bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activities of Sordarins in Experimental Models of Candidiasis, Aspergillosis, and Pneumocystosis
Authors: Martinez Antonio , Aviles Pablo , Jimenez Elena , Caballero Jesus , Gargallo-Viola Domingo 
Published: July 2002

ABSTRACT

Sordarin derivatives represent a new class of antifungal agents that act as potent inhibitors of fungal protein synthesis and possess a broad spectrum of activity. The in vivo activity of GM193663 and GM237354 was studied in mouse models of disseminated candidiasis and aspergillosis and in a rat model of pneumocystosis. The pharmacokinetic behavior of both sordarin derivatives was studied in mice and rats. In all studies, compounds were administered by the subcutaneous route. After a subcutaneous dose of 50 mg/kg of body weight to mice, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for GM193663 and GM237354 were 51.8 and 23 μg/ml, 79.5 and 46 μg · h/ml, 0.8 and 0.85 h, and 21 and 25 ml/h, respectively. Systemic candidiasis and aspergillosis were established in CD-1 male mice infected with
Candida albicans
or
Aspergillus fumigatus
. For systemic candidiasis, compounds were given three times per day for seven consecutive days at 15, 30, 60, or 120 mg/kg/day. GM193663 and GM237354 showed dose-related efficacy against
C. albicans
, with 50% effective doses, 1 month after infection, of 25.2 and 10.7 mg/kg/dose, respectively. In experimental infections with
A. fumigatus
, GM237354 was given three times per day at 30, 60, or 120 mg/kg/day for five consecutive days. Animals treated with GM237354 demonstrated irregular responses. The survival of animals treated with GM237354 was 0, 30, and 0% at 30, 60, and 120 mg/kg/day, respectively. The therapeutic efficacy of GM193663 and GM237354 against
Pneumocystis carinii
was studied in an experimental
P. carinii
pneumonia (PCP) rat model. After a subcutaneous dose of 10 mg/kg given to rats, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for GM193663 and GM237354 were 6.6 and 7.2 μg/ml, 8.5 and 11.8 μg · h/ml, 0.7 and 0.8 h, and 230 and 133 ml/h, respectively. To induce spontaneous PCP, rats were chronically immunosuppressed with dexamethasone. Infected animals were treated twice daily for 10 days at 0.2, 2, or 10 mg/kg/day. The therapeutic effect was estimated by the reduction in the number of cysts in the lungs of treated versus untreated animals. GM193663 and GM237354 significantly reduced the mean (± standard deviation) log number of cysts from 7.6 ± 0.2 in the untreated group to 4.7 ± 0.2 and 4.6 ± 0.1, respectively, when the drugs were administered at a dose of 2 mg/kg/day. The log number of cysts was also reduced in infected animals given lower doses of the compounds (0.2 mg/kg/day). In summary, GM193663 and GM237354 are new sordarin derivatives that may potentially play a major role in the treatment of candidiasis and PCP. Further testing with
Aspergillus
in other animal models is warranted.
Morphological Changes and Lysis Induced by β-Lactams Associated with the Characteristic Profiles of Affinities of Penicillin-Binding Proteins in
Actinobacillus pleuropneumoniae
Authors: Inui Takashi , Endo Toshio , Matsushita Tadahiro 
Published: July 2002

ABSTRACT

Actinobacillus pleuropneumoniae
, which was formerly classified in the genus
Haemophilus
, is a pathogen causing swine pleuropneumonia. We found that aspoxicillin showed strong activity and that meropenem had better lytic activity against this pathogen. In the present study, we for the first time identified penicillin-binding proteins (PBPs) of
A. pleuropneumoniae
in order to elucidate the relationship between the antibacterial and lytic activities of β-lactam antibiotics and affinities of the PBPs. The competitive assay using
3
H-labeled benzylpenicillin revealed seven PBPs in
A. pleuropneumoniae
; they were determined to be PBPs 1a, 1b, 2, 3, 4, 5, and 6, and the molecular masses of these PBPs were estimated to be 92, 80, 76, 72, 50, 44, and 30 kDa, respectively, by comparison with those of
Haemophilus influenzae
. Our detailed analysis of the affinities of the PBPs of
A. pleuropneumoniae
and of the bacterial lysis kinetics for several β-lactam antibiotics revealed that the strong antibacterial activity of aspoxicillin against this strain could be related to the higher affinity of PBP 3 and that preferential inactivation of PBP 1b could cause rapid lysis.
Depletion of the Squalene Synthase (
ERG9
) Gene Does Not Impair Growth of
Candida glabrata
in Mice
Authors: Nakayama Hironobu , Izuta Miho , Nakayama Noboru , Arisawa Mikio , Aoki Yuko 
Published: July 2002

