Comparative in vitro activities of daptomycin, linezolid, and quinupristin/dalfopristin against Gram-positive bacterial isolates from a large cancer center

Our objective was to evaluate and compare the in vitro activity of daptomycin, linezolid, and quinupristin/dalfopristin against clinical bloodstream isolates of Gram-positive pathogens from a large cancer center in the Northeastern United States. Minimum inhibitory concentrations (MICs) were determined for daptomycin, quinupristin/dalfopristin, and linezolid against 258 isolates; bactericidal activity was evaluated using time-kill experiments against 14 representative pathogens. Vancomycin-resistant enterococci represented the largest proportion of bacteria tested (32% of the isolates), followed by methicillin-resistant coagulase-negative staphylococci (23%), and vancomycin sensitive enterococci (14%). Against staphylococci, the MIC90 was 1 microg/mL for both daptomycin and quinupristin/dalfopristin and 4 microg/mL for linezolid. Against enterococci, the MIC90 for both daptomycin and linezolid was 4 microg/mL and was 16 microg/mL for quinupristin/dalfopristin. The quinupristin/dalfopristin MIC90 for Enterococcus faecium was 2 microg/mL. Two enterococci were linezolid resistant and remained susceptible to daptomycin. In vitro time-kill studies found daptomycin to be rapidly bactericidal against the majority of organisms tested, killing 99.9% of bacteria within 6 h. Quinupristin/dalfopristin was bactericidal against staphylococci and bacteriostatic against most enterococci. Linezolid was bacteriostatic against all organisms evaluated. Daptomycin, quinupristin/dalfopristin, and linezolid each demonstrated in vitro activity against this collection of organisms. Future clinical studies to evaluate a potential role for these agents in the management of infections in cancer patients, including the treatment of febrile neutropenia, appear warranted.     

Antipneumococcal activity of AZD2563, a new oxazolidinone,compared with nine other agents

The in vitro activity of AZD2563, a new oxazolidinone, was compared with that of linezolid, vancomycin, quinupristin/dalfopristin, amoxicillin, levofloxacin, penicillin, erythromycin, azithromycin and clindamycin against a range of pneumococci by microdilution and time-kill studies. Against 300 pneumococci (99 penicillin susceptible, 86 penicillin intermediate, 115 penicillin resistant, 185 erythromycin resistant, 35 quinolone resistant), both oxazolidinones remained active against isolates less susceptible to other agents, with MICs ranging between 0.125 and 2 mg/L; AZD2563 MICs were generally one dilution lower than those of linezolid. Both quinupristin/dalfopristin and vancomycin were active against all groups (MIC ranges 0.125-2 and 0.125-0.25 mg/L, respectively). Apart from 35 isolates with levofloxacin MICs > or= 8 mg/L, levofloxacin MICs were < or =0.25-4 mg/L. MICs of amoxicillin and erythromycin rose with penicillin G MICs; most macrolide-resistant isolates were either penicillin-intermediate or -resistant. Against 16 organisms with differing beta-lactam, macrolide and quinolone MICs, time-kill studies showed that AZD2563 was bactericidal (99.9% killing) at 4 x MIC against nine strains at 24 h, with 90% killing of all 16 strains at 2 x MIC after 12 h. Similar results were obtained with linezolid. Both oxazolidinones were bacteriostatic at the MIC against all 16 strains. Amoxicillin, levofloxacin and vancomycin, at 2 x MIC, were bactericidal against 15 of the 16 strains after 24 h. Quinupristin/dalfopristin yielded the most rapid killing, with bactericidal activity against 13 of 16 strains at the MIC after 3 h and against 15 strains at 2 x MIC after 24 h. Erythromycin was bactericidal against all 10 strains with MICs < or= 8 mg/L at 4 x MIC after 24 h.     

Comparative in vitro activity of quinupristin/dalfopristin against multidrug resistant Enterococcus faecium

The in vitro susceptibilities of 82 strains of vancomycin resistant Enterococcus faecium (VREF), (49 vanA and 33 vanB) from over 13 hospitals in Europe and United States were studied. The MIC for several antibiotics showed high levels of resistance to vancomycin, ampicillin, gentamicin, and imipenem. All VREF strains were highly susceptible to quinupristin/dalfopristin with a MIC 90% of 0.5 μg/ml for both vanA and vanB phenotypes. Time-kill and synergy studies of VREF for quinupristin/dalfopristin alone and quinupristin/dalfopristin in combination with several antibiotics (ampicillin, gentamicin, ciprofloxacin, rifampin and novobiocin) did not show bactericidal activity. In induction experiments using SF6550, (VREF, a vanA strain), quinupristin/dalfopristin showed a delay in the expression of vancomycin resistance by 2.5 hours. The results of this study show quinupristin/dalfopristin to have excellent in vitro activity versus multiple resistant E. faecium.     

