bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Amphotericin B in Combination with Flucytosine against Flucytosine-Susceptible or Flucytosine-Resistant Isolates of
Cryptococcus neoformans
during Disseminated Murine Cryptococcosis
Authors: Schwarz Patrick , Dromer Françoise , Lortholary Olivier , Dannaoui Eric 
Published: December 2005

ABSTRACT

Whether or not flucytosine should be administered to patients infected with
Cryptococcus neoformans
isolates found to be resistant to flucytosine in vitro remains a controversial issue. Thus, the efficacy of amphotericin B and flucytosine in combination was investigated by mortality and fungal burden studies in a murine model of disseminated cryptococcosis using two clinical isolates of
Cryptococcus neoformans
, one susceptible and one resistant (i.e., 64 μg/ml) to flucytosine. Amphotericin B was given intraperitoneally at 0.25 or 0.5 mg/kg/day, while flucytosine was given at 100 or 250 mg/kg/day orally. Treatment was started 24 h or day 6 after inoculation and continued for 5 days in fungal burden and mortality studies, respectively. The combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day was significantly more effective than monotherapies for reducing fungal burden in brain, spleen, and lungs after infection by the flucytosine-susceptible isolate and in brain and spleen for the flucytosine-resistant isolate. For the flucytosine-resistant isolate, the combination of amphotericin B at 0.5 mg/kg/day with flucytosine at 100 mg/kg/day was significantly better than monotherapies for reducing the fungal burden in the brain. Survival obtained after the combination of amphotericin B at 0.5 mg/kg/day and flucytosine at 250 mg/kg/day increased compared to that obtained with monotherapies for both isolates, but the difference was statistically significant only for the flucytosine-susceptible isolate. Antagonism was never observed. This study demonstrates the beneficial effect of the addition of flucytosine to amphotericin B against experimental disseminated cryptococcal infection even when the
C. neoformans
isolate is resistant to flucytosine.
In Vivo Efficacies and Pharmacokinetics of DX-619, a Novel Des-Fluoro(6) Quinolone, against
Streptococcus pneumoniae
in a Mouse Lung Infection Model
Authors: Fukuda Yuichi , Yanagihara Katsunori , Ohno Hideaki , Higashiyama Yasuhito , Miyazaki Yoshitsugu , Tsukamoto Kazuhiro , Hirakata Yoichi , Tomono Kazunori , Mizuta Yohei , Tashiro Takayoshi , Kohno Shigeru 
Published: December 2005

ABSTRACT

DX-619 is a novel des-fluoro(6) quinolone with potent activity against gram-positive pathogens. The in vivo activity of DX-619 against
Streptococcus pneumoniae
was compared with those of fluoro(6) quinolones, sitafloxacin, and ciprofloxacin in a mouse model. Two strains of
S. pneumoniae
were used: a penicillin-sensitive
S. pneumoniae
(PSSP) strain and a penicillin-resistant
S. pneumoniae
(PRSP) strain. Furthermore, these strains showed intermediate susceptibilities to ciprofloxacin. In murine lung infections caused by PSSP, the 50% effective doses (ED
50
s) of DX-619, sitafloxacin, and ciprofloxacin were 9.15, 11.1, and 127.6 mg/kg of body weight, respectively. Against PRSP-mediated pneumonia in mice, the ED
50
s of DX-619, sitafloxacin, and ciprofloxacin were 0.69, 4.84, and 38.75 mg/kg, respectively. The mean ± standard error of the mean viable bacterial counts in murine lungs infected with PSSP and treated with DX-619, sitafloxacin, ciprofloxacin (10 mg/kg twice daily), and saline (twice daily) were 1.75 ± 0.06, 1.92 ± 0.23, 6.48 ± 0.28, and 7.57 ± 0.13 log
10
CFU/ml, respectively. Furthermore, the numbers of viable bacteria in lungs infected with PRSP and treated with the three agents and not treated (control) were 1.73 ± 0.04, 2.28 ± 0.17, 4.61 ± 0.59, and 5.54 ± 0.72 log
10
CFU/ml, respectively. DX-619 and sitafloxacin significantly decreased the numbers of viable bacteria in the lungs compared to the numbers in the lungs of ciprofloxacin-treated and untreated mice. The pharmacokinetic parameter of the area under the concentration-time curve (AUC)/MIC ratio in the lungs for DX-619, sitafloxacin, and ciprofloxacin were 171.0, 21.92, and 1.22, respectively. The AUC/MIC ratio in the lungs was significantly higher for DX-619 than for sitafloxacin and ciprofloxacin. Our results suggest that DX-619 and sitafloxacin are potent against both PSSP and PRSP in our mouse pneumonia model.
Posaconazole as Salvage Therapy for Zygomycosis
Authors: Greenberg R. N. , Mullane K. , van Burik J.-A. H. , Raad I. , Abzug M. J. , Anstead G. , Herbrecht R. , Langston A. , Marr K. A. , Schiller G. , Schuster M. , Wingard J. R. , Gonzalez C. E. , Revankar S. G. , Corcoran G. , Kryscio R. J. , Hare R. 
Published: December 2005

