisms, including wild-type Enterobacteriaceae. We evaluated the in vitro activity of ceftaroline and selected comparator agents against bacterial isolates collected from patients with skin and soft tissue infections (SSTI) and community-acquired respiratory tract infections (CARTI) in the Asia-Pacific region and South Africa. A total of 2351 isolates, 1100 from SSTI and 1251 from CARTI, were collected from 25 medical centers distributed across 8 countries as part of the 2010 AWARE ceftaroline surveillance program and tested for susceptibility by reference broth microdilution methods. Ceftaroline was very active against S. aureus (MIC_50/90, 0.25/1 μg/mL; 93.4% susceptible), including MRSA (MIC_50/90, 1/2 μg/mL; 80.6% susceptible). Against β-hemolytic streptococci, ceftaroline demonstrated greater activity (MIC₉₀, 0.015 μg/mL) than penicillin (MIC₉₀, 0.06 μg/mL). Ceftaroline was also highly active against viridans group streptococci (MIC₉₀, 0.12 μg/mL). Similarly to ceftriaxone, ceftaroline activity against Escherichia coli (MIC_50/90, >32/>32 μg/mL) and Klebsiella spp. (MIC_50/90, 0.12/>32 μg/mL) was compromised by the high prevalence of isolates with an ESBL phenotype in the region, particularly in China. Ceftaroline was the most potent β-lactam tested against S. pneumoniae (MIC_50/90 of 0.015/0.25 μg/mL; 99.8% susceptible by Clinical and Laboratory Standards Institute [CLSI] criteria), and it was also highly potent against Haemophilus influenzae (MIC_50/90, ≤0.008/0.03 μg/mL; 100% susceptible by CLSI criteria). Ceftaroline was also active against H. parainfluenzae (MIC_50/90, ≤0.008/0.015 μg/mL) and Moraxella catarrhalis (MIC_50/90, 0.06/0.12 μg/mL). In summary, ceftaroline showed potent in vitro activity against a large collection of bacterial isolates (2351) associated with SSTI and CARTI from the Asia-Pacific region and South Africa.     

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 a new fluoroquinolone, DU-6859a, against quinolone-resistant clinical isolates ofPseudomonas aeruginosa with genetic alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV

The in vitro antimicrobial activity of DU-6859a, a new fluoroquinolone, was tested against 22 clinical isolates ofPseudomonas aeruginosa, including strains with fluoroquinolone resistance-associated alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV. The MICs of DU-6859a for 10 isolates with both altered GyrA and ParC and for 7 isolates with altered GyrA alone ranged from 1.56 to 25 μg/mL and from 0.78 to 6.25 μg/mL, respectively. The MIC of DU-6859a at which 90% of the strains were inhibited (MIC₉₀) of these 17 isolates was 12.5 μg/mL. However, there was no significant difference between DU-6859a and the other quinolones tested against 5 strains which did not have any alterations of either GyrA or ParC. Based on the MIC₉₀s, DU-6859a exhibited 8- to 32-fold greater activity than the currently available fluoroquinolones against strains having alterations in DNA gyrase and topoisomerase IV.     

Ceftaroline activity against bacterial organisms isolated from acute bacterial skin and skin structure infections in United States medical centers (2009–2011)

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a new cephalosporin with bactericidal activity against resistant Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant strains of Streptococcus pneumoniae, and commonly isolated Gram-negative organisms, including ceftriaxone-susceptible Enterobacteriaceae. We evaluated the in vitro activity of ceftaroline and selected comparator agents against bacterial isolates collected from patients with acute bacterial skin and skin structure infections (ABSSSIs) in the USA. A total of 6222 isolates were collected from 67 medical centers distributed across all nine USA census regions between 2009 and 2011 and tested for susceptibility by reference broth microdilution methods. Ceftaroline was very active against S. aureus (MIC_50/90, 0.5/1 μg/mL; 99.6% susceptible), including MRSA (MIC_50/90, 0.5/1 μg/mL; 99.1% susceptible). Against β-hemolytic streptococci, the activity of ceftaroline (MIC_50/90, ≤0.015/0.03 μg/mL; 100.0% susceptible) was comparable to that of both penicillin (MIC_50/90, ≤0.06/≤0.06 μg/mL; 100.0% susceptible) and ceftriaxone (MIC_50/90, ≤0.25/≤0.25 μg/mL; 100.0% susceptible). Ceftaroline was also highly active against viridans group streptococci (MIC_50/90, 0.03/0.06 μg/mL). Similar to ceftriaxone and ceftazidime, ceftaroline was active against wild-type strains of Escherichia coli (MIC_50/90, 0.12/0.25 μg/mL; 94.0% susceptible) and Klebsiella pneumoniae (MIC_50/90, 0.12/0.25 μg/mL; 96.8% susceptible); however, the ceftaroline activity was compromised among strains with an extended-spectrum β-lactamase-phenotype (MIC_50/90, >32/>32 μg/mL for both E. coli and K. pneumoniae). In summary, ceftaroline showed potent activity against a large contemporary collection (6222) of bacterial isolates associated with ABSSSI in the USA.     

