bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxfendazole Treatment for Cystic Hydatid Disease in Naturally Infected Animals
Authors: Blanton Ronald E. , Wachira Timothy M. , Zeyhle Eberhard E. , Njoroge Ernest M. , Magambo Japheth K. , Schantz Peter M. 
Published: October 2018

ABSTRACT

Few chemotherapeutic agents are available for the medical management of hydatid disease caused by the parasite
Echinococcus granulosus
. In order to test the potential of oxfendazole for the treatment of infection with this parasite, nine infected goats and four sheep were given oxfendazole twice weekly at a dose of 30 mg/kg of body weight for 4 weeks and monitored by ultrasound for an additional 4 weeks. Efficacy was finally evaluated by postmortem examination, including determination of protoscolex viability and cyst wall histology. In treated animals, protoscolices were dead or absent in 97% of cysts from oxfendazole-treated animals compared to 28% of cysts from untreated control animals. On postmortem examination, 53% of cysts from treated animals were found to be grossly degenerate. A sample of those cysts that appeared potentially viable all demonstrated evidence of severe damage to the cyst wall. By light microscopy, cysts showed severe disorganization of the adventitial layer with invasion of inflammatory cells and in some cases frank necrosis with no apparent adventitial layer. The follow-up period for assessment of the drug’s ability to cause complete degeneration and resorption of cysts was relatively short. This study, however, indicates that oxfendazole is at least as effective as and is easier to administer than albendazole for the treatment of hydatid disease.
Inter- and Intraquinolone Predictors of Antimicrobial Effect in an In Vitro Dynamic Model: New Insight into a Widely Used Concept
Authors: Firsov Alexander A. , Shevchenko Alexander A. , Vostrov Sergey N. , Zinner Stephen H. 
Published: October 2018

ABSTRACT

Earlier efforts to search for pharmacokinetic and bacteriological predictors of fluoroquinolone antimicrobial effects (AMEs) have resulted in conflicting findings. To elucidate whether these conflicts are real or apparent, several predictors of the AMEs of two pharmacokinetically different antibiotics, trovafloxacin (TRO) and ciprofloxacin (CIP), as well as different dosing regimens of CIP were examined. The AMEs of TRO given once daily (q.d.) and CIP given q.d. and twice daily (b.i.d.) against
Escherichia coli
,
Pseudomonas aeruginosa
, and
Klebsiella pneumoniae
were studied in an in vitro dynamic model. Different monoexponential pharmacokinetic profiles were simulated with a TRO half-life of 9.2 h and a CIP half-life of 4.0 h to provide similar eightfold ranges of the area under the concentration-time curve (AUC)-to-MIC ratios, from 54 to 432 and from 59 to 473 (μg · h/ml)/(μg/ml), respectively. In each case the observation periods were designed to incorporate full-term regrowth phases in the time-kill curves, and the AME was expressed by its intensity (

I
E

; the area between the control growth and time-kill and regrowth curves up to the point at which the viable counts of regrowing bacteria are close to the maximum values observed without drug). Species-independent linear relationships were established between

I
E

and log AUC/MIC, log AUC above MIC (log AUC
eff
), and time above the MIC (
T
eff
). Specific and nonsuperimposed

I
E

versus log AUC/MIC or log AUC
eff
relationships were inherent in each of the treatments: TRO given q.d. (
r
2
= 0.97 and 0.96), CIP given q.d. (
r
2
= 0.98 and 0.96), and CIP given b.i.d. (
r
2
= 0.95 and 0.93). This suggests that in order to combine data sets obtained with individual quinolones to examine potential predictors, one must be sure that these sets may be combined. Unlike AUC/MIC and AUC
eff
, the

I
E

-
T
eff
relationships plotted for the different quinolones and dosing regimens were nonspecific and virtually superimposed (
r
2
= 0.95). Hence, AUC/MIC, AUC
eff
, and
T
eff
were equally good predictors of the AME of each of the quinolones and each dosing regimen taken separately, whereas
T
eff
was also a good predictor of the AMEs of the quinolones and their regimens taken together. However, neither the quinolones nor the dosing regimens could be distinguished solely on the basis of
T
eff
, whereas they could be distinguished on the basis of AUC/MIC or AUC
eff
. Thus, two types of predictors of the quinolone AME may be identified: intraquinolone and/or intraregimen predictors (AUC/MIC, AUC
eff
and T
eff
) and an interquinolone and interregimen predictor (
T
eff
).
T
eff
may be able to accurately predict the AME of one quinolone on the basis of the data obtained for another quinolone.
Anti-
Pneumocystis
Activities of Aromatic Diamidoxime Prodrugs
Authors: Hall James Edwin , Kerrigan John E. , Ramachandran Kishore , Bender Brendan C. , Stanko Jason P. , Jones Susan K. , Patrick Donald A. , Tidwell Richard R. 
Published: October 2018

