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Biomedical subjects

Peter C Appelbaum

Publications and source records attributed to Peter C Appelbaum.

At least 19 recordsLinked to original sources
PubMed2007

Activity of daptomycin alone and in combination with rifampin and gentamicin against Staphylococcus aureus assessed by time-kill methodology.

The synergistic effects of daptomycin plus gentamicin or rifampin were tested against 50 Staphylococcus aureus strains, with daptomycin MICs ranging between 0.25 and 8 microg/ml. Daptomycin sub-MICs combined with gentamicin concentrations lower than the MIC yielded synergy in 34 (68%) of the 50 strains. Daptomycin combined with rifampin yielded synergy in one vancomycin-intermediate S. aureus strain only, and virtually all synergy occurred between daptomycin and gentamicin.

Anti-Bacterial Agents↗
PubMed2006

Multistep resistance selection and postantibiotic-effect studies of the antipneumococcal activity of LBM415 compared to other agents.

LBM415 is a peptide deformylase inhibitor active against gram-positive bacterial species and some gram-negative species. In multiselection studies, LBM415 had low MICs against all Streptococcus pneumoniae strains tested, regardless of their genotype, and selected resistant clones after 14 to 50 days. MIC increases correlated with changes mostly in the 70GXGXAAXQ77 motif in peptide deformylase. The postantibiotic effect of LBM415 ranged from 0.3 to 1.4 h.

Amidohydrolases↗
PubMed2006

Activity of DX-619 compared to other agents against viridans group streptococci, Streptococcus bovis, and Cardiobacterium hominis.

Against 198 viridans group streptococci, 25 Streptococcus bovis strains, and 5 Cardiobacterium hominis strains, MICs of DX-619, a des-F(6)-quinolone, were between 0.004 and 0.25 microg/ml. These MICs were lower than those of other quinolones (< or = 0.008 to > 32 microg/ml). Beta-lactam MICs were between < or = 0.008 and 16 microg/ml. Azithromycin resistance was found in most species, while most were telithromycin susceptible. Glycopeptides and linezolid were active against viridans group strains but inactive against C. hominis.

Acetamides↗
PubMed2006

Combination of altered PBPs and expression of cloned extended-spectrum beta-lactamases confers cefotaxime resistance in Haemophilus influenzae.

BACKGROUND: Resistance to beta-lactams in Haemophilus influenzae is mostly due to the presence of TEM beta-lactamases. beta-Lactamase-negative ampicillin resistance (BLNAR) also occurs as a result of PBP3 modifications. BLNAR strains are particularly common in Japan and France, and strains with combined mechanisms of altered PBP3 and beta-lactamase (BLPACR) are emerging. Although the prevalence of beta-lactamase-positive strains is high, TEM-derived extended-spectrum beta-lactamase (ESBL)-mediated cephalosporin resistance, which is common in Enterobacteriaceae, has not been reported in H. influenzae. In this study, the ability of ESBLs TEM-3, -4 and -5 to confer beta-lactam resistance in H. influenzae strains with or without modified PBP3 was tested. METHODS: The genes encoding TEM-1, -3, -4 and -5 were cloned into plasmid pLS88 and were used to transform H. influenzae Rd and BLNAR H. influenzae Rd strains with PBP3 modifications. MICs were determined using CLSI macrobroth dilution. The ability of amoxicillin/clavulanate pre-diffusion disc tests to discriminate between ESBL-producing strains and other strains was also tested. RESULTS: The presence of ESBLs in BLNAR strains conferred cefotaxime resistance, but H. influenzae Rd strains expressing ESBLs and BLNAR strains expressing TEM-1 remained cefotaxime susceptible. The amoxicillin/clavulanate pre-diffusion tests were able to discriminate the ESBL-producing strains from the other strains. CONCLUSIONS: The presence of altered PBP3 increases the effect of ESBLs in recombinant H. influenzae strains to produce cefotaxime resistance. Amoxicillin/clavulanate pre-diffusion disc tests can discriminate ESBL-producing strains from other strains.