ABSTRACT

Squalene synthase (farnesyl-diphosphate farnesyltransferase, EC
2.5.1.21
) is the first committed enzyme of the sterol biosynthesis pathway. Inhibitors of this enzyme have been intensively studied as potential antifungal agents. To assess the effect of deactivating squalene synthase on the growth of fungi in mice, we isolated the squalene synthase (
ERG9
) gene from the pathogenic fungus
Candida glabrata
and generated strains in which the
CgERG9
gene was under the control of the tetracycline-regulatable promoter. Depletion of the
ERG9
gene by doxycycline (DOX), a derivative of tetracycline, decreased the cell viability in laboratory media, whereas it did not affect cell growth in mice at all. The growth defect caused by DOX in laboratory media was suppressed by the addition of serum. Analyses of the sterol composition of the restored cells in serum-containing media suggest that the defect of ergosterol biosynthesis can be complemented by the incorporation of exogenous cholesterol into the cells. Thus, deactivation of squalene synthase did not affect fungal growth in mice, presumably because the cells were able to incorporate cholesterol from the serum. These results showed that squalene synthase could not be a suitable target of antifungals for the treatment of
C. glabrata
infection.
Efficacy of Ampicillin plus Arbekacin in Experimental Rabbit Endocarditis Caused by an
Enterococcus faecalis
Strain with High-Level Gentamicin Resistance
Authors: Kak Vivek , Donabedian Susan M. , Zervos Marcus J. , Kariyama Reiko , Kumon Hiromi , Chow Joseph W. 
Published: July 2002

ABSTRACT

Enterococcus faecalis
LC40 is an ampicillin-susceptible clinical isolate with high-level gentamicin resistance due to the
aac(6′)-Ie-aph(2")-Ia
aminoglycoside resistance gene. The combination of ampicillin plus arbekacin reduced mean bacterial vegetation counts significantly more than ampicillin alone or ampicillin plus gentamicin in a rabbit model of aortic-valve endocarditis caused by
E. faecalis
LC40.
Successful Trovafloxacin Prophylaxis against Experimental Streptococcal Aortic Valve Endocarditis
Authors: Katsarolis Ioannis , Pefanis Angelos , Iliopoulos Dimitrios , Siaperas Peter , Karayiannakos Panagiotis , Giamarellou Helen 
Published: July 2002

ABSTRACT

Single-dose trovafloxacin (15 mg/kg given intravenously [i.v.]) and ampicillin (40 mg/kg given i.v.) protected 38 and 33% of animals challenged with an ampicillin-tolerant strain of
Streptococcus oralis
, respectively. As a double-dose regimen, trovafloxacin afforded total protection (100%;
P
< 0.001 versus controls). Trovafloxacin is the first fluoroquinolone effective in preventing experimental streptococcal endocarditis.
SHV-14, a Novel β-Lactamase Variant in
Klebsiella pneumoniae
Isolates from Nijmegen, The Netherlands
Authors: Yuan Meifang , Hall Lucinda M. C. , Hoogkamp-Korstanje Jaa , Livermore David M. 
Published: July 2002