ABSTRACT
Zygomycosis, an infection that is associated with significant morbidity and mortality, is becoming common in immunocompromised patients. Posaconazole is a new extended-spectrum azole antifungal that has demonstrated in vitro and in vivo activity against zygomycetes. This report provides the results from the first 24 patients with active zygomycosis who were enrolled in two open-label, nonrandomized, multicentered compassionate trials that evaluated oral posaconazole as salvage therapy for invasive fungal infections. Posaconazole was usually given as an oral suspension of 200 mg four times a day or 400 mg twice a day. Eleven (46%) of the infections were rhinocerebral. Duration of posaconazole therapy ranged from 8 to 1,004 days (mean, 292 days; median, 182 days). Rates of successful treatment (complete cure and partial response) were 79% in 19 subjects with zygomycosis refractory to standard therapy and 80% in 5 subjects with intolerance to standard therapy. Overall, 19 of 24 subjects (79%) survived infection. Survival was also associated with surgical resection of affected tissue and stabilization or improvement of the subjects' underlying illnesses. Failures either had worsening of underlying illnesses or requested all therapy withdrawn; none of the failures received more than 31 days of posaconazole. Posaconazole oral solution was well tolerated and was discontinued in only one subject due to a drug rash. Posaconazole appears promising as an oral therapy for zygomycosis in patients who receive required surgery and control their underlying illness.
Preliminary Mapping of a Putative Inhibitor-Binding Pocket for Human Immunodeficiency Virus Type 1 Integrase Inhibitors
Authors: Lee Deborah J. , Robinson W. Edward 
Published: December 2005

ABSTRACT

Molecular modeling studies have identified a putative human immunodeficiency virus (HIV) integrase (IN) inhibitor-binding pocket for
l
-chicoric acid (
l
-CA) and other inhibitors of IN (C. A. Sotriffer, H. Ni, and A. McCammon, J. Med. Chem. 43:4109-4117, 2000). By using site-directed mutagenesis of several amino acid residues identified by modeling studies, a common inhibitor-binding pocket on IN was confirmed for
l
-CA and the diketo acid L-731,988. Specifically, the single mutations E92K, Q148A, K156A, K156R, G140S, and G149S, as well as the double mutations C65S-K156N and H67D-G140A were evaluated for their effects on enzymatic activity and inhibitor susceptibility. Each recombinant IN was attenuated for 3′-end processing and strand transfer activities. Most proteins were also attenuated for disintegration; the IN that contained K156R and C65S-K156N, however, displayed disintegration activity similar to that of IN from HIV
NL4-3
. All mutant IN proteins demonstrated decreased susceptibility to
l
-CA, while all mutant proteins except E92K and K156R demonstrated resistance to L-731,988. These data validate the computer modeling data and demonstrate that
l
-CA and L-731,988 share an overlapping inhibitor-binding pocket that involves amino acids Q148, C65, and H67. The resistance studies confirm that L-731,988 fills one-half of the inhibitor-binding pocket and binds to Q148 but excludes E92, while
l
-CA fills the entire binding groove and thus interacts with E92. These results provide “wet laboratory” evidence that molecular models of the HIV IN inhibitor-binding pocket can be used for drug discovery.
Open-Label, Randomized Comparison of Itraconazole versus Caspofungin for Prophylaxis in Patients with Hematologic Malignancies
Authors: Mattiuzzi Gloria N. , Alvarado Gladys , Giles Francis J. , Ostrosky-Zeichner Luis , Cortes Jorge , O'Brien Susan , Verstovsek Srdan , Faderl Stefan , Zhou Xian , Raad Issam I. , Bekele B. Nebiyou , Leitz G. J. , Lopez-Roman Ivonne , Estey Elihu H. 
Published: December 2005

ABSTRACTInvasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one withAspergilluspneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two withAspergilluspneumonia, and one with disseminatedFusariumspp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P= 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.
In Vitro Activity of Moxifloxacin against 923 Anaerobes Isolated from Human Intra-Abdominal Infections
Authors: Goldstein Ellie J. C. , Citron Diane M. , Warren Yumi A. , Tyrrell Kerin L. , Merriam C. Vreni , Fernandez Helen 
Published: December 2005

ABSTRACT

The in vitro activity of moxifloxacin against 923 recent anaerobic isolates obtained from pretreatment cultures in patients with complicated intra-abdominal infections was studied using the CLSI M11-A-6 agar dilution method. Moxifloxacin was active against 87% (96 of 110)
Bacteroides fragilis
strains at ≤1 μg/ml and 87% (79 of 90)
B. thetaiotaomicron
strains at ≤2 μg/ml. Species variation was seen, with
B. uniformis
,
B. vulgatus
,
Clostridium clostridioforme
, and
C. symbiosum
being least susceptible and accounting for most of the resistant isolates; excluding the aforementioned four resistant species, 86% (303 of 363) of
Bacteroides
species isolates and 94% (417 of 450) of all other genera and species were susceptible to ≤2 μg/ml of moxifloxacin. Overall, moxifloxacin was active against 763 of 923 (83%) of strains at ≤2 μg/ml, supporting its use as a monotherapy for some community-acquired intra-abdominal infections.
Tetracycline Resistance in
Escherichia coli
and Persistence in the Infantile Colonic Microbiota
Authors: Karami Nahid , Nowrouzian Forough , Adlerberth Ingegerd , Wold Agnes E. 
Published: December 2005

ABSTRACT

The ecological impact of antibiotic resistance in the absence of selective pressure has been poorly studied. We assessed the carriage of tetracycline resistance genes, persistence in the microbiota, fecal population counts and virulence factor genes in 309 commensal, intestinal
Escherichia coli
strains obtained from 128 Swedish infants followed during the first year of life with regular quantitative fecal cultures. No infant was given tetracycline, but 25% received other antibiotics. Tetracycline resistance was identified in 12% of strains, all of which carried either
tet
(A) (49%) or
tet
(B) (51%) genes. Resistance to other antibiotics occurred in 50% of
tet
(A)-positive strains, 42% of
tet
(B)-positive strains and 13% of tetracycline-sensitive strains. However, colonization with tetracycline-resistant strains was unrelated to treatment with antibiotics. Strains that were
tet
(B)- or
tet
(A)-positive carried the genes for P fimbriae and aerobactin, respectively, more often than susceptible strains. Tetracycline-resistant and -susceptible strains were equally likely to persist among the intestinal microbiota for ≥3 weeks and had similar population numbers. However, when a resistant strain and a susceptible strain colonized a child simultaneously, the resistant variety showed lower counts (
P
= 0.03). In cases of long-term colonization by initially tetracycline-resistant
E. coli
strains, loss of
tet
genes occurred in 3 of 13 cases with variable effects on population counts. The results indicate that there is limited pressure against the carriage of
tet
genes in the infantile gut microbiota even in the absence of antibiotics. Resistant strains may possess colonization factors that balance the cost of producing resistance elements.
In Vitro Effects of Thiazolides on
Giardia lamblia
WB Clone C6 Cultured Axenically and in Coculture with Caco2 Cells
Authors: Müller Joachim , Rühle Géraldine , Müller Norbert , Rossignol Jean-François , Hemphill Andrew 
Published: December 2005