In vitro activity of quinupristin/dalfopristin,linezolid, telithromycin and comparator antimicrobial agents against 13 species of coagulase-negative staphylococci

OBJECTIVES: To determine in vitro susceptibilities of a large series of speciated coagulase-negative staphylococci (CNS) against three new antibiotics, linezolid, quinupristin/dalfopristin and telithromycin. METHODS: Susceptibilities to three new antibiotics and oxacillin, vancomycin, clindamycin and erythromycin were determined by the agar dilution method, as described by the NCCLS. RESULTS: Resistance to linezolid was not observed in any isolates, although MIC90 values varied between species. Fifteen of 658 (2.3%) isolates were resistant to quinupristin/dalfopristin, but < 1% of the clinically most important isolates of Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus hominis demonstrated resistance to this agent. Susceptibility to clindamycin correlated with susceptibility to quinupristin/dalfopristin; however, resistance to clindamycin did not predict quinupristin/dalfopristin resistance. Telithromycin was the least active of the new agents tested, showing activity similar to that of clindamycin. Susceptibility and resistance to clindamycin were predictive of susceptibility and resistance to telithromycin. CONCLUSION: Clindamycin susceptibility can be used as a surrogate marker for susceptibility to quinupristin/dalfopristin and telithromycin. Quinupristin/dalfopristin and linezolid show good activity against both mecA-positive and -negative CNS.     

Antipneumococcal activity of MEN 10700, a new penem, compared with other compounds, by MIC and time-kill kinetics.

The antipneumococcal activity of MEN 10700 was compared with those of nine other compounds by MIC and time-kill kinetics. MIC90s (mg/L) of 202 penicillin-susceptible, -intermediate and -resistant pneumococci were: 0.06, 1.0 and 2.0 (MEN 10700); 0.06, 0.5-1.0 and 2.0 (amoxycillin +/- clavulanate); 0.06, 0.5 and 4.0 (cefotaxime); 0.125, 0.5 and 2.0 (cefepime); 0.016, 0.125 and 0.25 (imipenem); 0.03, 0.5 and 1.0 (meropenem); 2.0 (ciprofloxacin); 0.125, >64.0 and >64.0 (clarithromycin); and 0.5 (vancomycin). Time-kill kinetics showed that MEN 10700, at 4 x MIC, was bactericidal for all 12 isolates tested at 4 x MIC. Kinetics of other beta-lactams were similar to those of MEN 10700, relative to MICs. Ciprofloxacin, at 4 x MIC, was uniformly bactericidal after 24 h. Clarithromycin exhibited slow kill kinetics, after 24 h. Vancomycin was bactericidal against 11/12 isolates at 2 x MIC after 24 h.     

Activity of ceftobiprole compared with those of other agents against Staphylococcus aureus strains with different resistotypes by time-kill analysis

Among 10 hospital- and community-acquired Staphylococcus aureus strains with differing methicillin and vancomycin resistotypes, all strains were susceptible to ceftobiprole at MICs 相似文献   

Activities of the combination of quinupristin-dalfopristin with rifampin in vitro and in experimental endocarditis due to Staphylococcus aureus strains with various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics

We evaluated the activities of quinupristin-dalfopristin (Q-D), alone or in combination with rifampin, against three strains of Staphylococcus aureus susceptible to rifampin (MIC, 0.06 microg/ml) and to Q-D (MICs, 0.5 to 1 microg/ml) but displaying various phenotypes of resistance to macrolide-lincosamide-streptogramin antibiotics: S. aureus HM1054 was susceptible to quinupristin and dalfopristin (MICs of 8 and 4 microg/ml, respectively); for S. aureus RP13, the MIC of dalfopristin was high (MICs of quinupristin and dalfopristin for strain RP13, 8 and 32 microg/ml, respectively); and S. aureus HM1054R was obtained after conjugative transfer of macrolide-lincosamide-streptogramin B constitutive resistance to HM1054, and the MIC of quinupristin for this strain was high (MICs of quinupristin and dalfopristin, 64 and 4 microg/ml, respectively). In vitro time-kill curve studies showed an additive effect [corrected] between Q-D and rifampin, at a concentration of four times the MIC, against the three strains. Rabbits with aortic endocarditis were treated 4 days with Q-D, rifampin, or their combination. In vivo, the combination was highly bactericidal and synergistic against strains susceptible to quinupristin (HM1054 and RP13) and sterilized 94% of the animals. In contrast, the combination was neither synergistic nor bactericidal against the quinupristin-resistant strain (HM1054R) and did not prevent the emergence of mutants resistant to rifampin. We conclude that the in vivo synergistic and bactericidal activity of the combination of Q-D and rifampin against S. aureus is predicted by the absence of resistance to quinupristin but not by in vitro combination studies.     