Anti-Bacterial Agents↗
PubMed2006

Activities of ceftobiprole, a novel broad-spectrum cephalosporin, against Haemophilus influenzae and Moraxella catarrhalis.

Ceftobiprole, a broad-spectrum pyrrolidinone-3-ylidenemethyl cephem currently in phase III clinical trials, had MICs between 0.008 microg/ml and 8.0 microg/ml for 321 clinical isolates of Haemophilus influenzae and between < or =0.004 microg/ml and 1.0 microg/ml for 49 clinical isolates of Moraxella catarrhalis. Ceftobiprole MIC(50) and MIC(90) values for H. influenzae were 0.06 microg/ml and 0.25 microg/ml for beta-lactamase-positive strains (n = 262), 0.03 microg/ml and 0.25 microg/ml for beta-lactamase-negative strains (n = 40), and 0.5 microg/ml and 2.0 microg/ml for beta-lactamase-negative ampicillin-resistant strains (n = 19), respectively. Ceftobiprole MIC(50) and MIC(90) values for beta-lactamase-positive M. catarrhalis strains (n = 40) were 0.12 microg/ml and 0.5 microg/ml, respectively, whereas the ceftobiprole MIC range for beta-lactamase-negative M. catarrhalis strains (n = 9) was < or =0.004 to 0.03 microg/ml. Ceftriaxone MICs usually were generally at least twofold lower than those of ceftobiprole, whereas amoxicillin-clavulanate MICs usually were higher than those of ceftobiprole. Azithromycin and telithromycin had unimodal MIC distributions against H. influenzae, with MIC(90) values of azithromycin and telithromycin of 2 microg/ml and 4 microg/ml, respectively. Except for selected quinolone-nonsusceptible H. influenzae strains, moxifloxacin proved highly active, with MIC(90) values of 0.12 microg/ml. Time-kill analyses showed that ceftobiprole, ceftriaxone, cefpodoxime, amoxicillin-clavulanate, azithromycin, telithromycin, and moxifloxacin were bactericidal at 2x MIC by 24 h against all 10 H. influenzae strains surveyed. Only modest increases in MICs were found for H. influenzae or M. catarrhalis clones after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of H. influenzae or M. catarrhalis clones with elevated ceftobiprole MICs is quite low.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2006

Telithromycin-nonsusceptible clinical isolates of Streptococcus pneumoniae from Europe.

Telithromycin-nonsusceptible pneumococcal clinical isolates (n = 17) were analyzed for their antimicrobial susceptibility, macrolide resistance mechanisms, and genetic relatedness. All strains showed the erm(B) genotype and showed a wide range of combinations of macrolide resistance mechanisms. The predominant clone (n = 7) was serotype 14, sequence type 143.

Anti-Bacterial Agents↗
PubMed2006

Activity of LBM415 compared to those of 11 other agents against Haemophilus species.

When tested against 254 Haemophilus influenzae strains, LBM415, a peptide deformylase inhibitor, gave MIC50 and MIC90 values of 2.0 microg/ml and 8.0 microg/ml, respectively. The MICs were independent of beta-lactam or quinolone susceptibility and the presence or absence of macrolide efflux or ribosomal protein mutations. The MICs of LBM415 against 23 H. parainfluenzae strains were similar to those against H. influenzae. In contrast, erythromycin, azithromycin, and clarithromycin gave unimodal MIC distributions, and apart from beta-lactamase-negative, ampicillin-resistant strains, all strains were susceptible to the beta-lactams tested. Apart from selected quinolone-resistant strains, all strains were susceptible to ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin. Resistance to trimethoprim-sulfamethoxazole was common. The potencies of all drugs against 23 H. parainfluenzae strains were similar to those against H. influenzae. Time-kill studies with 10 Haemophilus strains showed LBM415 to be bactericidal at 2 x the MIC against 8 of 10 strains after 24 h. For comparison, the macrolides and beta-lactams were bactericidal against 8 to 10 strains each at 2 x the MIC after 24 h. Quinolones were bactericidal against all 10 strains tested at 2 x the MIC after 24 h. Against six H. influenzae strains, postantibiotic effects for LBM415 lasted between 0.8 and 2.2 h. In multistep resistance selection studies, LBM415 produced resistant clones in 7 of the 10 strains tested, with MICs ranging from 4 to 64 microg/ml. No mutations in deformylase (def) and formyltransferase (fmt) genes were detected in any of the LBM415-resistant mutants.

