[Show abstract][Hide abstract] ABSTRACT: TD-1792 is a glycopeptide-cephalosporin heterodimer antibiotic with activity against a broad spectrum of gram-positive pathogens that includes methicillin-susceptible and -resistant Staphylococcus aureus. The objective of the present study was to evaluate the in vitro activity of TD-1792 against a collection of clinical isolates of vancomycin-intermediate Staphylococcus spp. (VISS), heteroresistant VISS (hVISS), and vancomycin-resistant S. aureus (VRSA). The TD-1792, vancomycin, daptomycin, linezolid, and quinupristin-dalfopristin MICs and minimum bactericidal concentrations (MBCs) were determined for 50 VISS/hVISS isolates and 3 VRSA isolates. Time-kill experiments (TKs) were then performed over 24 h with two vancomycin-intermediate S. aureus strains and two VRSA strains, using each agent at multiples of the MIC. TD-1792 and daptomycin were also evaluated in the presence and absence of 50% human serum to determine the effects of the proteins on their activities. Most of the VISS/hVISS isolates were susceptible to all agents except vancomycin. TD-1792 exhibited the lowest MIC values (MIC(90) = 0.125 microg/ml), followed by quinupristin-dalfopristin and daptomycin (MIC(90) = 1 microg/ml) and then linezolid (MIC(90) = 2 microg/ml). The presence of serum resulted in a 2- to 8-fold increase in the TD-1792 and daptomycin MIC values. In TKs, QD demonstrated bactericidal activity at multiples of the MIC that simulated therapeutic levels, whereas linezolid was only bacteriostatic. Both TD-1792 and daptomycin demonstrated rapid bactericidal activities against all isolates tested. The presence of proteins had only a minimal impact on the activity of TD-1792 in TKs. TD-1792 exhibited significant in vitro activity against multidrug-resistant Staphylococcus isolates and represents a promising candidate for the treatment of infections caused by gram-positive organisms.
Antimicrobial Agents and Chemotherapy 09/2010; 54(9):3799-803. · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dalbavancin is an investigational semisynthetic lipoglycopeptide that is structurally related to teicoplanin. We examined the activity of dalbavancin (DAL) compared with tigecycline (TIG), minocycline (MIN), tetracycline (TET), teicoplanin (TEC) and vancomycin (VAN) against community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA) and multidrug-resistant hospital-associated meticillin-resistant S. aureus (MDR HA-MRSA). Two hundred and twenty clinical isolates of CA-MRSA and MDR HA-MRSA were utilised. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined according to Clinical and Laboratory Standards Institute guidelines. Selective time-kill studies were performed against CA-MRSA and MDR HA-MRSA in triplicate. Overall, DAL exhibited low MIC values against all strains of MRSA. Time-kill studies with CA-MRSA demonstrated DAL=VAN>TIG>MIN=TEC>TET (P<0.006), and with MDR HA-MRSA demonstrated DAL=VAN=TEC>TIG=MIN>TET (P>0.05). DAL demonstrated potent activity against clinical strains of CA-MRSA and MDR HA-MRSA, including tetracycline-resistant S. aureus.
International journal of antimicrobial agents 11/2009; 35(1):25-9. · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The increase in the incidence of both hospital- and community-acquired antibiotic-resistant infections is a major concern to the healthcare community. There have been only two new classes of antibiotics approved by the FDA over the past 40 years, and clearly there is a growing need for additional antimicrobial agents. In this paper, we present our work on the discovery of a class of benzophenone containing compounds that possess good activity against MRSA, VISA, VRSA, and VRE and moderate activity against E. coli. These compounds display MIC values in the 0.5-2.0 mg/L range and are not cytotoxic against mammalian cells. Extensive structure-activity relationship studies revealed that the benzophenone was absolutely essential for antibacterial activity as was the presence of a cationic group. Although these agents display DNA binding activity, we observed that these compounds do not inhibit any macromolecular synthesis reliant upon DNA nor do they inhibit lipid or cell wall biosynthesis. Instead, we found that these agents cause membrane depolarization, indicating that the bacterial membrane was the primary site of action for these agents. Our studies suggest that caution should be taken in assigning the mechanism of action for DNA binding antibiotics.
