bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Growth Rate on Resistance of
Candida albicans
Biofilms to Antifungal Agents
Authors: Baillie George S. , Douglas L. Julia 
Published: October 2018

ABSTRACT

A perfused biofilm fermentor, which allows growth-rate control of adherent microbial populations, was used to assess whether the susceptibility of
Candida albicans
biofilms to antifungal agents is dependent on growth rate. Biofilms were generated under conditions of glucose limitation and were perfused with drugs at a high concentration (20 times the MIC). Amphotericin B produced a greater reduction in the number of daughter cells in biofilm eluates than ketoconazole, fluconazole, or flucytosine. Similar decreases in daughter cell counts were observed when biofilms growing at three different rates were perfused with amphotericin B. In a separate series of experiments, intact biofilms, resuspended biofilm cells, and newly formed daughter cells were removed from the fermentor and were exposed to a lower concentration of amphotericin B for 1 h. The susceptibility profiles over a range of growth rates were then compared with those obtained for planktonic cells grown at the same rates under glucose limitation in a chemostat. Intact biofilms were resistant to amphotericin B at all growth rates tested, whereas planktonic cells were resistant only at low growth rates (≤0.13 h
−1
). Cells resuspended from biofilms were less resistant than intact biofilm populations but more resistant than daughter cells; the susceptibilities of both these cell types were largely independent of growth rate. Our findings indicate that the amphotericin B resistance of
C. albicans
biofilms is not simply due to a low growth rate but depends on some other feature of the biofilm mode of growth.
Antibacterial Activity of Gatifloxacin (AM-1155, CG5501, BMS-206584), a Newly Developed Fluoroquinolone, against Sequentially Acquired Quinolone-Resistant Mutants and the
norA
Transformant of
Staphylococcus aureus
Authors: Fukuda Hideyuki , Hori Satoshi , Hiramatsu Keiichi 
Published: October 2018

ABSTRACT

Alternate mutations in the
grlA
and
gyrA
genes were observed through the first- to fourth-step mutants which were obtained from four
Staphylococcus aureus
strains by sequential selection with several fluoroquinolones. The increases in the MICs of gatifloxacin accompanying those mutational steps suggest that primary targets of gatifloxacin in the wild type and the first-, second-, and third-step mutants are wild-type topoisomerase IV (topo IV), wild-type DNA gyrase, singly mutated topo IV, and singly mutated DNA gyrase, respectively. Gatifloxacin had activity equal to that of tosufloxacin and activity more potent than those of norfloxacin, ofloxacin, ciprofloxacin, and sparfloxacin against the second-step mutants (
grlA gyrA
; gatifloxacin MIC range, 1.56 to 3.13 μg/ml) and had the most potent activity against the third-step mutants (
grlA gyrA grlA
; gatifloxacin MIC range, 1.56 to 6.25 μg/ml), suggesting that gatifloxacin possesses the most potent inhibitory activity against singly mutated topo IV and singly mutated DNA gyrase among the quinolones tested. Moreover, gatifloxacin selected resistant mutants from wild-type and the second-step mutants at a low frequency. Gatifloxacin possessed potent activity (MIC, 0.39 μg/ml) against the NorA-overproducing strain
S. aureus
NY12, the
norA
transformant, which was slightly lower than that against the parent strain SA113. The increases in the MICs of the quinolones tested against NY12 were negatively correlated with the hydrophobicity of the quinolones (correlation coefficient, −0.93;
P
< 0.01). Therefore, this slight decrease in the activity of gatifloxacin is attributable to its high hydrophobicity. Those properties of gatifloxacin likely explain its good activity against quinolone-resistant clinical isolates of
S. aureus
harboring the
grlA
,
gyrA
, and/or
norA
mutations.
Efficacy of Nitazoxanide against
Cryptosporidium parvum
in Cell Culture and in Animal Models
Authors: Theodos Cynthia M. , Griffiths Jeffrey K. , D’Onfro Jennifer , Fairfield Alexandra , Tzipori Saul 
Published: October 2018