Amidohydrolases↗
PubMed2006

Antipneumococcal activity of DW-224a, a new quinolone, compared to those of eight other agents.

DW-224a is a new broad-spectrum quinolone with excellent antipneumococcal activity. Agar dilution MIC was used to test the activity of DW-224a compared to those of penicillin, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin against 353 quinolone-susceptible pneumococci. The MICs of 29 quinolone-resistant pneumococci with defined quinolone resistance mechanisms against seven quinolones and an efflux mechanism were also tested. DW-224a was the most potent quinolone against quinolone-susceptible pneumococci (MIC(50), 0.016 microg/ml; MIC(90), 0.03 microg/ml), followed by gemifloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. beta-Lactam MICs rose with those of penicillin G, and azithromycin resistance was seen mainly in strains with raised penicillin G MICs. Against the 29 quinolone-resistant strains, DW-224a had the lowest MICs (0.06 to 1 microg/ml) compared to those of gemifloxacin, clinafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. DW-224a at 2x MIC was bactericidal after 24 h against eight of nine strains tested. Other quinolones gave similar kill kinetics relative to higher MICs. Serial passages of nine strains in the presence of sub-MIC concentrations of DW-224a, moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin were performed. DW-224a yielded resistant clones similar to moxifloxacin and gemifloxacin but also yielded lower MICs. Azithromycin selected resistant clones in three of the five parents tested. Amoxicillin-clavulanate and cefuroxime did not yield resistant clones after 50 days.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2006

Single- and multistep resistance selection studies on the activity of retapamulin compared to other agents against Staphylococcus aureus and Streptococcus pyogenes.

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.

Amino Acid Sequence↗
PubMed2006

Activities of tizoxanide and nitazoxanide compared to those of five other thiazolides and three other agents against anaerobic species.

Agar dilution was used, and MICs of metronidazole, tizoxanide, nitazoxanide, denitrotizoxanide, RM 4803, RM 4807, RM 4809, RM 4819, amoxicillin-clavulanate, and clindamycin were measured against 412 anaerobes. Nitazoxanide, tizoxanide, RM 4807, and RM 4809 were active against all groups, except for gram-positive non-spore-forming rods with 50% minimum inhibitory concentrations (when the latter were excluded) of 1 to 2 microg/ml and 90% minimum inhibitory concentrations of 4 to 8 microg/ml, respectively. Metronidazole MICs were usually lower against all groups except clostridia.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2006

Effect of efflux on telithromycin and macrolide susceptibility in Haemophilus influenzae.

This study investigated the presence of telithromycin and azithromycin efflux in 58 clinical strains of Haemophilus influenzae with various susceptibilities to macrolides, azalides, and ketolides. Efflux pumps were studied by measuring accumulation of radioactive [3H]telithromycin and [N-methyl-3H]azithromycin in the presence and absence of carbonyl m-chlorophenylhydrazone (CCCP), a protonophore. In 17 strains for which the telithromycin MICs were 0.06 to 0.5 microg/ml (azithromycin MICs, < or = 0.06 to 0.125 microg/ml; clarithromycin MICs, < or = 0.06 to 2 microg/ml), telithromycin and azithromycin accumulations were high without CCCP and not affected by its addition, which indicates absence of efflux. In 22 strains for which the telithromycin MICs were 0.25 to 4 microg/ml (azithromycin MICs, 0.25 to 1 microg/ml; clarithromycin MICs, 1 to 8 microg/ml), initially low levels of telithromycin accumulation became higher after addition of CCCP, indicating a functioning efflux pump. Nineteen strains for which the telithromycin MICs were > or = 2 microg/ml had efflux as well as various mutations in ribosomal proteins L4, L22, and/or 23S rRNA (domains II and V). Of these 19 strains, the telithromycin MICs (> or = 8 microg/ml) for 17 of them were significantly raised (azithromycin, MICs 4 to >32 microg/ml; clarithromycin MICs, 8 to >32 microg/ml). From these results we conclude that telithromycin efflux with or without additional ribosomal alterations is present in all H. influenzae strains, except for those for which the telithromycin MICs were very low.