Journal of Medicinal Chemistry 09/2009; 52(16):5020-31. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We screened for heteroresistant, vancomycin-intermediate Staphylococcus aureus (hVISA) among clinical isolates of methicillin-resistant S. aureus collected from three hospitals (two urban teaching hospitals and one community hospital) in the Detroit metropolitan area over a 22-year period. The Macro Etest method was used to screen all available isolates. Confirmation of hVISA-positive screens were confirmed by population-area under the concentration-time curve (AUC) analysis. A total of 1,499 isolates revealed hVISA/VISA rates of 2.2/0.4% (n = 225; 1986 to 1993), 7.6/2.3% (n = 356; 1994 to 2002), and 8.3/0.3% (n = 917; 2003 to 2007). Population-AUC analysis confirmed 92.6% of the hVISA-positive strains determined by the Macro Etest method. For the isolates with known sources (1,208), the predominant source of hVISA was blood (60%), followed by lung (21%), skin and wound infections (14%), abscess (1%), and other (4%). The percentage of hVISA-positive strains appeared to increase as a function of the vancomycin MIC. Staphylococcal cassette chromosome mec (SCCmec) typing revealed that the majority (56.9%) of the hVISA strains were SCCmec type II and 39.4% were type IV; the majority of these strains were collected from 2000 to 2007. Our data indicate that the prevalence of hVISA may be increasing. Based on the association of vancomycin treatment failure in patients with hVISA, surveillance of hVISA strains is warranted.
Journal of clinical microbiology 09/2008; 46(9):2950-4. · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated the activity of ceftobiprole against 100 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and 100 hospital-associated MRSA (HA-MRSA) isolates. Eight isolates were evaluated by time-kill studies for kill rate and potential for synergy with tobramycin. Ceftobiprole MIC(50) and MIC(90) values were 1 and 2 microg/ml, respectively, against CA-MRSA and HA-MRSA. In time-kill analysis, ceftobiprole was bactericidal at all concentrations tested.
Antimicrobial Agents and Chemotherapy 08/2008; 52(8):2974-6. · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) is changing. We determined the inhibitory and bactericidal activity of select antimicrobial agents utilizing a well-characterized group of 200 staphylococcal cassette chromosome mec (SCCmec) type IV community-associated MRSA (CAMRSA) and 50 SCCmec type II health care-associated MRSA (HAMRSA). Differences in carriage of the Panton-Valentine leukocidin (PVL) genes, agr group, and agr function in CAMRSA and HAMRSA were also examined. Pulsed-field gel electrophoresis (PFGE) patterns were determined for a subset of study strains. CAMRSA typically belonged to the USA 300 PFGE profile, were associated with high rates of PVL carriage (78%), and primarily were agr group I. Susceptibility to daptomycin, linezolid, teicoplanin, and vancomycin was 100%. In contrast, HAMRSA isolates typically belonged to the USA 100 PFGE profile, were associated with low rates of PVL carriage (8%), and primarily were agr group II. Comparing susceptibilities between the 2 types of MRSA strains, there was a 2-fold increase in MIC for daptomycin, doxycycline, teicoplanin, trimethoprim-sulfamethoxazole (TMP/SMX), and vancomycin in HAMRSA versus CAMRSA. Levofloxacin and clindamycin susceptibly decreased dramatically by 66% and 54%, respectively, against HAMRSA versus CAMRSA. With respect to agr function, 3.5% of CAMRSA and 48% of HAMRSA displayed a down-regulated agr gene cluster. The comparative bactericidal activities of daptomycin were similar to those of vancomycin and clindamycin, but were significantly greater than those of linezolid, teicoplanin, and TMP/SMX against CAMRSA at 24-h terminal end points. Further studies are warranted against a larger number of molecularly defined, geographically diverse CAMRSA to confirm these findings.
[Show abstract][Hide abstract] ABSTRACT: The rise in the rates of glycopeptide resistance among Staphylococcus aureus isolates is concerning and underscores the need for the development of novel potent compounds. Ceragenins CSA-8 and CSA-13, cationic steroid molecules that mimic endogenous antimicrobial peptides, have previously been demonstrated to possess broad-spectrum activities against multidrug-resistant bacteria. We examined the activities of CSA-8 and CSA-13 against clinical isolates of vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycin-intermediate S. aureus (hVISA), as well as vancomycin-resistant S. aureus (VRSA) and compared them to those of daptomycin, linezolid, and vancomycin by susceptibility testing and killing curve analysis. We also examined CSA-13 for its concentration-dependent activity, inoculum effect, postantibiotic effect (PAE), and synergy in combination with various antimicrobials. Overall, the MICs and minimal bactericidal concentrations of CSA-13 were fourfold lower than those of CSA-8. Time-kill curve analysis of the VRSA, VISA, and hVISA clinical isolates demonstrated concentration-dependent bactericidal killing. An inoculum effect was also observed when a higher starting bacterial density was used, with the time required to achieve 99.9% killing reaching 1 h with a 6-log10-CFU/ml starting inoculum, whereas it was>or=24 h with a 8- to 9-log10-CFU/ml starting inoculum with 10x the MIC (P<or=0.001). A concentration-dependent PAE was demonstrated with CSA-13, nearly doubling from 2x to 4x the MIC (P=0.03). With respect to the CSA-13 antimicrobial combinations, time-kill curve analysis showed no difference in the log10 CFU/ml at 24 h for the majority of the organisms tested. However, early synergy at 4 to 8 h was detected against the VRSA Pennsylvania strain (2002) when CSA-13 was tested in combination with gentamicin, while early additivity was demonstrated against all of the other organisms.