ABSTRACT

The thiazolides represent a novel class of anti-infective drugs, with the nitrothiazole nitazoxanide [2-acetolyloxy-
N
-(5-nitro 2-thiazolyl) benzamide] (NTZ) as the parent compound. NTZ exhibits a broad spectrum of activities against a wide variety of helminths, protozoa, and enteric bacteria infecting animals and humans. In vivo, NTZ is rapidly deacetylated to tizoxanide (TIZ), which exhibits similar activities. We have here comparatively investigated the in vitro effects of NTZ, TIZ, a number of other modified thiazolides, and metronidazole (MTZ) on
Giardia lamblia
trophozoites grown under axenic culture conditions and in coculture with the human cancer colon cell line Caco2. The modifications of the thiazolides included, on one hand, the replacement of the nitro group on the thiazole ring with a bromide, and, on the other hand, the differential positioning of methyl groups on the benzene ring. Of seven compounds with a bromo instead of a nitro group, only one, RM4820, showed moderate inhibition of
Giardia
proliferation in axenic culture, but not in coculture with Caco2 cells, with a 50% inhibitory concentration (IC
50
) of 18.8 μM; in comparison, NTZ and tizoxanide had IC
50
s of 2.4 μM, and MTZ had an IC
50
of 7.8 μM. Moreover, the methylation or carboxylation of the benzene ring at position 3 resulted in a significant decrease of activity, and methylation at position 5 completely abrogated the antiparasitic effect of the nitrothiazole compound. Trophozoites treated with NTZ showed distinct lesions on the ventral disk as soon as 2 to 3 h after treatment, whereas treatment with metronidazole resulted in severe damage to the dorsal surface membrane at later time points.
Ciprofloxacin and Trimethoprim Cause Phage Induction and Virulence Modulation in
Staphylococcus aureus
Authors: Goerke Christiane , Köller Johanna , Wolz Christiane 
Published: December 2005

ABSTRACT

In
Staphylococcus aureus
strains of human origin, phages which integrate into the chromosomal gene coding for β-hemolysin (
hlb
) are widely distributed. Most of them encode accessory virulence determinants such as staphylokinase (
sak
) or enterotoxins. Here, we analyzed the effects of ciprofloxacin and trimethoprim on phage induction and expression of phage-encoded virulence factors by using isolates from patients with cystic fibrosis for which the induction of
hlb
-converting phages was demonstrated in vivo (C. Goerke, S. Matias y Papenberg, S. Dasbach, K. Dietz, R. Ziebach, B. C. Kahl, and C. Wolz, J. Infect. Dis. 189:724-734, 2004) as well as a φ13 lysogen of phage-cured strain 8325-4. Treatment of lysogens with subinhibitory concentrations of either antibiotic resulted in (i) delysogenization of strains resembling the isolates picked up after chronic lung infection and (ii) replication of phages in the bacterial host in a dose-dependent manner. Ciprofloxacin treatment resulted in enhanced
recA
transcription, indicating involvement of the SOS response in phage mobilization. Induction of φ13 was linked to elevated expression of the phage-encoded virulence gene
sak
, chiefly due to the activation of latent phage promoters. In summary, we could show the induction of
hlb
-converting phages and a subsequent virulence modulation of the host bacterium by ciprofloxacin and trimethoprim.
Novel Plasmid-Mediated 16S rRNA Methylase, RmtC, Found in a
Proteus mirabilis
Isolate Demonstrating Extraordinary High-Level Resistance against Various Aminoglycosides
Authors: Wachino Jun-ichi , Yamane Kunikazu , Shibayama Keigo , Kurokawa Hiroshi , Shibata Naohiro , Suzuki Satowa , Doi Yohei , Kimura Kouji , Ike Yasuyoshi , Arakawa Yoshichika 
Published: December 2005

ABSTRACT

Proteus mirabilis
ARS68, which demonstrated a very high level of resistance to various aminoglycosides, was isolated in 2003 from an inpatient in Japan. The aminoglycoside resistance of this strain could not be transferred to recipient strains
Escherichia coli
CSH-2 and
E. coli
HB101 by a general conjugation experiment, but
E. coli
DH5α was successfully transformed by electroporation with the plasmid of the parent strain, ARS68, and acquired an unusually high degree of resistance against aminoglycosides. Cloning and sequencing analyses revealed that the presence of a novel 16S rRNA methylase gene, designated
rmtC
, was responsible for resistance in strain ARS68 and its transformant. The G+C content of
rmtC
was 41.1%, and the deduced amino acid sequences of the newly identified 16S rRNA methylase, RmtC, shared a relatively low level of identity (≤29%) to other plasmid-mediated 16S rRNA methylases, RmtA, RmtB, and ArmA, which have also been identified in pathogenic gram-negative bacilli. Also, RmtC shared a low level of identity (≤28%) with the other 16S rRNA methylases found in aminoglycoside-producing actinomycetes. The purified histidine-tagged RmtC clearly showed methyltransferase activity against
E. coli
16S rRNA in vitro.
rmtC
was located downstream of an IS
Ecp1
-like element containing
tnpA
. Several plasmid-mediated 16S rRNA methylases have been identified in pathogenic gram-negative bacilli belonging to the family
Enterobacteriaceae
, and some of them are dispersing worldwide. The acceleration of aminoglycoside resistance among gram-negative bacilli by producing plasmid-mediated 16S rRNA methylases, such as RmtC, RmtB, and RmtA, may indeed become an actual clinical hazard in the near future.
Phenothiazinium Antimicrobial Photosensitizers Are Substrates of Bacterial Multidrug Resistance Pumps
Authors: Tegos George P. , Hamblin Michael R. 
Published: December 2005