Comparative activity of the new lipoglycopeptide telavancin in the presence and absence of serum against 50 glycopeptide non-susceptible staphylococci and three vancomycin-resistant Staphylococcus aureus

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Bactericidal activity of daptomycin against Streptococcus pneumoniae compared with eight other antimicrobials

A spectrum of pneumococci with varying susceptibilities to beta-lactams, macrolides and quinolones was tested for susceptibility to nine antibiotics, including the novel lipopeptide daptomycin. Daptomycin was active against all strains (MIC range 90% killing at 1 h.     

Novel antibiotic regimens against Enterococcus faecium resistant to ampicillin, vancomycin, and gentamicin.

Enterococci have emerged as significant nosocomial pathogens. Enterococci with resistance to commonly used antibiotics are appearing more frequently. We encountered at our institution several infections caused by Enterococcus faecium with high-level resistance to ampicillin, vancomycin, and gentamicin. The optimal antibiotic therapy for serious infections with unusually resistant enterococci has not been established. Using time-kill studies, we tested the effectiveness of various antibiotic combinations against 15 isolates of multidrug-resistant enterococci. No antibiotic was consistently effective when used alone. The combination of ampicillin plus ciprofloxacin was bactericidal for the 12 isolates for which the ciprofloxacin MIC was < or = 8 micrograms/ml. The combination of ciprofloxacin plus novobiocin also demonstrated activity against these isolates. No combination was found to be bactericidal for the remaining three isolates, which were highly ciprofloxacin resistant. These antibiotic combinations may be important for the future treatment of serious infections caused by these resistant pathogens.     

Comparative in-vitro activities of moxifloxacin, trovafloxacin, quinupristin/dalfopristin and linezolid against staphylococci.

The antistaphylococcal activities of four newly developed antibiotics, moxifloxacin (an 8-methoxyfluoroquinolone), trovafloxacin (a naphthyridone), quinupristin/dalfopristin (a semisynthetic streptogramin) and linezolid (an oxazolidinone), were examined and compared with those of ciprofloxacin, vancomycin and teicoplanin, using an agar dilution method. A total of 245 clinical isolates of staphylococci, including a large number of clonally different methicillin-resistant strains, were tested. The new agents tested exhibited wide-spectrum antistaphylococcal activity against both methicillin-susceptible and methicillin-resistant strains. In contrast to the quinolones, the in-vitro activities of quinupristin/dalfopristin, linezolid and the glycopeptides remained almost unchanged, irrespective of the resistance phenotype for methicillin. A number of isolates with elevated quinolone MICs were observed.     

In vitro activity and post-antibiotic effect of quinupristin/dalfopristin (Synercid)

The in vitro activities of quinupristin/dalfopristin (Synercid), ampicillin, erythromycin, clarithromycin, vancomycin, teicoplanin, ciprofloxacin and tetracycline were examined and compared against 526 gram-positive bacteria. The minimal inhibitory concentrations (MICs) for quinupristin/dalfopristin against Staphylococcus aureus, including methicillin-resistant strains, were low (MIC(90) = 0.5 mg/l), and were comparable with those of vancomycin and teicoplanin. This compound was superior to the macrolides and highly active against Streptococcus pneumoniae (both penicillin-sensitive and penicillin-resistant strains), with MIC(90) = 2 mg/l. It was also active against other streptococci, with MIC(90) = 4 mg/l. However, this agent is less active against enterococci (MIC(90) = 32 mg/l). Quinupristin/dalfopristin showed high activity against gram-positive anaerobes, including Clostridium spp., Peptococcus spp. and Peptostreptococcus spp., with MIC(90) < or = 2 mg/l. Quinupristin/dalfopristin was also investigated for its post-antibiotic effect (PAE) and bactericidal kinetics against nine strains of gram-positive organisms, including staphylococci, enterococci and pneumococci. Exponentially growing (log phase) cultures were exposed to quinupristin/dalfopristin at 2 x MIC. Growth kinetics was evaluated using viable counting. The drug was uniformly bactericidal against pneumococci and staphylococci within 2 and 8 h of exposure, respectively. The killing activity against enterococci was weak; there was little or no reduction in bacterial count over 24 h of incubation. PAEs ranging from 2.13 to 3.28 h, 0.92 to 3.02 h and 1.89 to 7.07 h were produced on the tested pneumococci, staphylococci and enterococci, respectively. This study showed that quinupristin/dalfopristin is a promising agent active against gram-positive bacteria. The prolonged PAEs also suggest that the drug could be used intermittently at more widely spaced dosing intervals against gram-positive organisms.     