Anti-Bacterial Agents↗
PubMed2006

Activity of retapamulin against Streptococcus pyogenes and Staphylococcus aureus evaluated by agar dilution, microdilution, E-test, and disk diffusion methodologies.

The in vitro activity of retapamulin against 106 Staphylococcus aureus isolates and 109 Streptococcus pyogenes isolates was evaluated by the agar dilution, broth microdilution, E-test, and disk diffusion methodologies. Where possible, the tests were performed by using the CLSI methodology. The results of agar dilution, broth microdilution, and E-test (all with incubation in ambient air) for S. aureus yielded similar MICs, in the range of 0.03 to 0.25 microg/ml. These values corresponded to zone diameters between 25 and 33 mm by the use of a 2-microg retapamulin disk. Overall, 99% of the agar dilution results and 95% of E-test results for S. aureus were within +/-1 dilution of the microdilution results. For S. pyogenes, the MICs obtained by the agar and broth microdilution methods (both after incubation in ambient air) were in the range of 0.008 to 0.03 microg/ml, and E-test MICs (with incubation in ambient air) were 0.016 to 0.06 microg/ml. For S. pyogenes, 100% of the agar dilution MIC results were within +/-1 dilution of the broth microdilution results. E-test MICs (after incubation in ambient air) were within +/-1 and +/-2 dilutions of the broth microdilution results for 76% and 99% of the isolates, respectively. E-test MICs for S. pyogenes strains in CO(2) were up to 4 dilutions higher than those in ambient air. Therefore, it is recommended that when retapamulin MICs are determined by E-test, incubation be done in ambient air and not in CO(2), due to the adverse effect of CO(2) on the activity of this compound. Diffusion zones (with incubation in CO(2)) for S. pyogenes were 18 to 24 mm. Retapamulin MICs for all strains by all methods (with incubation in ambient air) were < or =0.25 microg/ml. These results demonstrate that S. pyogenes (including macrolide-resistant strains) and S. aureus (including methicillin-resistant and vancomycin-nonsusceptible strains) are inhibited by very low concentrations of retapamulin and that all four testing methods are satisfactory for use for susceptibility testing.

Anti-Bacterial Agents↗
PubMed2006

Two new colorimetric methods for early detection of vancomycin and oxacillin resistance in Staphylococcus aureus.

We developed two colorimetric methods for the detection of vancomycin- and oxacillin-resistant Staphylococcus aureus in </=6 h: (i) a nitrate reductase assay and (ii) a resazurin microplate method. MICs agreed with results obtained by CLSI methods for oxacillin. However, detection of vancomycin resistance required a larger inoculum. These methods may be recommended for the detection of vancomycin- and oxacillin-resistant S. aureus.

Anti-Bacterial Agents↗
PubMed2006

Nadifloxacin: a quinolone for topical treatment of skin infections and potential for systemic use of its active isomer, WCK 771.

Nadifloxacin is a potent, broad-spectrum, quinolone agent approved for topical use in acne vulgaris and skin infections in Japan. As exposure of pathogenic and colonising bacteria to antibiotics results in drug resistance, it is not desirable to use an important, broad-spectrum antibiotic, which belongs to a class of agents widely used systemically to treat a wide variety of infections, as a topically applied preparation. On this basis, nadifloxacin is not a good option for topical treatment of acne when other effective non-antibiotic treatments are available. Nadifloxacin has potential as a topical agent for short-term treatment of skin infections. The arginine salt of its (-)-(S)-isomer is being developed as a parenteral agent based on its potency against methicillin and quinolone-resistant Staphylococcus aureus.