ABSTRACT

Four ceftazidime-resistant isolates of a
Klebsiella pneumoniae
strain were collected from intensive care unit patients in Nijmegen, The Netherlands. These isolates had TEM-29 and SHV-14 β-lactamases. SHV-14 is a novel variant, with two substitutions compared with the sequence of SHV-1: Ile8Phe and Arg43Ser. Its gene also had a silent C→T mutation at nucleotide 481. The SHV-14 enzyme had slightly higher
V
max
rates than SHV-1 for oxyimino-aminothiazolyl cephalosporins, but this activity was insufficient for the enzyme to count as an extended-spectrum β-lactamase.
In Vitro Antibiotic Susceptibility of
Neisseria gonorrhoeae
in Jakarta, Indonesia
Authors: Lesmana Murad , Lebron Carlos I. , Taslim Djufri , Tjaniadi Periska , Subekti Decy , Wasfy Momtaz O. , Campbell James R. , Oyofo Buhari A. 
Published: July 2002

ABSTRACT

Antibiotic susceptibilities were determined for 122
Neisseria gonorrheae
isolates obtained from 400 sex workers in Jakarta, Indonesia, and susceptibilities to ciprofloxacin, cefuroxime, cefoxitin, cefotaxime, ceftriaxone, chloramphenicol, and spectinomycin were found. All isolates were resistant to tetracycline. A number of the isolates demonstrated decreased susceptibilities to erythromycin (MIC ≥ 1.0 μg/ml), thiamphenicol (MIC ≥ 1.0 μg/ml), kanamycin (MIC ≥ 16.0 μg/ml), penicillin (MIC ≥ 2.0 μg/ml), gentamicin (MIC ≥ 16.0 μg/ml), and norfloxacin (MIC = 0.5 μg/ml). These data showed that certain antibiotics previously used in the treatment of gonorrhea are no longer effective.
Effects of New Quinolones on Transepithelial Electrical Potential Difference of Tracheal Mucosa In Vivo
Authors: Kanoh Soichiro , Tamaoki Jun , Kondo Mitsuko , Nagano Yuko , Nagai Atsushi 
Published: July 2002

ABSTRACT
Superfusion of canine tracheal mucosa with 100 μg each of grepafloxacin and ciprofloxacin per ml reduced the electrical transepithelial potential difference in vivo by more than 50%. This effect was dose dependent, specific for new quinolones, and inhibited by Cl channel blockers, indicating that new quinolones attenuate Cl secretion across the airway epithelium.
New Model of Oropharyngeal Candidiasis in Mice
Authors: Kamai Yasuki , Kubota Mikie , Kamai Yoko , Hosokawa Tsunemichi , Fukuoka Takashi , Filler Scott G. 
Published: July 2002

ABSTRACT

We established a straightforward murine model of oropharyngeal candidiasis. Mice were immunosuppressed with cortisone acetate, anesthetized, and then inoculated by placing cotton wool balls saturated with
Candida albicans
sublingually for 2 h. A prolonged, reproducible infection was induced. This model may be useful for antifungal screening or pathogenesis studies.
Fungal Phospholipase Activity and Susceptibility to Lipid Preparations of Amphotericin B
Authors: Gottfredsson Magnus , Jessup Chad J. , Cox Gary M. , Perfect John R. , Ghannoum Mahmoud A. 
Published: July 2002

ABSTRACT

It has been postulated that phospholipases of fungal origin can affect in vitro susceptibility testing of amphotericin B lipid complex (ABLC). We used specific phospholipase-deficient mutants of
Candida albicans
and
Cryptococcus neoformans
in susceptibility testing and demonstrated that extracellular fungal phospholipase activity does not influence the in vitro susceptibilities of these two fungi to ABLC.
In Vitro and In Vivo Effects of Quinupristin-Dalfopristin against
Pneumocystis carinii
Authors: Walzer Peter D. , Ashbaugh Alan , Collins Margaret , Cushion Melanie T. 
Published: July 2002