In vitro susceptibility of Bacillus anthracis to various antibacterial agents and their time-kill activity

OBJECTIVES: To investigate the in vitro acquisition of resistance to antibiotics by Bacillus anthracis. METHODS: The in vitro activities of 18 antibacterial agents against two strains of B. anthracis, the Sterne strain and the Russian anthrax vaccine strain ST-1, were tested by determining the MICs and by measuring the rates of antibiotic kill at 5x and 10x MIC. RESULTS: The fluoroquinolones ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin, the beta-lactams penicillin G and amoxicillin, the macrolide clarithromycin, the ketolide telithromycin, as well as clindamycin, rifampicin and quinupristin/dalfopristin had MICs in the range of 0.03-0.25 mg/L. Minocycline had an MIC of 0.03 mg/L, as did penicillin, against the ST-1 strain. Ciprofloxacin had an MIC of 0.03 mg/L against both strains. Erythromycin, vancomycin and the oxazolidinone linezolid were less active (MIC 0.5-2.5 mg/L). Ceftriaxone was the least active, having an MIC of 8.0 mg/L. Chloramphenicol was inactive (MIC > 256 mg/L). Quinupristin/dalfopristin, rifampicin and moxifloxacin showed the most rapid bacterial killing, achieving a complete eradication of detectable organisms (2 log(10) reduction within 0.5-3 h and 4 log(10) reduction within 0.5-4 h for both strains at concentrations of 5x and 10x the MIC). The beta-lactams and vancomycin demonstrated a 2-4 log(10) reduction within 5-15 h. Ceftriaxone had a similar effect to penicillin and amoxicillin against the ST-1 strain, but a slower effect than these two beta-lactams against the Sterne strain. The macrolides, tetracyclines and linezolid demonstrated a lower kill rate, while chloramphenicol did not kill at all. CONCLUSIONS: These data expand on the spectrum of agents recommended for the treatment of anthrax (ciprofloxacin, penicillin G and tetracyclines) and add new options, such as other fluoroquinolones, amoxicillin, rifampicin and quinupristin/dalfopristin, as potential therapeutic agents.     

Comparative in-vitro susceptibilities of Pseudomonas aeruginosa, Xanthomonas maltophilia, and Pseudomonas spp. to sparfloxacin (CI-978, AT-4140, PD131501) and reference antimicrobial agents.

The susceptibility of sparfloxacin, a new broad spectrum fluoroquinolone, was determined for 72 clinical isolates of Pseudomonas aeruginosa, 15 Xanthomonas maltophilia, and 19 Pseudomonas spp. The activity of sparfloxacin was compared with that of ciprofloxacin and other reference antibiotics. Sparfloxacin was the most active antibiotic tested against X. maltophilia (MIC90 1 mg/l) and the most active quinolone against P. cepacia and P. putrifaciens. Ciprofloxacin, however, demonstrated greater activity than sparfloxacin against P. fluorescens and P. stutzeri. P. aeruginosa was most susceptible to ciprofloxacin with an MIC90 of 2 mg/l, compared with an MIC90 of 8 mg/l for sparfloxacin and ofloxacin. Although cross-resistance between quinolones was noted, cross-resistance between antibiotic classes was not seen. Aminoglycoside-resistant and aminoglycoside-susceptible P. aeruginosa strains were equally susceptible to sparfloxacin. Kill curves showed sparfloxacin to be rapidly bactericidal against P. aeruginosa at 1 x MIC. Sparfloxacin demonstrated greater bactericidal activity than ciprofloxacin at 1 x and 2 x their MICs. Unlike ciprofloxacin and gentamicin, sparfloxacin showed sustained bactericidal activity at greater than or equal to 1 MIC for 24 h.     

