Resistance in these 28 strains was associated with mutations in parC, gyrA, parE, and/or gyrB or efflux, with some strains having multiple resistance mechanisms. For 12 penicillin-susceptible and -resistant pneumococcal strains (2 quinolone resistant), time-kill results showed that levofloxacin at the MIC, gemifloxacin and sparfloxacin at two times the MIC, and ciprofloxacin, grepafloxacin, and trovafloxacin at four times the MIC were bactericidal for all strains after 24 h. Gemifloxacin was uniformly bactericidal after 24 h at <0.5 g/ml. Various degrees of 90 and 99% killing by all quinolones were detected after 3 h. Gemifloxacin and trovafloxacin were both bactericidal at two times the MIC for the two quinolone-resistant pneumococci. Amoxicillin at two times the MIC and cefuroxime at four times the MIC were uniformly bactericidal after 24 h, with some degree of killing at earlier time points. Macrolides gave slower killing against the seven susceptible strains tested, with 99.9% killing of all strains at two to four times the MIC after 24 h. PAEs for five quinolonesusceptible strains were similar (0.3 to 3.0 h) for all quinolones, and significant quinolone PAEs were found for the quinolone-resistant strain.The incidence of pneumococci resistant to penicillin G and other -lactam and non--lactam compounds has increased worldwide at an alarming rate, including in the United States. Major foci of infections presently include South Africa, Spain, Central and Eastern Europe, and parts of Asia (1, 9, 10, 13, 14). In the United States a recent survey has shown an increase in resistance to penicillin from Ͻ5% before 1989 (including Ͻ0.02% of isolates for which MICs were Ն2.0 g/ml) to 6.6% in 1991 to 1992 (with 1.3% of isolates for which MICs were Ն2.0 g/ml) (3). In another, more recent survey, 23.6% (360) of 1,527 clinically significant pneumococcal isolates were not susceptible to penicillin (8). It is also important to note the high rates of isolation of penicillin-intermediate and -resistant pneumococci (approximately 30%) in middle ear fluids from patients with refractory otitis media, compared to other isolation sites (2). The problem of drug-resistant pneumococci is compounded by the ability of resistant clones to spread from country to country and from continent to continent (16,17).There is an urgent need for oral compounds for outpatient treatment of otitis media and respiratory tract infections caused by penicillin-intermediate and -resistant pneumococci (9,10,13,14). Available quinolones such as ciprofloxacin and ofloxacin yield moderate in vitro activity against pneumococci, with MICs clustering around the breakpoints (22,25,26). Gemifloxacin (SB 265805; LB 20304a) is a new broad-spectrum fluoronaphthyridone carboxylic acid with a novel pyrrolidone substituent (5,12,19). Previous preliminary studies (5,12,19) have shown that this compound is very active against pneumococci. This study further examined the antipneumococcal activity of gemifloxacin compared to those of ciprofloxacin, levofloxacin, sparfloxa...
Retapamulin had the lowest rate of spontaneous mutations by single-step passaging and the lowest parent and selected mutant MICs by multistep passaging among all drugs tested for all Staphylococcus aureus strains and three Streptococcus pyogenes strains which yielded resistant clones. Retapamulin has a low potential for resistance selection in S. pyogenes, with a slow and gradual propensity for resistance development in S. aureus.Pleuromutilins are a new class of antimicrobials which inhibit protein synthesis by interacting at a unique site on the 70S ribosome and demonstrate excellent in vitro activity against gram-positive and some gram-negative bacteria (2,5,9). This study used multi-and single-step passage studies to test the ability of retapamulin ( Fig. 1), compared to those of mupirocin, fusidic acid (only against Staphylococcus aureus strains), cephalexin, erythromycin, linezolid, vancomycin, and quinupristindalfopristin, to select for resistance in 12 Staphylococcus aureus and 10 Streptococcus pyogenes strains.S. aureus strains comprised three methicillin-and quinolonesusceptible, four methicillin-and quinolone-resistant, three vancomycin-intermediate, and two vancomycin-resistant (VRSA) strains. The 10 S. pyogenes strains comprised two macrolidesusceptible strains, two erm(B)-, three mef(A)-, and two erm(TR)-positive strains, and one strain with a mutation in the L4 ribosomal protein (68KGT insertion). Retapamulin and mupirocin powders were obtained from GlaxoSmithKline, Collegeville, Pa., and other drugs were obtained from their respective manufacturers. Initial MICs were determined by the CLSI agar dilution method (7).Multipassage resistance selection was done as described previously (3, 6). Daily passages were continued until a more-thanfour-fold increase in the MIC was found (minimum passage number, 14; maximum passage number, 50). If MICs of Ն32 g/ml were found, subculturing in the presence of an antibiotic ceased. Prolonged selection for the full 50 days was conducted for three random staphylococcal strains and all three streptococcal strains showing retapamulin resistance development. The stability of acquired resistance was determined by MIC determination after 10 daily passages on drug-free agar.The frequency of spontaneous single-passage mutations was determined as described previously (3, 6). Pulsed-field gel electrophoresis was used to confirm the identities of all parents and clones (3,6).Genes encoding the L3 ribosomal protein were amplified and sequenced from all parents and from clones for which an elevation in the retapamulin MIC was observed by the multipassage study. Eight S. aureus and seven S. pyogenes singlepassage mutants were randomly selected for L3 analysis. The genes encoding ribosomal proteins L4 and L22 and domains II and V of 23S rRNA were amplified and sequenced for all S.