Therapeutic efficacies of penicillin G,cefotaxime, and imipenem/cilastatin against penicillin-resistant pneumococcal pneumonia in CBA/J mice

We compared the therapeutic efficacies of penicillin G (PCG), cefotaxime (CTX), and imipenem/cilastatin (IPM/CS) against penicillin-resistantStreptococcus pneumoniae pneumonia in CBA/J mice. In pneumonia induced by strain TUH39 (PCG MIC; 0.063 μg/mL), eight 2.5 mg/kg doses of PCG administered at 1.5 hour intervals beginning 36 hours after infection reduced the number of bacteria in the lungs below the limit of detection. In contrast, a similar regimen failed to lower the number of organisms following infection with strain TUM741 (PCG MIC; 1 μg/mL); however, PCG doses of 8 × 10 and 8 × 40 mg/kg reduced bacterial numbers in a dose-dependent manner. CTX (MIC; 0.5 μg/mL) and IPM/CS (MIC; 0.125 μg/mL) at 6 × 40 mg/kg were more effective than PCG at the same dose against strain TUM741 pneumonia; these antibiotics eradicated bacteria in lungs of 2 out of 5 and 5 out of 5 mice, respectively. In accord with the pulmonary clearance results, survival of mice treated with PCG (6 × 40 and 6 × 160 mg/kg), CTX (6 × 40 mg/kg) and IPM/CS (6 × 40 mg/kg) were 30%, 80%, 40% and 100%, respectively. Pharmacokinetic analysis in lungs revealed that IPM/CS was superior to CTX and PCG in several parameters. These results demonstrate therapeutic responses to CTX, IPM/CS and high-dose PCG in a CBA/J mouse model of penicillin-resistant pneumococcal pneumonia. Results with IPM/CS were particularly favorable, suggesting this antibiotic combination as a potential first-line treatment for penicillin-resistantS. pneumoniae pneumonia.     

Spectrum and potency of ceftaroline tested against leading pathogens causing community-acquired respiratory tract infections in Europe (2010)

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a novel cephalosporin exhibiting in vitro bactericidal activity against Gram-positive organisms, including Streptococcus pneumoniae and methicillin-susceptible and -resistant Staphylococcus aureus, as well as common Gram-negative organisms. The objective of this study was to determine the spectrum and potency of ceftaroline against recent leading pathogens causing community-acquired respiratory tract infections (CARTI) isolated in Europe. A total of 1563 isolates from the 2010 Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) Program were identified as CARTI pathogens by the infection type and/or specimen type recorded by the participating laboratory. Isolates were collected from patients in 52 medical centers located in 19 European countries (including Israel and Turkey). Susceptibility testing for ceftaroline and commonly used antimicrobials was performed by Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology. Susceptibility interpretations for comparators were as published in CLSI and the European Committee on Antimicrobial Susceptibility Testing guidelines, and for ceftaroline US-FDA breakpoints were also applied. Ceftaroline was very active overall against 799 S. pneumoniae (MIC_50/90, ≤0.008/0.12 μg/mL) and inhibited 100.0% of all isolates at a MIC ≤0.5 μg/mL. Ceftaroline was very potent against penicillin-resistant (CLSI oral penicillin V breakpoints) and -intermediate S. pneumoniae (MIC_50/90, 0.12/0.25 and 0.03/0.12 μg/mL, respectively), but potency was lower than observed against penicillin-susceptible isolates (MIC_50/90, ≤0.008/≤0.008 μg/mL). Ceftaroline was also very active (MIC_50/90, ≤0.008/0.015 μg/mL) against 515 Haemophilus influenzae, including β-lactamase–producing strains (MIC_50/90, 0.015/0.06 μg/mL). Ceftaroline also demonstrated good activity against 205 Moraxella catarrhalis isolates (MIC_50/90, 0.06/0.12 μg/mL). This study demonstrated the potent in vitro activity of ceftaroline against contemporary pathogens isolated from patients with documented CARTI from Europe. These data suggest that ceftaroline fosamil has an acceptable in vitro spectrum and potency against CARTI pathogens.     