ABSTRACT

Quinupristin-dalfopristin (Q-D), which is active against bacteria and
Toxoplasma gondii
, was examined for its activity against
Pneumocystis carinii
. After 72 h of incubation with rat
P. carinii
in an ATP cytotoxicity assay, the 50% inhibitory concentration of Q-D was 10.6 μg/ml, a level that can be achieved in serum with high-dose administration. Q-D administered intraperitoneally at doses of 50 to 200 mg per kg of body weight per day in the treatment and 100 mg/kg/day three times per week in the prophylaxis of pneumocystosis in immunosuppressed mice reduced the organism burden up to 15- and 302-fold, respectively. We conclude that Q-D has activity against
P. carinii
in vitro and in vivo.
Evolution of TEM-Related Extended-Spectrum β-Lactamases in Korea
Authors: Pai Hyunjoo , Lee Hoan-Jong , Choi Eun-Hwa , Kim Jungmin , Jacoby George A. 
Published: July 2002

ABSTRACT
TEM-52, differing from TEM-1 by having the substitutions Glu-104→Lys, Met-182→Thr, and Gly-238→Ser, has previously been described as the most prevalent extended-spectrum β-lactamase (ESBL) in Korea. In a further survey, we discovered the ESBLs TEM-15, which is like TEM-52 but lacks the substitution at residue 182, and TEM-88, which is like TEM-52 with an additional Gly-196→Asp substitution. TEM-88 retained the activity of TEM-52 against moxalactam. Otherwise, the kinetic properties of the three ESBLs failed to show an advantage to this evolution.
Optimal Susceptibility Testing Conditions for Detection of Azole Resistance in
Aspergillus
spp.: NCCLS Collaborative Evaluation
Authors: Espinel-Ingroff A. , Bartlett M. , Chaturvedi V. , Ghannoum M. , Hazen K. C. , Pfaller M. A. , Rinaldi M. , Walsh T. J. 
Published: July 2002

ABSTRACT

The most important role of susceptibility testing is to identify potentially resistant isolates for the agent being evaluated. Standard testing guidelines recently have been proposed for antifungal susceptibility testing of filamentous fungi (molds). This collaborative (eight centers) study evaluated further newly proposed guidelines (NCCLS, proposed standard M38-P, 1998) and other testing conditions for antifungal susceptibility testing of
Aspergillus
spp. to itraconazole and three new triazoles, posaconazole (SCH56592), ravuconazole (BMS-207147), and voriconazole. MICs of itraconazole, posaconazole, ravuconazole, and voriconazole for 15 selected isolates of three species of
Aspergillus
(
A. fumigatus, A. flavus
, and
A. terreus
) with well documented in vitro, clinical, or animal data were determined in each center by using four medium formulations (standard RPMI-1640 [RPMI], RPMI with 2% dextrose, antibiotic medium 3 [M3], and M3 with 2% dextrose) and two criteria of MIC determination (complete [MIC-0s] and prominent [MIC-2s] growth inhibition) at 24, 48, and 72 h. The highest reproducibility (92 to 99%) was seen with the standard RPMI and M3 media. Moreover, the distinction between itraconazole-resistant (MICs of >8 μg/ml for clinically resistant strains) and -susceptible (MICs of 0.03 to 1 μg/ml) isolates, as well as between a voriconazole-resistant laboratory mutant and other isolates (voriconazole MICs of 2 to >8 versus 0.12 to 2 μg/ml), was more consistently evident with the standard RPMI medium and when MIC-0s were determined at 48 h. These results provide further refinement of the testing guidelines for susceptibility testing of
Aspergillus
spp. and warrant consideration for inclusion in the future NCCLS document M38-A.
Evaluation of Susceptibility Testing To Detect Fluoroquinolone Resistance Mechanisms in
Streptococcus pneumoniae
Authors: Richardson David C. , Bast Darrin , McGeer Allison , Low Donald E. 
Published: July 2002

ABSTRACT

To determine if susceptibility testing of
Streptococcus pneumoniae
could detect those isolates that had one of the recognized mechanisms of fluoroquinolone resistance, 101 isolates were selected; the levofloxacin MIC for 28 of these isolates was ≥4 μg/ml. Only isolates with both
parC
and
gyrA
mutations or with no recognized resistance mechanisms were reliably identified by using these results. Isolates with only a
parC
mutation could not be detected reliably using any susceptibility testing method.
Macrolide-Resistant
Streptococcus pneumoniae
in Canada during 1998–1999: Prevalence of
mef
(A) and
erm
(B) and Susceptibilities to Ketolides
Authors: Hoban Daryl J. , Wierzbowski Aleksandra K. , Nichol Kim , Zhanel George G. 
Published: July 2002