Dalbavancin, tested against 146 staphylococci, was more potent than other drugs tested, with an MIC at which 50% of staphylococci were inhibited of 0.03 g/ml and an MIC at which 90% of staphylococci were inhibited of 0.06 g/ml by microdilution. For all strains, MICs of vancomycin, linezolid, ranbezolid, oritavancin, daptomycin, and quinupristin-dalfopristin were <4.0 g/ml. Dalbavancin was bactericidal at four times the MIC against all six strains tested.Emergence of staphylococci that are intermediate and resistant to methicillin and quinolone and recently to vancomycin, as well as the propensity of these organisms to cause serious systemic infections in immunocompromised hosts, necessitates other therapeutic modalities (2,3,10,11,15,18,21,25). During 2002, two clinical strains of vancomycin-resistant Staphylococcus aureus (VRSA) carrying van(A), one from Detroit, Mich., and one from our hospital, were isolated (3). Most methicillin-resistant staphylococci are also resistant to available quinolones, such as ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin (2,10,15,18,21). Thus, these last compounds may not be safely used in empirical therapy for patients with methicillin-resistant staphylococcal infections.Dalbavancin is an experimental glycopeptide with a long half-life (4) with excellent activity against gram-positive aerobic and anaerobic bacteria (1,4,8,13,24). This study examined the susceptibilities of 146 staphylococci to dalbavancin compared to susceptibilities to vancomycin, teicoplanin, linezolid, ranbezolid, oritavancin, daptomycin, and quinupristin-dalfopristin by MIC and time-kill analysis. Although dalbavancin activity by MIC is well known, little has thus far been published on its kill kinetics against staphylococci.Twenty-nine methicillin-resistant and 43 methicillin-susceptible S. aureus strains as well as 36 methicillin-resistant and 38 methicillin-susceptible coagulase-negative staphylococci were studied by microdilution, and six strains (three S. aureus strains and three coagulase-negative staphylococci: two methicillin resistant strains and one methicillin-susceptible strain in each group) were subjected to time-kill analysis. Sources of drugs were as follows: dalbavancin, Vicuron Pharmaceuticals, King of Prussia, Pa.; vancomycin, Sigma, Inc., St. Louis, Mo.; oritavancin (as LY 333328), Eli Lilly & Co., Indianapolis, Ind.; teicoplanin and quinupristin-dalfopristin, Aventis Pharma, Romainville, France; linezolid, Pfizer, Inc., Groton, Conn.; ranbezolid, Ranbaxy Laboratories, New Delhi, India; and daptomycin, Cubist Pharmaceuticals, Lexington, Mass. Microdilutions were performed as recommended by NCCLS (17) using commercially prepared trays (TREK, Inc., Westlake, Ohio) with dehydrated dalbavancin and all other drugs in the frozen state. MICs of vancomycin were read after a full 24-h incubation. Calcium was added to daptomycin wells, as recommended by NCCLS (17).For time kills, tubes containing 5 ml of cation-adjusted Mueller-Hinton broth (BBL) with doubling antibiotic concentrations...