Prospective, open-label investigation of the pharmacokinetics of daptomycin during cardiopulmonary bypass surgery

As methicillin-resistant Staphylococcus aureus (MRSA) becomes more prevalent, vancomycin is becoming increasingly used as a prophylaxis against surgical-site infections for cardiothoracic surgeries. However, vancomycin administration can be challenging, and the pharmacokinetics of alternative antibiotics in this setting are poorly understood. The primary objective of this investigation was to describe the pharmacokinetics of daptomycin in patients undergoing coronary artery bypass graft surgery. We enrolled 15 patients undergoing coronary artery bypass surgery requiring cardiopulmonary bypass. Each subject was administered a single open-label dose of daptomycin (8 mg/kg of body weight) for surgical prophylaxis. Fourteen daptomycin plasma samples were collected. Safety outcomes between subjects who received daptomycin and 15 control subjects who received the standard-of-care antibiotic were compared. The mean maximal concentration of daptomycin (C_max) was 84.4 ± 27.1 μg/ml; the mean daptomycin concentration during the cardiopulmonary bypass procedure was 33.2 ± 11.4 μg/ml and was 30.9 ± 12.7 μg/ml at sternum closure. Mean daptomycin concentrations at 12, 18, 24, and 48 h were 22.7 ± 9.7, 16.2 ± 8.2, 12.0 ± 4.7, and 3.5 ± 2.3 μg/ml, respectively. Mean daptomycin concentrations were consistently above the MIC at which 90% of the tested isolates are inhibited (MIC₉₀) for S. aureus and S. epidermidis during the cardiopulmonary bypass procedure. Daptomycin was not associated with surgical-site infections or differences in adverse events compared to findings for control subjects. We found that a single dose of daptomycin at 8 mg/kg was well tolerated and achieved adequate plasma concentrations against common pathogens associated with surgical-site infections after cardiothoracic surgery. Daptomycin may be considered an alternative surgical prophylaxis antibiotic for patients undergoing cardiothoracic bypass surgery who are unable to receive vancomycin.     

Antimicrobial resistance in clinical isolates of Neisseria subflava from the oral cavities of a Japanese population

A recent study indicated that Neisseria subflava, one of the commensal Neisseria species, may play an important role in the emergence of Neisseria gonorrhoeae strains with chromosomally mediated resistance to penicillin or cephalosporin by the horizontal genetic exchange of penA genes encoding the target site for penicillin or cephalosporin. The present investigation examined the antimicrobial susceptibility of 45 isolates of N. subflava from the oral cavities of Japanese men and women to various agents used for the treatment of gonococcal infections. Of the 45 isolates, 40 (88.9%) and 4 (8.8%) were intermediately resistant and resistant to penicillin, respectively, with the minimal inhibitory concentration (MIC)₅₀ and MIC₉₀ of penicillin being 0.5 mg/l and 1 mg/l, respectively. Of the 45 isolates, 13 (28.9%) and 14 (31.1%) were resistant to tetracycline and ciprofloxacin, respectively, and 3 (6.7%) showed reduced susceptibility to cefixime (although the susceptibility category was not determined). These results indicate that several isolates of N. subflava have acquired resistance or intermediate resistance to various antimicrobial agents, including penicillin, cephalosporin, tetracycline, and ciprofloxacin. The present study may thus confirm that N. subflava may be involved in the emergence of N. gonorrhoeae strains with either intermediate or total resistance to penicillin or cephalosporin by the horizontal genetic exchange of the penA gene.     