ABSTRACT

In this study (1998–1999), we collected 215 macrolide-resistant
Streptococcus pneumoniae
isolates from an ongoing Canadian Respiratory Organism Surveillance Study involving 23 centers representing all regions of Canada. The prevalence of erythromycin-resistant
S. pneumoniae
was 8% (215 of 2,688). Of the 215 isolates, 48.8% (105 of 215) were PCR positive for
mef
(A) and 46.5% (100 of 215) were PCR positive for
erm
(B). The ketolides telithromycin and ABT-773 demonstrated excellent activity against both
mef
(A) (MIC for 90% of strains [MIC
90
], 0.06 and 0.03 μg/ml, respectively) and
erm
(B) (MIC
90
, 0.06 and 0.03 μg/ml, respectively) strains of
S. pneumoniae
.
In Vitro Activities of MK-0826 and 16 Other Antimicrobials against
Bacteroides fragilis
Group Strains
Authors: Betriu Carmen , Sánchez Ana , Palau Marı́a Luisa , Gómez Marı́a , Picazo Juan J. 
Published: July 2002

ABSTRACT

The activity of MK-0826, a new carbapenem, against 309
Bacteroides fragilis
group strains was investigated and compared with that of 11 other β-lactam and 5 non-β-lactam agents. MK-0826 showed excellent activity (MICs ranged from ≤0.06 to 4 μg/ml). The new carbapenem may be useful in the treatment of mixed anaerobic infections involving
B. fragilis
group strains.
Efficacies of BMS 284756 against Penicillin-Sensitive, Penicillin-Resistant, and Quinolone-Resistant Pneumococci in Experimental Meningitis
Authors: Cottagnoud Philippe , Acosta Fernando , Cottagnoud Marianne , Pfister Marc , Täuber Martin G. 
Published: July 2002

ABSTRACT

BMS 284756 penetrated well into inflamed meninges (44% ± 11%) and produced good bactericidal activity (−0.82 ± 0.22 Δlog
10
CFU/ml · h) in the treatment of experimental meningitis in rabbits due to a penicillin-sensitive strain. BMS 284756 monotherapy had a greater potency than the standard regimen of ceftriaxone and vancomycin (−0.49 ± 0.08 Δlog
10
CFU/ml · h) against a penicillin-resistant strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, BMS 284756 showed good bactericidal activity (−0.52 ± 0.12 Δlog
10
CFU/ml · h). The antibacterial activity of BMS 284756 was confirmed by time-killing assays over 8 h in vitro.
Conversion of Oxacillin-Resistant Staphylococci from Heterotypic to Homotypic Resistance Expression
Authors: Finan J. E. , Rosato A. E. , Dickinson T. M. , Ko D. , Archer Gordon L. 
Published: July 2002