ABSTRACT

Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against
Pneumocystis carinii
in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-
Pneumocystis
activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-
Pneumocystis
activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.
In Vitro Activities of Quinupristin-Dalfopristin and the Streptogramin RPR 106972 against
Mycoplasma pneumoniae
Authors: Izumikawa Koichi , Hirakata Yoichi , Yamaguchi Toshiyuki , Yoshida Ryoji , Tanaka Hironori , Takemura Hiromu , Maesaki Shigefumi , Tomono Kazunori , Kaku Mitsuo , Izumikawa Kin-Ichi , Kamihira Shimeru , Kohno Shigeru 
Published: October 2018

ABSTRACT

The in vitro activities of quinupristin-dalfopristin and streptogramin RPR 106972 were determined with 44 strains of
Mycoplasma pneumoniae
and compared to those of macrolides, minocycline, and quinolones. All isolates tested were highly susceptible to macrolides and to quinupristin-dalfopristin (MIC at which 90% of the isolates are inhibited [MIC
90
], 0.0625 μg/ml), followed by RPR 106972 (MIC
90
, 0.5 μg/ml), quinolones, and minocycline.
Duration and Clinical Relevance of Postantibiotic Effect in Relation to the Dosing Interval
Authors: den Hollander Jan G. , Fuursted Kurt , Verbrugh Henri A. , Mouton Johan W. 
Published: October 2018

ABSTRACT

The influence of half-life on the postantibiotic effect (PAE) of tobramycin against
Pseudomonas aeruginosa
and
Staphylococcus aureus
was investigated during one dosing interval. Tobramycin half-lives of 0.5 to 2.5 h were simulated in an in vitro model, and the PAE was determined by an enzymatic inactivation method at different time points, i.e., when the tobramycin concentrations were 20×, 5×, and 1× the MIC. At the time point during therapy when the tobramycin concentrations had declined to 1× the MIC, at a tobramycin half-life of 0.5 h, the times of the PAEs were approximately 0.7 and 1.7 h for
P. aeruginosa
and
S. aureus
, respectively, and the PAE disappeared completely at half-lives corresponding to those found in humans (i.e., 2 to 2.5 h). The PAE itself cannot be fully explained by the presence of free intrabacterial tobramycin or the emergence of resistant subpopulations. The explanation for the disappearance of the PAE during the dosing interval may therefore be explained by the repair of sublethal damage. Since the standard method of determining the PAE in animal models is somewhat different from the method used for measurement of the PAE in vitro, the conditions under which the PAE is measured in vivo were also simulated in the in vitro model. This resulted in PAEs longer than those found by the standard method of obtaining in vitro PAE measurements. We conclude that the PAE of tobramycin, as determined by conventional in vitro methods, has virtually no clinical importance. PAEs determined in vivo may have some clinical relevance, but they are probably primarily caused by sub-MIC effects.
Amphotericin B in Lipid Emulsion: Stability, Compatibility, and In Vitro Antifungal Activity
Authors: Walker Scott , Tailor Sandra A. N. , Lee Mark , Louie Lisa , Louie Marie , Simor Andrew E. 
Published: October 2018

ABSTRACT

Newer formulations of amphotericin B (AmB) complexed with liposomes or lipid suspensions have been developed. Preliminary studies have suggested that AmB in Intralipid (IL) may be as effective as, but less toxic than, conventional formulations of AmB, but few data are available regarding its stability, compatibility, or in vitro antifungal activity. A compatibility study was done to evaluate the effects of AmB concentrations in IL containing either 10 or 20% soybean oil. The effects of temperature, shaking, and AmB and IL concentrations on the stability of AmB-IL suspensions were analyzed by visual inspection and liquid chromatography. The in vitro antifungal activity of AmB-IL, compared to that of AmB alone against reference strains of
Candida
species was determined by using a broth macrodilution method in accordance with National Committee for Clinical Laboratory Standards guidelines (M27-T). Samples of AmB-IL which were lightly shaken retained more than 90% of the AmB concentration over 21 days when stored at either 4 or 23°C. Varying the AmB concentration did not appear to affect the stability of AmB-IL. However, a precipitate was formed when mixtures with more than 30% lipid as a proportion of the total volume were centrifuged. AmB-IL and AmB alone had similar in vitro antifungal activities against reference strains of yeasts. Further pharmacologic and clinical studies with AmB-IL are warranted, although AmB should not be combined with IL in concentrations capable of producing a precipitate.
Activity of Amoxicillin-Clavulanate against Penicillin-Resistant
Streptococcus pneumoniae
in an Experimental Respiratory Infection Model in Rats
Authors: Smith Gillian M. , Slocombe Brian , Abbott Karen H. , Mizen Linda W. 
Published: October 2018

