bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose Range Evaluation of Liposomal Nystatin and Comparisons with Amphotericin B and Amphotericin B Lipid Complex in Temporarily Neutropenic Mice Infected with an Isolate of
Aspergillus fumigatus
with Reduced Susceptibility to Amphotericin B
Authors: Denning David W. , Warn Peter 
Published: October 2018

ABSTRACT

Using an isolate of
Aspergillus fumigatus
that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [
P
= 0.24] and 1 mg/kg [
P
< 0.0001]), ABLC (5 mg/kg [
P
= 0.014] and 1 mg/kg [
P
< 0.0001]), and amphotericin B deoxycholate (5 mg/kg [
P
= 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (
P
= 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [
P
= 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.
Synergistic Fungistatic Effects of Lactoferrin in Combination with Antifungal Drugs against Clinical
Candida
Isolates
Authors: Kuipers M. E. , de Vries H. G. , Eikelboom M. C. , Meijer D. K. F. , Swart P. J. 
Published: October 2018

ABSTRACT

Because of the rising incidence of failures in the treatment of oropharyngeal candidosis in the case of severely immunosuppressed patients (mostly human immunodeficiency virus [HIV]-infected patients), there is need for the development of new, more effective agents and/or compounds that support the activity of the common antifungal agents. Since lactoferrin is one of the nonspecific host defense factors present in saliva that exhibit antifungal activity, we studied the antifungal effects of human, bovine, and iron-depleted lactoferrin in combination with fluconazole, amphotericin B, and 5-fluorocytosine in vitro against clinical isolates of
Candida
species. Distinct antifungal activities of lactoferrin were observed against clinical isolates of
Candida
. The MICs generally were determined to be in the range of 0.5 to 100 mg · ml
−1
. Interestingly, in the combination experiments we observed pronounced cooperative activity against the growth of
Candida
by using lactoferrin and the three antifungals tested. Only in a limited concentration range was minor antagonism detected. The use of lactoferrin and fluconazole appeared to be the most successful combination. Significant reductions in the minimal effective concentrations of fluconazole were found when it was combined with a relatively low lactoferrin concentration (1 mg/ml). Such combinations still resulted in complete growth inhibition, while synergy of up to 50% against several
Candida
species was observed. It is concluded that the combined use of lactoferrin and antifungals against severe infections with
Candida
is an attractive therapeutic option. Since fluconazole-resistant
Candida
species have frequently been reported, especially in HIV-infected patients, the addition of lactoferrin to the existing fluconazole therapy could postpone the occurrence of species resistance against fluconazole. Clinical studies to further elucidate the potential utility of this combination therapy have been initiated.
Competition of Various β-Lactam Antibiotics for the Major Penicillin-Binding Proteins of
Helicobacter pylori
: Antibacterial Activity and Effects on Bacterial Morphology
Authors: DeLoney Cindy R. , Schiller Neal L. 
Published: October 2018

ABSTRACT

The penicillin-binding proteins (PBPs) of helical (log-phase)
Helicobacter pylori
ATCC 43579 were identified by using biotinylated ampicillin. The major PBPs had apparent molecular masses of 47, 60, 63, and 66 kDa; an additional minor PBP of 95 to 100 kDa was also detected. The relative affinities of various β-lactams for these PBPs were tested by competitive-binding assays. Only PBP63 appeared to be significantly bound to each of the competing antibiotics, whereas PBP66 strongly bound mezlocillin, oxacillin, amoxicillin, and ceftriaxone. Whereas most of the β-lactams significantly bound two or more PBPs, aztreonam specifically targeted PBP63. The influence of sub-MICs of these β-lactams on the morphologies of log-phase
H. pylori
was observed at both the phase-contrast and transmission electron microscopy levels. Each of the eight β-lactams examined induced blebbing and sphere formation, whereas aztreonam was the only antibiotic studied which induced pronounced filamentation in
H. pylori
. Finally, studies comparing the PBPs of helical (log-phase) cultures with those of coccoid (7-, 14-, and 21-day-old) cultures of
H. pylori
revealed that the major PBPs at 60 and 63 kDa seen in the helical form were almost undetectable in the coccoid forms, whereas PBP66 remained the major PBP in the coccoid forms, although somewhat reduced in level compared to the helical form. PBP47 was present in both forms at approximately equal concentrations. These studies thus identified the major PBPs in both helical and coccoid forms of
H. pylori
and compared the relative affinities of seven different β-lactams for the PBPs in the helical forms and their effects on bacterial morphology.
Mechanisms of Fluoroquinolone Transport by Human Neutrophils
Authors: Walters John D. , Zhang Fanjie , Nakkula Robin J. 
Published: October 2018