ABSTRACT

Nitazoxanide (NTZ), a drug currently being tested in human clinical trials for efficacy against chronic cryptosporidiosis, was assessed in cell culture and in two animal models. The inhibitory activity of NTZ was compared with that of paromomycin (PRM), a drug that is partially effective against
Cryptosporidium parvum
. A concentration of 10 μg of NTZ/ml (32 μM) consistently reduced parasite growth in cell culture by more than 90% with little evidence of drug-associated cytotoxicity, in contrast to an 80% reduction produced by PRM at 2,000 μg/ml (3.2 mM). In contrast to its efficacy in vitro, NTZ at either 100 or 200 mg/kg of body weight/day for 10 days was ineffective at reducing the parasite burden in
C. parvum
-infected, anti-gamma-interferon-conditioned SCID mice. Combined treatment with NTZ and PRM was no more effective than treatment with PRM alone. Finally, NTZ was partially effective at reducing the parasite burden in a gnotobiotic piglet diarrhea model when given orally for 11 days at 250 mg/kg/day but not at 125 mg/kg/day. However, the higher dose of NTZ induced a drug-related diarrhea in piglets that might have influenced its therapeutic efficacy. As we have previously reported, PRM was effective at markedly reducing the parasite burden in piglets at a dosage of 500 mg/kg/day. Our results indicate that of all of the models tested, the piglet diarrhea model most closely mimics the partial response to NTZ treatment reported to occur in patients with chronic cryptosporidiosis.
In Vivo Activity and Pharmacokinetic Evaluation of a Novel Long-Acting Carbapenem Antibiotic, MK-826 (L-749,345)
Authors: Gill Charles J. , Jackson Jesse J. , Gerckens Lynn S. , Pelak Barbara A. , Thompson Randall K. , Sundelof Jon G. , Kropp Helmut , Rosen H. 
Published: October 2018

ABSTRACT

MK-826 (formerly L-749,345), is a potent 1-β-methyl carbapenem with a long half-life and broad spectrum of activity. This compound is presently in phase-II clinical trials. Its activity against a number of gram-positive and gram-negative organisms was compared to those of imipenem (IPM) and eight other β-lactam agents in two in vivo murine infection models. The distribution in tissue and pharmacokinetic properties of MK-826 and ceftriaxone (CTRX) were also evaluated in CD-1 mice following a single intraperitoneal dose (10 mg/kg of body weight). In addition, concentrations in plasma as well as biliary and urinary recovery of MK-826 were compared to that of CTRX in a cannulated rat model. In a localized murine thigh infection model, MK-826 and IPM were superior to a variety of β-lactam antibiotics in reduction of
Staphylococcus aureus
CFU compared with results from nontreated controls (eliminating ≥4 log
10
CFU). Similar activities of IPM and MK-826 were observed in a gram-positive bacterial murine systemic infection model. While IPM demonstrated greater efficacy than MK-826 against
Enterobacter cloacae
(50% effective doses [ED
50
s] of 0.062 and 0.227 mg/kg, respectively) and
Pseudomonas aeruginosa
(ED
50
s of 0.142 and 3.0 mg/kg, respectively) systemic infections, MK-826 was 8- to 350-fold more efficacious than IPM against all other gram-negative organisms in this infection model. In mice, MK-826 demonstrated a higher peak concentration in serum (62.8 versus 42.6 μg/ml) and a larger area under the curve (AUC) (150.8 versus 90.0 μg · hr/ml) than CTRX. The concentrations of MK-826 and CTRX in serum declined slowly, with levels of 3.6 and 2.0 μg/ml remaining, respectively, at 6 h posttreatment. The rat pharmacokinetic model showed the average AUC of MK-826 to be greater than that of CTRX (284 versus 142 μg · hr/ml) following a single 10-mg/kg dose. Also, a half-life of MK-826 longer than that of CTRX (3.2 versus 2.3 h) was observed in this species. The total amount of drug excreted in the bile in 8 h was greater for CTRX (55 to 64% of the dose) than for MK-826 (6 to 12.5% of the dose). Urinary recovery was similar for both antibiotics, with 16 to 18% of the dose recovered over an 8-h period. This excellent broad-spectrum in vivo efficacy of MK-826, together with advantageous pharmacokinetics, supports the argument for its further clinical development.
Activities of Three Quinolones, Alone and in Combination with Extended-Spectrum Cephalosporins or Gentamicin, against
Stenotrophomonas maltophilia
Authors: Visalli Melissa A. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT

The present study examined the activities of trovafloxacin, levofloxacin, and ciprofloxacin, alone and in combination with cefoperazone, ceftazidime, cefpirome, and gentamicin, against 100 strains of
Stenotrophomonas maltophilia
by the MIC determination method and by synergy testing of the combinations by the time-kill and checkerboard titration methods for 20 strains. The respective MICs at which 50% and 90% of isolates were inhibited for the drugs used alone were as follows: trovafloxacin, 0.5 and 2.0 μg/ml; levofloxacin, 2.0 and 4.0 μg/ml; ciprofloxacin, 4.0 and 16.0 μg/ml; cefoperazone, >128.0 and >128.0 μg/ml; ceftazidime, 32.0 and >128.0 μg/ml; cefpirome, >128.0 and >128.0 μg/ml; and gentamicin, 128.0 and >128.0 μg/ml. Synergistic fractional inhibitory concentration indices (≤0.5) were found for ≥50% of strains for trovafloxacin-cefoperazone, trovafloxacin-ceftazidime, levofloxacin-cefoperazone, levofloxacin-ceftazidime, ciprofloxacin-cefoperazone, and ciprofloxacin-ceftazidime, with other combinations affecting fewer strains. For 20 strains tested by the checkerboard titration and time-kill methods, synergy (≥100-fold drop in count compared to the count achieved with the more active compound) was more pronounced after 12 h due to regrowth after 24 h. At 12 h, trovafloxacin at 0.004 to 0.5 μg/ml showed synergy with cefoperazone for 90% of strains, with ceftazidime for 95% of strains with cefpirome for 95% of strains, and with gentamicin for 65% of strains. Levofloxacin at 0.03 to 0.5 μg/ml and ciprofloxacin at 0.5 to 2.0 μg/ml showed synergy with cefoperazone for 80% of strains, with ceftazidime for 90 and 85% of strains, respectively, with cefpirome for 85 and 75% of strains, respectively, and with gentamicin for 65 and 75% of strains, respectively. Time-kill assays were more discriminatory than checkerboard titration assays in demonstrating synergy for all combinations.
Rapid Detection and Evaluation of Clinical Characteristics of Emerging Multiple-Drug-Resistant Gram-Negative Rods Carrying the Metallo-β-Lactamase Gene
bla
IMP
Authors: Hirakata Yoichi , Izumikawa Koichi , Yamaguchi Toshiyuki , Takemura Hiromu , Tanaka Hironori , Yoshida Ryoji , Matsuda Junichi , Nakano Michiko , Tomono Kazunori , Maesaki Shigefumi , Kaku Mitsuo , Yamada Yasuaki , Kamihira Shimeru , Kohno Shigeru 
Published: October 2018

ABSTRACT

Gram-negative rods (GNR) carrying the transferable carbapenem resistance gene
bla
IMP
, including
Pseudomonas aeruginosa
and
Serratia marcescens
, have been isolated from more than 20 hospitals in Japan. Although the emergence of such multiple-drug-resistant bacteria is of utmost clinical concern, little information in regard to the distribution of
bla
IMP
-positive GNR in hospitals and the clinical characteristics of infected patients is available. To address this, a system for the rapid detection of the
bla
IMP
gene with a simple DNA preparation and by enzymatic detection of PCR products was developed. A total of 933 ceftazidime-resistant strains of GNR isolated between 1991 and 1996 at Nagasaki University Hospital, Nagasaki, Japan, were screened for the
bla
IMP
gene; 80 isolates were positive, including 53
P. aeruginosa
isolates, 13 other glucose-nonfermenting bacteria, 13
S. marcescens
isolates, and 1
Citrobacter freundii
isolate. Most of the patients from whom
bla
IMP
-positive organisms were isolated had malignant diseases (53.8%). The organisms caused urinary tract infections, pneumonia, or other infections in 46.3% of the patients, while they were just colonizing the other patients evaluated. It was possible that
bla
IMP
-positive
P. aeruginosa
strains contributed to the death of four patients, while the other infections caused by GNR carrying
bla
IMP
were not lethal. DNA fingerprinting analysis by pulsed-field gel electrophoresis suggested the cross transmission of strains within the hospital. The isolates were ceftazidime resistant and were frequently resistant to other antibiotics. Although no particular means of pathogenesis of
bla
IMP
-positive GNR is evident at present, the rapid detection of such strains is necessary to help with infection control practices for the prevention of their dissemination and the transmission of the resistance gene to other pathogenic bacteria.
Population Pharmacokinetics of Rifabutin in Human Immunodeficiency Virus-Infected Patients
Authors: Gatti Giorgio , Papa Pietro , Torre Donato , Andreoni Massimo , Poggio Antonio , Bassetti Matteo , Marone Piero 
Published: October 2018

ABSTRACT

Rifabutin pharmacokinetics were studied by the population approach (NONMEM) with 40 human immunodeficiency virus-infected patients receiving rifabutin at different doses for prophylaxis or therapy of mycobacterial infections. A two-compartment open model with first-order absorption was used as the structural pharmacokinetic model. Parameter estimates were the absorption rate constant (0.201/h), clearance/bioavailability (CL/
F
; 60.9 liters/h), volume of the central compartment/bioavailability (231 liters), intercompartmental clearance (60.3 liters/h), and volume of the peripheral compartment/bioavailability (