ABSTRACT

Staphylococci that acquire the
mecA
gene are usually resistant to β-lactam antibiotics (methicillin or oxacillin resistance).
mecA
encodes a penicillin-binding protein (PBP 2a) that has a reduced affinity for β-lactams. In some isolates with methicillin or oxacillin resistance, only a small proportion (≤0.1%) of the population expresses resistance to ≥10 μg of oxacillin per ml (heterotypic resistance [HeR]), while in other isolates most of the population expresses resistance (homotypic resistance [HoR]). In the present study, growth of
Staphylococcus aureus
or
Staphylococcus epidermidis
strains with HeR in concentrations of oxacillin (0.3 to 0.7 μg/ml) that produced a fall or a lag in optical density converted the strains from the HeR to the HoR phenotype. The conversion from the HeR to the HoR phenotype appeared to be due to the selection of a highly resistant mutant population, as determined by fluctuation analysis and the failure of populations with HoR to revert to HeR after 60 generations of growth in antibiotic-free media. The frequencies of conversion were as high as 10
−3
to 10
−2
. Conversion to HoR required an intact
mecA
gene and an increase in the level of
mecA
transcription since no highly resistant subpopulation could be selected after growth in oxacillin when
mecA
transcription was constitutively repressed or when
mecA
had been inactivated. In addition, in both
S. epidermidis
and
S. aureus
the level of resistance to vancomycin, which also acts directly on the staphylococcal cell wall, was greater among convertants with HoR than their isogenic parents. The conversion of a population from HeR to HoR involves the selection of a mutation(s) that occurs at a high frequency and most likely requires abundant PBP 2a.
Evaluation of T-3811ME (BMS-284756), a New Des-F(6)-Quinolone, for Treatment of Meningitis Caused by Penicillin-Resistant
Streptococcus pneumoniae
in Rabbits
Authors: Takahata Masahiro , Yamada Hiroshi , Morita Teiichi , Furubou Shinichi , Minami Shinzaburo , Todo Yozo , Watanabe Yasuo , Narita Hirokazu 
Published: July 2002

ABSTRACT

T-3811ME (BMS-284756) is a new des-F(6)-quinolone with high levels of activity against gram-positive bacteria, including penicillin-resistant
Streptococcus pneumoniae
(PRSP) strains. T-3811, the free base of T-3811ME, exhibited potent activity against 28 clinical strains of PRSP isolated clinically (MIC at which 90% of the isolates tested are inhibited, 0.0625 μg/ml). After the intravenous dosing of T-3811ME (20 mg/kg of body weight as T-3811) in rabbits with meningitis caused by PRSP, the area under the concentration-time curve (AUC) of T-3811 in cerebrospinal fluid (CSF) was 5.79 μg · h/ml and was 4.5-fold higher than that of T-3811in the CSF of rabbits without meningitis. In addition, the AUC/MIC for T-3811ME (20 mg/kg as T-3811) in CSF was 185, which was 4.3-fold higher than that for ceftriaxone (administered intravenously at 100 mg/kg). After the administration of any dose of T-3811ME (5, 10, and 20 mg/kg as T-3811), the viable cell counts in CSF decreased in a dose-dependent manner. In particular, after dosing of 20 mg/kg (as T-3811), the viable cell counts in CSF were significantly less than those in the nontreated group (
P
< 0.01). By histopathological evaluation, 6 h after the administration of T-3811ME (20 mg/kg as T-3811), the thickening of the cerebral meninx and the infiltration of neutrophils into the cerebral meninx were less severe in the treated group than in the nontreated group. T-3811ME (BMS-284756) may be expected to be evaluated for the management of meningitis caused by highly penicillin-resistant pneumococci.
Combinations of Lysostaphin with β-Lactams Are Synergistic against Oxacillin-Resistant
Staphylococcus epidermidis
Authors: Kiri Nandini , Archer Gordon , Climo Michael W. 
Published: July 2002

ABSTRACT

Oxacillin-resistant
Staphylococcus aureus
is rapidly killed by the endopeptidase lysostaphin, and the addition of β-lactam antibiotics provides synergistic killing. We investigated the possibility that β-lactams given in combination with lysostaphin would improve the activity of lysostaphin against oxacillin-resistant
Staphylococcus epidermidis
(ORSE), which is normally less susceptible to lysostaphin. Checkerboard synergy testing was performed for lysostaphin given in combination with oxacillin against 10 ORSE isolates for which the lysostaphin MICs were ≥ 8 μg/ml. The fractional inhibitory concentration index ranged from 0.0234 to 0.2656, indicating synergy, which was confirmed in growth curve experiments. In the rabbit model of experimental aortic valve endocarditis using an ORSE strain, the combination of lysostaphin and nafcillin was as effective as vancomycin alone and significantly better than lysostaphin or nafcillin alone. We conclude that β-lactam antibiotics given in combination with lysostaphin are synergistic against many strains of ORSE.