ABSTRACT

Neutrophils accumulate ciprofloxacin and other fluoroquinolones, a process that enhances the killing of intracellular pathogens and could facilitate the delivery of these agents to infection sites by migrating neutrophils. The mechanisms by which transport occurs have not been characterized. In the present study, quiescent neutrophils transported ciprofloxacin with an observed

K
m

of 167 μg/ml (501 μM) and a maximum velocity of 25.2 ng/min/10
6
cells. When neutrophils were stimulated with phorbol myristate acetate (PMA), a second component of ciprofloxacin transport was induced. This pathway had an apparent

K
m

of 9.76 μg/ml (29.3 μM) and a maximum velocity of 59.3 ng/min/10
6
cells. Transport by both pathways was Na
+
independent. Ciprofloxacin transport by quiescent cells was relatively insensitive to pH and
N
-ethylmaleimide but was competitively inhibited by adenine (

K
i

= 1.55 mM). Papaverine, a benzylisoquinoline known to inhibit nucleobase transport, also inhibited ciprofloxacin transport by quiescent cells. In contrast, transport by PMA-stimulated cells was enhanced at pH 8.2, inhibited at pH 6.2, and blocked by
N
-ethylmaleimide. Cationic and neutral amino acids and cystine competitively inhibited ciprofloxacin transport by PMA-stimulated neutrophils (

K
i

= 158 μM for ornithine) but had little effect on quiescent cells. PMA-activated transport was not inhibited when the Na
+
in the medium was replaced with K
+
or Li
+
, and the pattern of inhibition by cationic and neutral amino acids was similar. In summary, neutrophils continuously transport ciprofloxacin via a transport pathway shared by adenine. Activation by PMA induces a separate, higher-affinity transport pathway shared by a broad scope of amino acids. Neutrophils utilize one or both of these mechanisms to transport other fluoroquinolones.
Antimicrobial Susceptibility Testing of
Helicobacter pylori
in a Large Multicenter Trial: the MACH 2 Study
Authors: Mégraud Francis , Lehn Norbert , Lind Tore , Bayerdörffer Ekkehard , O’Morain Colm , Spiller Robin , Unge Peter , van Zanten Sander Veldhuyzen , Wrangstadh Michael , Burman Carl Fredrik 
Published: October 2018

ABSTRACT

Culture and susceptibility testing of
Helicobacter pylori
strains was performed in a large multinational, multicenter randomized clinical trial. Culture was carried out on gastric biopsy samples obtained from 516 patients at entry and had a sensitivity of 99% when the [
13
C]urea breath test was used as a reference. Susceptibility testing was performed for clarithromycin and metronidazole on 485 strains by an agar dilution method and the epsilometer test (Etest) and for amoxicillin by an agar dilution method only. Resistance to clarithromycin (>1 μg/ml) was found in 3% of the
H. pylori
strains, with a perfect correlation between Etest and agar dilution methods. Resistance to metronidazole (>8 μl/ml) was found in 27% of the strains by agar dilution, but there were important discrepancies between it and the Etest method. No resistance to amoxicillin was found. The logarithms of the MICs of the three antibiotics against susceptible strains had a distribution close to normal. The impact of resistance was tested in the four arms of the trial. There were not enough clarithromycin-resistant strains to evaluate the impact of resistance on the cure rate of clarithromycin-based regimens. For metronidazole-resistant strains, the impact noted in the clarithromycin-metronidazole arm was partially overcome when omeprazole was added (76% eradication for resistant strains versus 95% for susceptible strains). Secondary resistance to clarithromycin occurred in strains from 12 of 105 patients (11.4%) after the failure of a clarithromycin-based regimen to effect eradication. The detection of point mutations in clarithromycin-resistant strains was performed by a combination of PCR and restriction fragment length polymorphism. Mutations (A2142G and 2143G) were found in all strains tested except one. This study stresses the importance of performing susceptibility tests in clinical trials in order to explain the results of different treatments.
Differential Modulatory Effects of Clarithromycin on the Production of Cytokines by a Tumor
Authors: Sassa Kazuhiko , Mizushima Yutaka , Kobayashi Masashi 
Published: October 2018