In vitro evaluation of the activity of β-lactams,new quinolones,and other antimicrobial agents againstStreptococcus pneumoniae

The in vitro activities of the β-lactam and quinolone antibiotics panipenem, cefpodoxime, cefdinir, cefditoren, faropenem, tosufloxacin, levofloxacin and grepafloxacin were compared with similar conventional antibiotics against penicillin-resistantStreptococcus pneumoniae (PRSP). Pneumococcal isolates collected from October 1994 to March 1995 (n=1283) consisted of penicillin-susceptibleS. pneumoniae (PSSP; 59.2%), penicillin-intermediately-resistantS. pneumoniae (PISP;11.2%), and PRSP (29.6%). The isolates were highly susceptible to panipenem, faropenem and cefditoren with MIC₉₀ values of 0.125 μg/mL, 0.5 μg/mL and 0.5 μg/mL, respectively. Correlation coefficients for the relationships between the MICs of these β-lactam agents and that of penicillin G ranged from γ=0.7652 to γ=0.8022. These new β-lactam agents produced excellent bactericidal responses at concentrations greater than their MICs for PSSP concomitant with appropriate cellular morphologic changes. However, the bactericidal action of these antibiotics against PRSP was less pronounced and fewer instances of cell lysis were observed. The MIC₉₀ of cefpodoxime was similar to that of cefaclor, whereas that of cefdinir was between those of faropenem and cefpodoxime. The MIC distribution of the new quinolone agents showed 1 peak, but the MIC₉₀ values of tosufloxacin and grepafloxacin were both 0.5 μg/mL and that of levofloxacin was 2.0 μg/mL. Only 1% of all isolates demonstrated cross-resistance to all quinolone agents.     

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.     

In vitro activities of new ketolide, telithromycin, and eight other macrolide antibiotics against Streptococcus pneumoniae having mefA and ermB genes that mediate macrolide resistance

The comparative in vitro activity of a new ketolide, telithromycin (TEL), and eight other macrolide-lincosamide antibiotics (MLS) against 215 strains, of Streptococcus pneumoniae including penicillin-resistant isolates (PRSP), was determined by the agar dilution method. These strains were isolated from patients with pneumonia, otitis media, and purulent meningitis between 1995 and 1997. Two genes, mefA and ermB, that encode MLS resistance in the strains were identified by polymerase chain reaction (PCR). Of the strains, 30.2% (n = 65) had the mefA gene, 37.7% (n = 81) had the ermB gene, and 1.4% (n = 3) had both resistant genes. The minimum inhibitory concentration (MIC_90s) of TEL and 16-membered ring MLS for strains having the mefA gene were 0.063–0.25µg/ml, which were the same level as those for MLS-susceptible strains. On the other hand, the strains with the mefA gene showed low-level resistance to 14- and 15-membered ring MLS, with MIC_90s ranging from 1 to 4µg/ml. Only the MIC₉₀ of TEL at 0.5µg/ml, for strains having the ermB gene was superior to that of the 14-, 15-, and 16-membered ring MLS (MIC₉₀, 64µg/ml). TEL also showed excellent activity against PRSP having abnormal pbp1a, pbp2x, and pbp2b genes. Most strains having the mefA and ermB genes were serotyped to 3, 6, 14, 19, and 23. These results suggest that TEL may be a useful chemotherapeutic agent for respiratory tract infections caused by S. pneumoniae.     

Antibacterial effects of lactoferrin and a pepsin-generated lactofferrin peptide againstHelicobacter pylori in vitro