Clostridium difficile is a leading cause of antibiotic-associated diarrhea, especially in hospitals and long-term facilities (8,11,12). The organism accounts for about 20% of hospitalized patients who develop diarrhea after treatment with anti-infectives (and occasionally cytotoxic chemotherapeutic agents) and the majority of cases of antibiotic-associated colitis (3,7,10,17). The rising incidence of C. difficile-associated diarrhea has been attributed to the increasingly common prescription of broad-spectrum antibiotics (16). It is also important to note that the etiology of pseudomembranous colitis appears to be multifactorial and not dependent only on the in vitro activity of an agent against C. difficile (17).Initial treatment involves discontinuation of the offending medication, as well as supportive therapy, but antimicrobial therapy is necessary if these measures fail to alleviate the symptoms (7, 10). The two most commonly used antimicrobial therapies are vancomycin and metronidazole, and while both are effective in treating the infection, both have shortcomings, including high (approximately 20%) relapse rates (6). In addition, metronidazole may have significant side effects, including nausea, neuropathy, leukopenia, and seizures (6, 18), while widespread use of vancomycin may lead to increased vancomycin resistance in enterococci and staphylococci (2, 4). The above-described shortcomings have necessitated a search for new therapeutic options for this disease.OPT-80 (Fig. 1) is a novel macrocycle which is inactive against gram-negative organisms with moderate activity against gram-positive organisms, such as staphylococci and enterococci, but excellent activity against clostridia. This study compares the in vitro activity of OPT-80 to those of linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/ clavulanate, imipenem, clindamycin, and metronidazole against 350 anaerobes.All anaerobes were clinical strains identified by standard procedures (9) and kept frozen in double-strength skim milk (dehydrated skim milk: Difco Laboratories, Detroit, Mich.) at Ϫ70°C until use. All organisms, including the 21 C. difficile strains, were separate isolates and not clonally related. Prior to testing, strains were subcultured twice onto enriched Brucella agar plates (13). OPT-80 was obtained from Optimer Pharmaceuticals, Inc., San Diego, Calif., and other drugs were obtained from respective manufacturers. Agar dilution susceptibility testing was carried out according to the latest method recommended by the NCCLS (13), using Brucella agar with 5% sterile defibrinated laked sheep blood. Clavulanate was combined with amoxicillin in a 1:2 ratio. All quality-control gram-negative and -positive strains recommended by NCCLS (13) were included with each run: in every case, results (where available) were in range.Results of MIC testing are presented in Table 1. As can be seen, OPT-80 was active only against gram-positive anaerobes, especially against Clostridium species (including C. difficile), with MICs ra...
Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC 50 and MIC 90 values (g/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristindalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1؋ and 2؋ the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2؋ the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2؋ the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.The incidence of pneumococci resistant to penicillin G and other -lactam antibiotics, as well as non--lactam antibiotics, has increased worldwide at an alarming rate. Major foci of infection include South Africa, Spain, and central and eastern Europe (1,21,22,35,48). A survey published in the mid-1990s showed an increase in resistance by pneumococci to penicillin from Ͻ5% before 1989 (including Ͻ0.02% of isolates with MICs of Ն2 g/ml) to 6.6% in 1991 to 1992 (with 1.3% of isolates with MICs of Ն2 g/ml) (5). A more recent survey (23) reported that 50.4% of 1,476 clinically significant pneumococcal isolates were not susceptible to penicillin and that high rates of macrolide-resistant pneumococci occurred in strains with elevated penicillin MICs, for an overall pneumococcal macrolide resistance rate of approximately 33%. Rates of macrolide resistance are even higher in Spain, France, central and eastern Europe, Korea, and Japan (1, 23, 24, 35). Although pneumococcal fluoroquinolone resistance is still uncommon, relatively high rates have been reported in Canada, Hong Kong, Spain, and Croatia (19,29,39,45). Moreover, there is a high rate of isolation of penicillin-intermediate and -resistant pneumococci (approximately 30%) in middle ear fluids from patients with refractory otitis media, compared to rates from other isolation sites (3,15,16). The problem of drug-resistant pneumococci is compounded by the ability of resistant clones to spread rapi...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.