ABSTRACT
In vitro treatment with clarithromycin inhibited the expression of the matrix metalloproteinase-9, transforming growth factor β, and tumor necrosis factor alpha genes in 13762NF rat mammary adenocarcinoma cells. Transient enhancement, rather than inhibition, was observed for the interleukin-6 gene, and no significant change was observed for the tissue inhibitor of metalloproteinase-2 gene. Such an effect was not observed for cefotiam or gentamicin.
Efficacies of High-Dose Fluconazole plus Amphotericin B and High-Dose Fluconazole plus 5-Fluorocytosine versus Amphotericin B, Fluconazole, and 5-Fluorocytosine Monotherapies in Treatment of Experimental Endocarditis, Endophthalmitis, and Pyelonephritis Due to
Candida albicans
Authors: Louie Arnold , Liu Weiguo , Miller Dorothy A. , Sucke Alana C. , Liu Qing-Feng , Drusano George L. , Mayers Martin , Miller Michael H. 
Published: October 2018

ABSTRACT

We compared the efficacies of fluconazole (Flu), amphotericin B (AmB), and 5-fluorocytosine (5FC) monotherapies with the combination of Flu plus 5FC and Flu plus AmB in a rabbit model of
Candida albicans
endocarditis, endophthalmitis, and pyelonephritis. The dose of Flu used was that which resulted in an area under the concentration-time curve in rabbits equivalent to that seen in humans who receive Flu at 1,600 mg/day, the highest dose not associated with central nervous system toxicity in humans. Quantitative cultures of heart valve vegetations, the choroid-retina, vitreous humor, and kidney were conducted after 1, 5, 14, and 21 days of therapy. All untreated controls died within 6 days of infection; animals treated with 5FC monotherapy all died within 18 days. In contrast, 93% of animals in the other treatment groups appeared well and survived until they were sacrificed. At day 5, the relative decreases in CFU per gram in the vitreous humor were greater in groups that received Flu alone and in combination with 5FC or AmB than in groups receiving AmB or 5FC monotherapies (
P
< 0.005) but were similar thereafter. In the choroid-retina, 5FC was the least-active drug. However, there were no differences in choroidal fungal densities between the other treatment groups. On days 5 and 14 of therapy, fungal densities in kidneys of AmB recipients were lower than those resulting from the other therapies (
P
< 0.001 and
P
≤ 0.038, respectively) and AmB-plus-Flu therapy was antagonistic; however, all therapies for fungal pyelonephritis were similar by treatment day 21. While fungal counts in cardiac valves of Flu recipients were similar to those of controls on day 5 of therapy and did not change from days 1 to 21, AmB therapy significantly decreased valvular CFUs versus Flu at days 5, 14, and 21 (
P
< 0.005 at each time point). 5FC plus Flu demonstrated enhanced killing in cardiac vegetations compared with Flu or 5FC as monotherapies (
P
< 0.03). Similarly, the combination of AmB and Flu was more active than Flu in reducing the fungal density in cardiac vegetations (
P
< 0.03). However, as in the kidney, AmB plus Flu demonstrated antagonism versus AmB monotherapy in the treatment of
C. albicans
endocarditis (
P
< 0.05,
P
= 0.036, and
P
< 0.008 on days 5, 14, and 21, respectively).
Pharmacokinetics of Cefepime in Patients with Thermal Burn Injury
Authors: Bonapace Charles R. , White Roger L. , Friedrich Lawrence V. , Norcross E. Douglas , Bosso John A. 
Published: October 2018