Acne Vulgaris↗
PubMed2005

A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus.

There is an urgent medical need for novel antibacterial agents to treat hospital infections, specially those caused by multidrug-resistant Gram-positive pathogens. The need may also be fulfilled by either exploring antibacterial agents having new mechanism of action or expanding known classes of antibacterial drugs. The paper describes a new chemical entity, compound 21, derived from hitherto little known "floxacin". The choice of the entity was made from a series of synthesized prodrugs and salts of the active chiral benzoquinolizine carboxylic acid, S-(-)-nadifloxacin. The chemistry, physicochemical characteristics, and essential bioprofile of 21 qualifies it for serious consideration as a novel drug entity against hospital infections of multi-drug-resistant Staphylococcus aureus, and its progress up to clinical phase I trials in humans is described.

Animals↗
PubMed2005

Disc diffusion-based screening tests for extended-spectrum beta-lactamases in Haemophilus influenzae.

OBJECTIVES: To establish a suitable screening test for the detection of extended-spectrum beta-lactamases (ESBLs) in Haemophilus influenzae. METHODS: Double disc diffusion tests using cephalosporin discs adjacent to an amoxicillin/clavulanate 3 microg disc, prediffusion tests, where an amoxicillin/clavulanate 3 microg disc was prediffused before being replaced with a cephalosporin disc, and combination cephalosporin/clavulanate discs were used to screen recombinant H. influenzae expressing cloned ESBLs. Methods initially determined to be suitable were validated by testing a range of clinical strains. RESULTS: Enhanced zones around cephalosporin discs due to synergy with an adjacent amoxicillin/clavulanate disc were not reliably demonstrated with the recombinant H. influenzae strains expressing ESBLs. Cefotaxime 5 microg or 30 microg and cefpodoxime 10 microg discs prediffused with an amoxicillin/clavulanate 3 microg disc, and cefotaxime 30 microg/clavulanate 10 microg and cefpodoxime 10 microg/clavulanate 1 microg combination discs all gave zone sizes > or = 5 mm greater than the corresponding plain disc for all recombinant ESBL-producing strains. None of the clinical strains gave enhanced zones. CONCLUSIONS: Cefotaxime 5 or 30 microg or cefpodoxime 10 microg discs prediffused with an amoxicillin/clavulanate 3 microg disc, or cefotaxime 30 microg/clavulanate 10 microg and cefpodoxime 10 microg/clavulanate 1 mug combination discs are all suitable for screening H. influenzae isolates for the presence of ESBLs. ESBL-producing strains should show an increase in zone diameter of > or = 5 mm compared with the corresponding plain cephalosporin disc.

Amoxicillin↗
PubMed2005

Recently approved and investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria.

The development of resistance in the major pathogenic Gram-positive genera Staphylococcus and Streptococccus has led to the need for new agents that are able to overcome existing resistance mechanisms or that have novel mechanisms of action. There is currently a dearth of new agents that are active against resistant bacterial species. Agents that have recently been approved for clinical use include linezolid, the first oxazolidinone in clinical use, daptomycin, the first lipopeptide in clinical use, and telithromycin, a ketolide that is derived from clarithromycin. Agents currently in clinical development include tigecycline, a broad-spectrum intravenous tetracycline, ceftobiprole, a broad-spectrum cephalosporin that has activity against methicillin-resistant staphylococci, DX-619 and WCK-771, which are potent quinolones that have activity against quinolone-resistant staphylococci, oritavancin and dalbavancin, both of which are new glycopeptides, and iclaprim, which is a diaminopyrimidine. Additional agents that are in preclinical development against Gram-positive pathogens include quinoline-naphthyridine agents, which target novel DNA gyrase sites, other novel quinolones that have high potency, peptide deformylase inhibitors, and new lincosamide, oxazolidinone, lipopeptide and cephalosporin derivatives. Misuse of potent new agents will, however, result in the inevitable development of resistance to these agents; responsible use of potent new agents is required to prevent continuation of this vicious cycle.

Anti-Bacterial Agents↗