Helicobacter pylori is an etiologic agent of gastritis and peptic ulcer disease in humans. We investigated the antibacterial activities of lactoferrin and Lactoferricin^® (an antimicrobial peptide derived from lactoferrin) against this bacterium. The minimum bactericidal concentrations of bovine and human lactoferrins were 1.25 to 2.50 mg/mL, while it was greater than 5.0 mg/L for bovine Lactoferricin^®. Time-kill studies withH. pylori grown in brucella broth demonstrated that the antibacterial effects of the lactoferrins were dose-dependent within the range of 0.8 to 2.0 mg/mL and began when the cells were in the exponential phase of growth. Iron-saturated lactoferrin did not inhibit the growth ofH. pylori. Bovine Lactoferricin^® showed only weak activity againstH. pylori in brucella broth, however, a rapid bactericidal effect was observed in 1% Bacto-peptone medium within 1 hour of exposure at concentrations in the range of 0.1 to 1.0 mg/mL. Under these conditions, bovine lactoferrin showed little effect. Moreover, bovine Lactoferricin^® inhibited the urease activity ofH. pylori, which is one of the virulence factors of this bacterium. These results indicate thatH. pylori is susceptible to inhibition and inactivation by both lactoferrin and Lactoferricin^® in laboratory media. The antibacterial effect of lactoferrin appeared to be dependent on its iron status, the cellular phase of growth, and has a mechanism of action different from that of Lactoferricin^®.     

Superior in vitro activity of carbapenems over anti-methicillin-resistant Staphylococcus aureus (MRSA) and some related antimicrobial agents for community-acquired MRSA but not for hospital-acquired MRSA

Eighty-eight strains of Panton-Valentine leukocidin (PVL)-positive and -negative community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and 152 strains of hospital-acquired MRSA (HA-MRSA) were examined for susceptibility to carbapenems, oxacillin, and other antimicrobial agents. CA-MRSA strains were more susceptible to carbapenems (MIC₉₀, 1–4 μg/ml) than HA-MRSA strains (MIC₉₀, 32–64 μg/ml). Among the carbapenems examined, CA-MRSA strains were most susceptible to imipenem (MIC₅₀, 0.12 μg/ml; MIC₉₀, 1 μg/ml). A similar tendency was observed with oxacillin, but less markedly (MIC₉₀: 32 μg/ml for CA-MRSA and ≥256 μg/ml for HA-MRSA). This difference was also observed between CA-MRSA and HA-MRSA in susceptibility levels to cephems, erythromycin, clindamycin, and levofloxacin, but not to ampicillin, vancomycin, teicoplanin, linezolid, and arbekacin. The data indicate that, in terms of MIC₅₀ or MIC₉₀ values, CA-MRSA is 64–256 times more susceptible to imipenem than HA-MRSA, and for CA-MRSA, some carbapenems, e.g., imipenem, show better in vitro activity than anti-MRSA or some related agents.     

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.     

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

CEM-101 is a novel fluoroketolide with reported high potency against diverse groups of Gram-positive (Micrococcus spp., viridans group streptococci, Corynebacterium spp. Listeria monocytogenes, Clostridium spp., etc.) and Gram-negative bacteria (Neisseria gonorrhoeae, Campylobacter jejuni, Helicobacter pylori, Bacteroides fragilis, Shigella spp., etc.), including mycoplasma and ureaplasma, as well as bacteria commonly associated with community-acquired respiratory tract infections and skin and skin structure infections. In this study, CEM-101 and comparator antimicrobials were tested against a collection of very low prevalence aerobic and anaerobic bacteria collected via the SENTRY Antimicrobial Surveillance Program platform. CEM-101 was highly active against all Gram-positive organisms (MIC₅₀, 0.015 μg/mL) as compared with telithromycin (MIC₅₀, 0.06 μg/mL), clarithromycin (MIC₅₀, 0.12 μg/mL), and erythromycin (MIC₅₀, 0.25 μg/mL). Among Gram-negative pathogens, CEM-101 also displayed a high potency against most strains (MIC₅₀, 4 μg/mL) but was found to be equivalent or less active when compared with other antimicrobials tested with MIC₅₀ values ranging from ≤0.12 μg/mL for levofloxacin to 8 μg/mL for telithromycin. Among the strict anaerobic species, CEM-101 activity mirrored that of the aerobic species: high activity against the Gram-positive anaerobes (MIC₅₀ results ranging from ≤0.03 μg/mL to 0.12 μg/mL) and equivalent or less susceptible against Gram-negative anaerobes. Our in vitro antimicrobial susceptibility results for CEM-101 demonstrate better activity compared with other MLS_B class agents among a diverse group of uncommonly isolated bacterial pathogens; these results provide an impetus for possible expanded indications during Phase 2 and 3 clinical trials.