ABSTRACT

The pharmacokinetics of cefepime following administration of a single 2-g dose were evaluated for 12 adult patients with thermal burn injury and suspected or documented infection. Serial blood and urine samples for cefepime concentration determination were obtained for 24 h following drug administration. Serum and urine cefepime concentrations were determined by high-performance liquid chromatography and serum concentrations were fit to a two-compartment pharmacokinetic model. Mean (standard deviation [SD]) age, actual body weight (ABW), percent total body surface area burned, and days postburn at the time of study were 41 (13) years, 84 (22) kg, 36 (17)%, and 9 (3) days, respectively. Mean (SD) measured creatinine clearance (CL
CR
), total clearance (CL
T
), renal clearance (CL
R
), alpha phase half-life, beta phase half-life, and volume of distribution at steady state (
V
SS
) were 135 (31) ml/min, 8.8 (2.4) liters/h, 8.1 (2.0) liters/h, 0.33 (0.14) h, 2.8 (0.6) h, and 0.43 (0.10) liters/kg ABW, respectively. Cefepime CL
T
and CL
R
in burn patients were similar to previously reported values for healthy volunteers when normalized by CL
CR
. Stepwise multiple regression was used to associate CL
T
with CL
CR
and days postburn (
r
2
= 0.861), CL
R
with CL
CR
and days postburn (
r
2
= 0.773), nonrenal clearance with percent third-degree (% 3°) burn and albumin concentration (
r
2
= 0.550), and
V
SS
only with % 3° burn (
r
2
= 0.624). Simulated steady-state serum concentrations obtained by using the patients’ pharmacokinetic parameters exceeded the susceptibility interpretive standard (breakpoint) of cefepime for at least 60% of the dosing interval with dosing regimens of 1 g every 8 h (q8h), 2 g q8h, and 2 g q12h. Despite differences in pharmacokinetic parameters between our patients and healthy volunteers, it appears that these dosing regimens may be adequate in similar burn patients.
Comparison of In Vitro Activities of Camptothecin and Nitidine Derivatives against Fungal and Cancer Cells
Authors: Del Poeta Maurizio , Chen Shih-Fong , Von Hoff Daniel , Dykstra Christine C. , Wani Mansukh C. , Manikumar Govindarajan , Heitman Joseph , Wall Monroe E. , Perfect John R. 
Published: October 2018

ABSTRACT

The activities of a series of camptothecin and nitidine derivatives that might interact with topoisomerase I were compared against yeast and cancer cell lines. Our findings reveal that structural modifications to camptothecin derivatives have profound effects on the topoisomerase I-drug poison complex in cells. Although the water-soluble anticancer agents topotecan and irinotecan are less active than the original structure, camptothecin, other derivatives or analogs with substitutions that increase compound solubility have also increased antifungal activities. In fact, a water-soluble prodrug appears to penetrate into the cell and release its active form; the resulting effect in complex with
Cryptococcus neoformans
topoisomerase I is a fungicidal response and also potent antitumor activity. Some of the compounds that are not toxic to wild-type yeast cells are extremely toxic to the yeast cells when the
C. neoformans
topoisomerase I target is overexpressed. With the known antifungal mechanism of a camptothecin-topoisomerase I complex as a cellular poison, these findings indicate that drug entry may be extremely important for antifungal activity. Nitidine chloride exhibits antifungal activity against yeast cells through a mechanism(s) other than topoisomerase I and appears to be less active than camptothecin analogs against tumor cells. Finally, some camptothecin analogs exhibit synergistic antifungal activity against yeast cells in combination with amphotericin B in vitro. Our results suggest that camptothecin and/or nitidine derivatives can exhibit potent antifungal activity and that the activities of camptothecin derivatives with existing antifungal drugs may be synergistic against pathogenic fungi. These new compounds, which exhibit potent antitumor activities, will likely require further structural changes to find more selective activity against fungal versus mammalian cells to hold promise as a new class of antifungal agents.
Hydroxyurea Potentiates the Antiherpesvirus Activities of Purine and Pyrimidine Nucleoside and Nucleoside Phosphonate Analogs
Authors: Neyts J. , De Clercq E. 
Published: October 2018