ABSTRACT

Antimicrobial photodynamic therapy (PDT) combines a nontoxic photoactivatable dye, or photosensitizer (PS), with harmless visible light to generate singlet oxygen and free radicals that kill microbial cells. Although the light can be focused on the diseased area, the best selectivity is achieved by choosing a PS that binds and penetrates microbial cells. Cationic phenothiazinium dyes, such as methylene blue and toluidine blue O, have been studied for many years and are the only PSs used clinically for antimicrobial PDT. Multidrug resistance pumps (MDRs) are membrane-localized proteins that pump drugs out of cells and have been identified for a wide range of organisms. We asked whether phenothiazinium salts with structures that are amphipathic cations could potentially be substrates of MDRs. We used MDR-deficient mutants of
Staphylococcus aureus
(NorA),
Escherichia coli
(TolC), and
Pseudomonas aeruginosa
(MexAB) and found 2 to 4 logs more killing than seen with wild-type strains by use of three different phenothiazinium PSs and red light. Mutants that overexpress MDRs were protected from killing compared to the wild type. Effective antimicrobial PSs of different chemical structures showed no difference in light-mediated killing depending on MDR phenotype. Differences in uptake of phenothiazinium PS by the cells depending on level of MDR expression were found. We propose that specific MDR inhibitors could be used in combination with phenothiazinium salts to enhance their photodestructive efficiency.
Simultaneous Detection of Nine Antibiotic Resistance-Related Genes in
Streptococcus agalactiae
Using Multiplex PCR and Reverse Line Blot Hybridization Assay
Authors: Zeng Xianyu , Kong Fanrong , Wang Hui , Darbar Archie , Gilbert Gwendolyn L. 
Published: December 2005

ABSTRACT

Streptococcus agalactiae
(group B streptococcus [GBS]) is the leading cause of neonatal and maternal sepsis. Penicillin is recommended for intrapartum prophylaxis, but erythromycin or clindamycin is used for penicillin-allergic carriers. Antibiotic resistance (AR) has increased recently and needs to be monitored. We have developed a multiplex PCR-based reverse line blot (mPCR/RLB) hybridization assay to detect, simultaneously, seven genes encoding AR—
erm
(A/TR),
erm
(B),
mef
(A/E),
tet
(M),
tet
(O),
aphA-3
, and
aad
-
6
—and two AR-related genes,
int
-Tn and
mreA
. We tested 512 GBS isolates from Asia and Australasia and compared mPCR/RLB with antibiotic susceptibility phenotype or single-gene PCR. Phenotypic resistance to tetracycline was identified in 450 (88%) isolates, of which 442 had
tet
(M) (93%) and/or
tet
(O) (6%). Of 67 (13%) erythromycin-resistant isolates, 18 were susceptible to clindamycin, i.e., had the M phenotype, encoded by
mef
(A/E); 39 had constitutive (cMLS
B
) and 10 inducible clindamycin resistance, and of these, 34 contained
erm
(B) and 12
erm
(A/TR). Of four additional isolates with
mef
(A/E), three contained
erm
(B) with cMLS
B
and one was erythromycin susceptible. Of 61 (12%) clindamycin-resistant isolates, 20 were susceptible to erythromycin and two had intermediate resistance. Based on sequencing, 21 of 22 isolates with
mef
had
mef
(E), and 8 of 353 with
int
-Tn had an atypical sequence. Several AR genes,
erm
(B),
tet
(O),
aphA-3
,
aad
-
6
, and
mef
(A/E), were significantly more common among Asian than Australasian isolates, and there were significant differences in distribution of AR genes between GBS serotypes. Our mPCR/RLB assay is simple, rapid, and suitable for surveillance of antibiotic resistance in GBS.