Antimicrobial Agents and Chemotherapy 05/2007; 51(4):1268-73. · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Telavancin, a new multifunctional lipoglycopeptide antibiotic, exhibits broad-spectrum Gram-positive activity against a variety of pathogens. We examined the effects of human serum and antimicrobial concentrations on the activity of telavancin against glycopeptide-intermediate staphylococcal species (GISS), heteroresistant GISS (hGISS) and three vancomycin-resistant Staphylococcus aureus (VRSA) compared with vancomycin, quinupristin/dalfopristin, linezolid and daptomycin.
MIC and MBCs were performed against all antimicrobials. Time-kill experiments were performed using two strains of GISS (Mu50; NJ992) and VRSA (VRSAMI; VRSAPA) at 1, 2, 4, 8, 16 and 32x MIC. Telavancin and daptomycin were evaluated in the presence and absence of serum.
All GISS and hGISS were susceptible to the tested agents with telavancin and quinupristin/dalfopristin demonstrating the lowest MIC, followed by daptomycin, linezolid and vancomycin. Against VRSA, daptomycin and quinupristin/dalfopristin had the lowest MIC, followed by linezolid, telavancin and vancomycin. In the presence of serum, telavancin and daptomycin MICs increased 1- to 4-fold. Concentration-dependent activity was demonstrated by telavancin and daptomycin, in the presence and absence of serum. Telavancin and daptomycin were bactericidal against GISS and performed similarly in the presence of serum. Quinupristin/dalfopristin demonstrated bactericidal activity at clinically achievable concentrations, whereas linezolid was bacteriostatic.
Telavancin demonstrated concentration-dependent bactericidal activity against GISS, hGISS and VRSA at concentrations equal to or above 4x MIC, which corresponds to therapeutic levels against GISS and clinically achieved concentrations against the VRSA. Similar to daptomycin, telavancin activity was diminished in the presence of serum but bactericidal activity was maintained. Further investigation with telavancin against GISS, hGISS and VRSA is warranted.
Journal of Antimicrobial Chemotherapy 09/2006; 58(2):338-43. · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Susceptibility testing was used to evaluate potential spectrum of action for piperazinyl-cross-linked fluoroquinolone dimers against test strains of Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and vancomycin-resistant Enterococcus faecium (VRE) and to evaluate dimers against fluoroquinolone-resistant and fluoroquinolone-susceptible strains of streptococci. Individual dimers displayed equivalent or lowered MIC values compared with parent fluoroquinolone monomers against test strains of S. pneumoniae, S. pyogenes, E. coli, and VRE. Raised MIC values were observed for all dimers in comparison to monomers against test strains of P. aeruginosa and E. coli. In comparison to parent fluoroquinolones, all dimers displayed decreased percent inhibition of growth against M. tuberculosis. Structural requirements for activity of dimers and partial dimers against all organisms, including lower MICs against certain fluoroquinolone-resistant and fluoroquinolone-susceptible strains of streptococci, were consistent with requirements previously observed for dimers against fluoroquinolone-susceptible and fluoroquinolone-resistant strains of S. aureus. In contrast, the 10- to 100-fold lowering of MICs against wild-type and fluoroquinolone-resistant strains of S. aureus previously observed for individual cross-linked dimers was not observed with test strains of the various organisms used here.
[Show abstract][Hide abstract] ABSTRACT: We evaluated pulsatile dosing of clarithromycin and amoxicillin alone or combined against Streptococcus pneumoniae with various susceptibilities. When combined, pulsatile amoxicillin with clarithromycin was superior to either 8- or 12-h dosing against the intermediate strain and was identical for the susceptible strain. Pulse dosing of antimicrobials warrants further investigation.
Antimicrobial Agents and Chemotherapy 03/2006; 50(2):813-6. · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fifty isolates of Staphylococcus aureus, obtained during a multicenter clinical trial evaluating the efficacy of teicoplanin that was performed between 1987 and 1992, underwent glycopeptide susceptibility testing, and 2 isolates were found to be capable of growth on agar containing 4 or 8 mg/L of vancomycin. Both of these isolates were from patients that had received prolonged teicoplanin therapy and were deemed clinical failures. Extended susceptibility testing combined with mecA gene probing revealed that one isolate was susceptible to oxacillin, the other was resistant, and both were susceptible to a variety of nonglycopeptide agents. Population analyses revealed heterogeneous vancomycin- and teicoplanin-susceptibility profiles. Both strains were differentiated from recent glycopeptide intermediately resistant Staphylococcus aureus isolates by pulse-field analysis and by the fact that the resistance phenotype was stable to multiple serial passages. To our knowledge, this is the earliest report of S. aureus clinical isolates having reduced vancomycin and teicoplanin susceptibility.