ABSTRACT

Hydroxyurea has been shown to potentiate the anti-human immunodeficiency virus activities of 2′,3′-dideoxynucleoside analogs such as didanosine. We have now evaluated in vitro the effect of hydroxyurea on the antiherpesvirus activities of several nucleoside analogs (acyclovir [ACV], ganciclovir [GCV], penciclovir [PCV], lobucavir [LBV], (
R
)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine [H2G], and brivudin and nucleoside phosphonate analogs (cidofovir [CDV] and adefovir [ADV]). When evaluated in cytopathic effect (CPE) reduction assays, hydroxyurea by itself had little effect on CPE progression and potentiated in a subsynergistic (herpes simplex virus type 1 [HSV-1]) to synergistic (HSV-2) fashion the antiviral activities of ACV, GCV, PCV, LBV, H2G, ADV, and CDV. Hydroxyurea also caused marked increases in the activities of ACV, GCV, PCV, LBV, and H2G (compounds that depend for their activation on a virus-encoded thymidine kinase [TK]) against TK-deficient (TK
−
) HSV-1. In fact, in combination with hydroxyurea the 50% effective concentrations of these compounds for inhibition of TK
−
HSV-1-induced CPE decreased from values of 20 to ≥100 μg/ml (in the absence of hydroxyurea) to values of 1 to 5 μg/ml (in the presence of hydroxyurea at 25 to 100 μg/ml). When evaluated in a single-cycle virus yield reduction assay, hydroxyurea at a concentration of 100 μg/ml inhibited progeny virus production by 60 to 90% but had little effect on virus yield at a concentration of 25 μg/ml. Under these assay conditions hydroxyurea still elicited a marked potentiating effect on the antiherpesvirus activities of GCV and CDV, but this effect was less pronounced than that in the CPE reduction assay. It is conceivable that the potentiating effect of hydroxyurea stems from a depletion of the intracellular deoxynucleoside triphosphate pools, thus favoring the triphosphates of the nucleoside analogues (or the diphosphates of the nucleoside phosphonate analogues) in their competition with the natural nucleotides at the viral DNA polymerase level. The possible clinical implications of these findings are discussed.
Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1
Authors: Corbett Jeffrey W. , Ko Soo S. , Rodgers James D. , Jeffrey Susan , Bacheler Lee T. , Klabe Ronald M. , Diamond Sharon , Lai Chii-Ming , Rabel Shelley R. , Saye Jo Anne , Adams Stephen P. , Trainor George L. , Anderson Paul S. , Erickson-Viitanen Susan K. 
Published: October 2018

ABSTRACT

A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3,4-dihydro-2(1
H
)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3,4-dihydro-2(1
H
)quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.
High-Dose Isoniazid Therapy for Isoniazid-Resistant Murine
Mycobacterium tuberculosis
Infection
Authors: Cynamon M. H. , Zhang Y. , Harpster T. , Cheng S. , DeStefano M. S. 
Published: October 2018

ABSTRACT

The use of isoniazid (INH) for the treatment of INH-resistant
Mycobacterium tuberculosis
infection has been controversial. The purpose of the present studies was to determine if there is a dose response with INH for INH-susceptible
M. tuberculosis
Erdman (ATCC 35801), and whether high-dose INH (100 mg/kg of body weight) was more effective than standard-dose INH (25 mg/kg) for therapy of tuberculosis infections caused by INH-resistant mutants of
M. tuberculosis
Erdman. Six-week-old CD-1 mice were infected with approximately 10
7
viable mycobacteria. Early control groups of infected but untreated mice were euthanized by CO
2
inhalation 1 week later when treatment was initiated. INH (25, 50, 75, and 100 mg/kg) was given by gavage 5 days/week for 4 weeks. Late control groups of untreated mice and treated mice were sacrificed 2 days after the last dose of drug. Spleens and right lungs were removed aseptically and homogenized, and viable cell counts were determined by titration on 7H10 agar plates. In the next study, INH at 100 mg/kg was compared to INH at 25 mg/kg against an isogenic mutant of
M. tuberculosis
Erdman (INH MIC, 2 μg/ml) and the parent strain. This mutant was found to have a mutation in the KatG protein (Phe to Leu at position 183). In the first study, there was no dose response with increasing doses of INH. In the second study, there was no significant difference between the reduction of viable cell counts for mice treated with INH at 100 mg/kg and that for mice treated with INH at 25 mg/kg (parent or INH-resistant mutant). These preliminary results suggest that INH may be useful in combination therapy of
M. tuberculosis
infections caused by low-level INH-resistant organisms (INH MICs, 0.2 to 5 μg/ml) and that higher doses of INH are unlikely to be more efficacious than the standard 300-mg/day dose.