V
p
/F

; 1,050 liters). The distribution and elimination half-lives were 1.24 and 25.4 h, respectively. The covariates tested for influence on CL/
F
and

V
p
/F

were sex, age, weight, height, body surface area, tobacco smoking, drug addiction, alanine aminotransferase levels, creatinine clearance, total protein, bilirubin, numbers of CD4
+
cells, presence of diarrhea, cachexia index, rifabutin use (prophylaxis versus therapy), rifabutin dose, study site, and the concomitant administration of clarithromycin, fluconazole, phenobarbital, ciprofloxacin, azithromycin, or benzodiazepines. The only statistically significant effects on rifabutin pharmacokinetic parameters were a 27% decrease in

V
p
/F

due to the concomitant administration of azithromycin and a 39% increase in

V
p
/F

due to tobacco smoking. Such effects may be considered clinically unimportant. Our results confirm the lack of a correlation of rifabutin pharmacokinetic parameters with parameters of disease progression and gastrointestinal function. Also, the lack of a correlation with covariates which were previously found to be significant, such as concomitant fluconazole and clarithromycin use, may suggest that the effect of such covariates may be less important in the real clinical setting, in which several concomitant factors may influence pharmacokinetic parameters, with an overall effect of no apparent correlation.
In Vitro Susceptibility of
Mycobacterium ulcerans
to Clarithromycin
Authors: Portaels F. , Traore H. , De Ridder K. , Meyers W. M. 
Published: October 2018

ABSTRACT

Buruli ulcer (BU), caused by
Mycobacterium ulcerans
, was recently recognized by the World Health Organization as an important emerging disease. While antimycobacterial therapy is often effective for the earliest nodular or ulcerative lesions, medical management of BU lesions in patients presenting for treatment is usually disappointing, leaving wide surgical excision the only alternative. Advanced ulcerated lesions of BU rarely respond to antimycobacterial agents; however, perioperative administration of such drugs may prevent relapses or disseminated infections. Clarithromycin possesses strong activity in vitro and in vivo against most nontuberculous mycobacteria. In this study we determined the antimycobacterial activity of this drug in vitro against 46 strains of
M. ulcerans
isolated from 11 countries. The MIC of clarithromycin was determined at pH 6.6 (on 7H11 agar) and at pH 7.4 (on Mueller-Hinton agar). The MICs ranged from 0.125 to 2 μg/ml at pH 6.6 and from <0.125 to 0.5 μg/ml at pH 7.4. For the majority of the strains, geographic origin did not play a significant role. Thirty-eight strains (83%) were inhibited by 0.5 μg/ml at pH 7.4. These MICs are below peak therapeutic concentrations of clarithromycin obtainable in blood. These results suggest that clarithromycin is a promising drug both for the treatment of early lesions of
M. ulcerans
and for the prevention of hematogenous dissemination of the etiologic agent during and after surgery. Studies should be initiated to evaluate the effects of clarithromycin in combination with ethambutol and rifampin on
M. ulcerans
both in vitro and in experimentally infected mice. Multidrug regimens containing clarithromycin may also help control the secondary bacterial infections sometimes seen in BU patients, most importantly osteomyelitis.
Confirmatory Evidence from 18S rRNA Gene Analysis for In Vivo Development of Propamidine Resistance in a Temporal Series of
Acanthamoeba
Ocular Isolates from a Patient
Authors: Ledee Dolena R. , Seal David V. , Byers Thomas J. 
Published: October 2018

ABSTRACT

DNA sequences of three 18S rRNA gene alleles present in trophozoites obtained before and after therapy for
Acanthamoeba
keratitis substantiate a previous report that the infection was due to a single
Acanthamoeba
strain. Thus, the possibility that propamidine resistance which developed during therapy was due to a mixed infection was ruled out.
Influence of the TonB Energy-Coupling Protein on Efflux-Mediated Multidrug Resistance inPseudomonas aeruginosa
Authors: Zhao Qixun , Li Xian-Zhi , Mistry Anita , Srikumar Ramakrishnan , Zhang Li , Lomovskaya Olga , Poole Keith 
Published: October 2018