In vitro activity of sparfloxacin and six reference antibiotics against gram-positive bacteria.

The in vitro activity of sparfloxacin, a new fluoroquinolone, was assessed against 234 gram-positive bacterial isolates by agar dilution (10(4) CFU/spot). Sparfloxacin activity was compared with that of ciprofloxacin and five other antibiotics. Sparfloxacin was the most active drug tested against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MIC90, 0.125-0.25 mg/l). Sparfloxacin was also the most active drug tested against Enterococcus faecalis (MIC90, 1 mg/l) and showed equal activity against gentamicin-susceptible and gentamicin-resistant (MIC greater than 2,000 mg/l) enterococci. Sparfloxacin was the most active quinolone tested against Streptococcus pneumoniae and S. pyogenes (MIC90, 1 mg/l). Most Corynebacterium jeikeium showed exquisite susceptibility to sparfloxacin (MIC, 0.06-0.25 mg/l). For MRSA, time-kill curves showed sparfloxacin to be rapidly bactericidal at the MIC of the organism. Sparfloxacin showed greater and more sustained bactericidal activity than ciprofloxacin and vancomycin at 1x and 2x the MIC. Reduction in the activity of sparfloxacin occurred with decreased agar pH (from 7.0 to 6.0) and increased bacterial inoculum. Sparfloxacin showed superior activity compared to reference drugs against most gram-positive bacteria.     

Comparison of in vitro activity of quinolone antibiotics and vancomycin against gentamicin- and methicillin-resistant Staphylococcus aureus by time-kill kinetic studies.

Quinolone antibiotics have been proposed as possible alternatives to vancomycin for methicillin-resistant Staphylococcus aureus infections. We investigated the activities of amifloxacin, ciprofloxacin, norfloxacin, and vancomycin by time-kill kinetic studies. Antibiotic concentrations of 0, 1.0, and 4.0 times the MIC were used against four strains of gentamicin- and methicillin-resistant S. aureus. Staphylococci were plated onto ciprofloxacin-containing agar at all time points, in repeat time-kill kinetic studies. Macrobroth dilution MICs and MBCs were determined. Ciprofloxacin levels were measured by bioassay. Replica plating was performed from the original susceptible inoculum (MIC, 0.125 micrograms/ml) onto ciprofloxacin-supplemented agar. At 4.0 times the MIC, only with ciprofloxacin was there regrowth at 24 and 48 h. All four strains of staphylococci grew on agar supplemented with 1 microgram of ciprofloxacin per ml; three of four grew on agar supplemented with 2 micrograms of ciprofloxacin per ml. MICs and MBCs for these resistant clones ranged from 8 to 32 micrograms/ml. No degradation in activity or amount of ciprofloxacin could be detected in the bioassay. Replica-plated staphylococci grew on agar containing 1 microgram/ml but not higher concentrations of ciprofloxacin at 48 h. Amifloxacin and norfloxacin sustained bactericidal activity comparable to that of vancomycin. We conclude that heteroresistant subpopulations of gentamicin- and methicillin-resistant S. aureus can emerge under antibiotic selection pressure. Such resistant clones may then mutate in the presence of subinhibitory concentrations of antibiotic to higher levels of ciprofloxacin resistance.     

In vitro activity of fosfomycin in combination with various antistaphylococcal substances

Using the chequerboard technique we studied the in vitro activity of the broad spectrum antibiotic fosfomycin in combination with vancomycin, rifampicin, linezolid, quinupristin/ dalfopristin, cefazolin, meropenem and moxifloxacin against two Staphylococcus epidermidis strains (ATCC 12228, DSM 3269) and five Staphylococcus aureus isolates (ATCC 29213, DSM 683, DSM 46320, GISA 323/93, MRSA 3558/00). The phenomena of 'trailing' and 'skipped wells' did not present a problem. Synergy was the most common effect of all drugs tested in combination with fosfomycin; only combination with vancomycin showed antagonism for two of seven isolates. Using a killing-curve technique fosfomycin showed cidal activity, where increasing the drug concentration above the MIC did not enhance killing velocity. Inhibitory concentrations of vancomycin plus fosfomycin against DSM 46320 caused effects identical to those observed with vancomycin alone. The combination of fosfomycin plus linezolid exerted the bacteriostatic effect found with linezolid alone. Fosfomycin plus quinupristin/dalfopristin exhibited the bactericidal effect found with fosfomycin alone (in contrast to the rapidly bactericidal effect of quinupristin/dalfopristin). Electron microscopy showed that fosfomycin given in combination with linezolid, quinupristin/dalfopristin or moxifloxacin (substances that do not cause morphological alterations when given alone) resulted in 'cauliflower-shaped' distortion as caused by fosfomycin alone. Our in vitro data indicate considerable potential for fosfomycin used in combination with other antistaphylococcal antimicrobials, especially linezolid or quinupristin/dalfopristin.     