ABSTRACTTonB couples the energized state of the cytoplasmic membrane to the operation of outer membrane receptors responsible for Fe(III) siderophore uptake across the outer membrane of gram-negative bacteria. AtonBmutant ofPseudomonas aeruginosadeficient in iron siderophore uptake was shown in the present study to be hypersusceptible to a wide variety of antibiotics, reminiscent of the phenotype of mutants defective in themexAB-oprMantibiotic efflux operon. This was not related to influences of atonBmutation on the iron status of the cell, and indeed, intrinsic antibiotic susceptibility andmexAB-oprMexpression were unaffected by iron levels in the growth medium. The presence oftonBon a multicopy plasmid increased the level of resistance of a MexAB-OprM+strain but not that of a MexAB-OprM−strain to a variety of antimicrobial agents.mexAB-oprMexpression was not, however, altered in atonBdeletion mutant, indicating that any influence of TonB on MexAB-OprM-mediated multidrug resistance was at the level of pump activity. Consistent with this, drug accumulation assays revealed that thetonBdeletion mutant exhibited decreased levels of drug efflux. Still, the multidrug resistance of analBstrain was not wholly abrogated by atonBmutation, indicating that it is likely not an essential component of the efflux apparatus. Similarly, elimination oftonBfrom annfxBstrain only partially compromised MexCD-OprJ-mediated multidrug resistance. Intriguingly, the drug susceptibility of amexAB-oprMdeletion strain was increased following deletion oftonB, suggesting that TonB may also influence antibiotic resistance mediated by determinants other than MexAB-OprM (and MexCD-OprJ). Thus, TonB plays an important role in both intrinsic and acquired antibiotic resistance inP. aeruginosa.
Incidence of Foscarnet Resistance and Cidofovir Resistance in Patients Treated for Cytomegalovirus Retinitis
Authors: Jabs Douglas A. , Enger Cheryl , Forman Michael , Dunn J. P. , Retinitis for The Cytomegalovirus , Group Viral Resistance Study 
Published: October 2018

ABSTRACT

Cytomegalovirus (CMV) retinitis is a common opportunistic infection in patients with AIDS. With long-term therapy for CMV retinitis, resistant CMV may develop. In a prospective study of 122 patients with CMV retinitis, 2.4 and 0.8% of patients had foscarnet-resistant blood culture isolates (50% inhibitory concentration [IC
50
], >400 μM) and urine culture isolates, respectively, at diagnosis of CMV retinitis prior to treatment, whereas 4.1 and 6.6% had cidofovir-resistant (IC
50
, >2 μM) blood and urine culture isolates, respectively. Patients were treated according to best medical judgement. Of 44 foscarnet-treated patients, 26% had a resistant blood or urine culture isolate by 6 months of treatment and 37% had a resistant isolate by 9 months; of 13 cidofovir-treated patients, 29% had a resistant blood or urine culture isolate by 3 months of therapy. The probabilities of developing foscarnet resistance while on foscarnet and developing cidofovir resistance while on cidofovir were not significantly different from that for developing ganciclovir resistance while on ganciclovir (odds ratios, 1.87 [
P
= 0.19] and 2.28 [
P
= 0.15], respectively).
Antimalarial Synergy of Cysteine and Aspartic Protease Inhibitors
Authors: Semenov Andrey , Olson Jed E. , Rosenthal Philip J. 
Published: October 2018

ABSTRACT

It has been proposed that the
Plasmodium falciparum
cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured
P. falciparum
parasites, cysteine and aspartic protease inhibitors exhibited synergistic effects in blocking parasite metabolism and development. The inhibitors also demonstrated apparent synergistic inhibition of plasmodial hemoglobin degradation both in culture and in a murine malaria model. When evaluated for the treatment of murine malaria, a combination of cysteine and aspartic protease inhibitors was much more effective than higher concentrations of either compound used alone. These results support a model whereby plasmodial cysteine and aspartic proteases participate in the degradation of hemoglobin, and they suggest that combination antimalarial therapy with inhibitors of the two classes of proteases is worthy of further study.
Influence of Assay Methodology on the Measurement of Free Serum Ceftriaxone Concentrations
Authors: Kohlhepp Sue J. , Gilbert David N. , Leggett James E. 
Published: October 2018

ABSTRACT

The influence of assay methodology on the measurement of the active free fraction of ceftriaxone in plasma was determined. The free fraction was measured by three methods: agar diffusion bioassay, precipitation of plasma protein with methanol followed by high-performance liquid chromatography (HPLC) of the supernatant, and ultrafiltration of plasma followed by HPLC of the filtrate. In human serum, the free ceftriaxone levels were significantly lower (
P
= 0.03) when measured on ultrafiltrates compared to the other two methods. This difference disappeared when dolphin serum was studied. After ultrafiltration, human serum was shown, by Scatchard plot analysis, to have two ceftriaxone binding sites. Species differences were also demonstrated. Hence, in humans, determination of free plasma ceftriaxone varies with the assay method employed.