Activity of telavancin compared to other agents against coagulase-negative staphylococci with different resistotypes by time kill

Among 10 coagulase-negative staphylococci, telavancin, quinupristin/dalfopristin, and tigecycline were the most potent antimicrobials. Telavancin exhibited bactericidal effect to 9 strains out of 10 tested at 4× MIC after 24 h of exposure similar to those of vancomycin and daptomycin. By contrast, linezolid was mainly bacteriostatic and teicoplanin was bactericidal to 7 strains tested at 4× MIC after 24 h.     

In vitro Gram-positive antimicrobial activity of evernimicin (SCH 27899), a novel oligosaccharide, compared with other antimicrobials: a multicentre international trial

The antimicrobial activity of evernimicin (formerly SCH 27899), a novel oligosaccharide antimicrobial of the everninomicin class, was evaluated against four groups of Gram-positive pathogens: (i) Streptococcus pneumoniae (n = 1452); (ii) methicillin- or oxacillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MR-CoNS; n = 1427); (iii) enterococci (n = 1517); and (iv) non-pneumococcal streptococci (n = 1388), using the Etest method at each study centre throughout Eastern and Western Europe, Scandinavia, South Africa, Turkey and North America. Comparative MICs were determined for a variety of reference compounds, including vancomycin, quinupristin/dalfopristin, chloramphenicol, penicillin, ampicillin, oxacillin, ceftriaxone and ciprofloxacin. Evernimicin was highly active against all strains tested, with MIC90 values < or = 1.0 mg/L, ranging from 0.047 mg/L against S. pneumoniae to 1.0 mg/L against MRSA/MR-CoNS and enterococci. Compared with the reference agents, the MIC90 of evernimicin were lower against all species. Against MRSA and MR-CoNS the MIC90s of evernimicin, quinupristin/dalfopristin and vancomycin (the three most active agents) were 1.0, 1.5 and 3.0 mg/L, respectively. Against all species tested, the relative activities and spectra of these agents were: evernimicin > vancomycin > quinupristin/dalfopristin. The Etest proved to be reliable and reproducible, despite occasional interpretive difficulties caused by observer inexperience. Quality control results were excellent among the 33 participant sites. The results of this in vitro, multicentre, multinational study demonstrate that evernimicin possesses high antimicrobial activity against Gram-positive organisms that compares favourably with established antibacterial treatments and newer agents such as quinupristin/dalfopristin. Further clinical investigations of everninomicin class compounds appear warranted.     

Comparative Antimicrobial Activity and Kill-Curve Investigations of Novel Ketolide Antimicrobial Agents (HMR 3004 and HMR 3647) Tested against Haemophilus influenzae and Moraxella catarrhalis Strains

The activity of two ketolide compounds, HMR 3004 and 3647, were compared to those of five macrolides, quinupristin/dalfopristin, ciprofloxacin, and ampicillin. The rate of killing for the ketolides was also assessed against Haemophilus influenzae and Moraxella catarrhalis. One hundred H. influenzae and 148 M. catarrhalis isolates were tested using broth microdilution and appropriate growth media. The killing rates of HMR 3004 and 3647 were analyzed using the time-kill method against five strains from each of the two species. Against H. influenzae, the activity of the ketolides (MIC₉₀, 2 or 4 μg/mL) resembled that of azithromycin and quinupristin/dalfopristin and was more active than any tested macrolide. Against M. catarrhalis, HMR 3004 and 3647 were equally potent as azithromycin and clarithromycin (MIC₅₀, 0.06 μg/mL and MIC₉₀, 0.12 μg/mL) and more potent than all other macrolides or quinupristin/dalfopristin. Time-kill kinetic studies revealed that like the macrolide compounds, the ketolides are bacteristatic at or near the MIC for both H. influenzae and M. catarrhalis. This activity can be increased to a bactericidal level if the concentration is increased four- or eightfold the MIC for H. influenzae. In conclusion, HMR 3004 and 3647 have bacteristatic activity against tested respiratory pathogens and may prove to have an important role against macrolide-resistant isolates.