ABSTRACT

High doses of amoxicillin, equivalent to those produced by 500- and 750-mg oral doses in humans (area under the plasma concentration-time curve), were effective against a penicillin-resistant strain of
Streptococcus pneumoniae
in an experimental respiratory tract infection in immunocompromised rats; this superior activity confirms the results of previous studies. An unexpected enhancement of amoxicillin’s antibacterial activity in vivo against penicillin-resistant and -susceptible
S. pneumoniae
strains was observed when subtherapeutic doses of amoxicillin were coadministered with the β-lactamase inhibitor potassium clavulanate. The reason for this enhancement was unclear since these organisms do not produce β-lactamase. The differential binding of clavulanic acid and amoxicillin to penicillin-binding proteins may have contributed to the observed effects.
Population Pharmacokinetic Study of Amikacin Administered Once or Twice Daily to Febrile, Severely Neutropenic Adults
Authors: Tod Michel , Lortholary Olivier , Seytre Delphine , Semaoun Rémi , Uzzan Bernard , Guillevin Loïc , Casassus Philippe , Petitjean Olivier 
Published: October 2018

ABSTRACT

Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population. In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, <500/mm
3
) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d. (
n
= 29) or 20 mg/kg o.d. (
n
= 28) and administered intravenously over 0.5 h. A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique. A mixed-effect modeling approach was used to fit a bicompartmental model to the data (NONMEM software). The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model. The dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg. Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively. On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CL
CR
) are proposed: for patients with normal renal function (CL
CR
of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for patients with severe renal impairment (CL
CR
, 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.
Efficacy of Trovafloxacin against Penicillin-Susceptible and Multiresistant Strains of
Streptococcus pneumoniae
in a Mouse Pneumonia Model
Authors: Bédos Jean-Pierre , Rieux Véronique , Bauchet Jacqueline , Muffat-Joly Martine , Carbon Claude , Azoulay-Dupuis Esther 
Published: October 2018

ABSTRACT

The increasing emergence of penicillin-resistant and multidrug-resistant strains of
Streptococcus pneumoniae
will create a serious therapeutic problem in coming years. Trovafloxacin is a novel naphthyridone quinolone with promising activity against
S. pneumoniae
, including penicillin-resistant strains (MIC for 90% of the isolates tested, 0.25 μg/ml). We compared its in vivo efficacy with that of other fluoroquinolones (ciprofloxacin, temafloxacin, and sparfloxacin) and a reference beta-lactam (amoxicillin) in a model of acute experimental pneumonia. Immunocompetent Swiss mice were infected by peroral tracheal delivery of a virulent, penicillin-susceptible strain (MIC, 0.03 μg/ml); leukopenic Swiss mice were infected with three poorly virulent, penicillin-resistant strains (MICs, 4 to 8 μg/ml) and a ciprofloxacin-resistant strain (MIC, 32 μg/ml). Treatments were started 6 h (immunocompetent mice) or 3 h (leukopenic mice) after infection. Doses ranging from 12.5 to 300 mg/kg were given at 12- or 8-h intervals for 3 days. Trovafloxacin (25 mg/kg) was the most effective agent in vivo against penicillin-susceptible and -resistant strains. Corresponding survival rates were 2- to 4-fold higher than with 50-mg/kg sparfloxacin or temafloxacin and 8- to 16-fold higher than with 100-mg/kg ciprofloxacin. The ratios of the area under the concentration-time curve to the MIC in serum and lung tissue were more favorable with trovafloxacin than with the other quinolones. Efficacy in vivo correlated with pharmacokinetic parameters. Trovafloxacin shows potential for the treatment of infections due to penicillin-susceptible and -resistant
S. pneumoniae
but appears to be ineffective against a ciprofloxacin-resistant strain.
Comparison of Fungizone, Amphotec, AmBisome, and Abelcet for Treatment of Systemic Murine Cryptococcosis
Authors: Clemons Karl V. , Stevens David A. 
Published: October 2018

ABSTRACT

Three lipid-based formulations of amphotericin B have been approved for use in various countries. The aim of this study was to compare Amphotec (ABCD; Sequus), AmBisome (AmBi; Nexstar), Abelcet (ABLC; The Liposome Co.), and conventional deoxycholate amphotericin B (Fungizone; Bristol Meyers Squibb) for the treatment of experimental systemic cryptococcosis. A model was established in 10-week-old female CD-1 mice by intravenous (i.v.) injection of 6.25 × 10
5
viable
Cryptococcus neoformans
yeast cells. Therapy began 4 days later, with i.v. administration three times per week for 2 weeks. Mice received either no treatment, 1 mg of Fungizone per kg of body weight, or 1, 5, or 10 mg of ABCD, AmBi, or ABLC per kg. Ninety percent of control mice died between days 15 and 34. All treatment regimens except ABLC at 1 mg/kg prolonged survival compared with no treatment (
P
< 0.01 to 0.001). All mice receiving 5 or 10 mg of ABCD or AmBi per kg and 90% of mice given 10 mg of ABLC per kg survived, whereas ≤50% of those given other treatment regimens survived. Fungizone was the least effective of the four formulations, with 5 or 10 mg of ABCD, AmBi, or ABLC per kg resulting in a significantly better outcome than Fungizone (
P
< 0.001). Among the three formulations, ABCD and AmBi were equally effective, both being better than ABLC at equal 5- or 10-mg/kg doses (
P
< 0.001). Comparison of residual infectious burdens in various organs showed that each drug had some dose-responsive efficacy in three or more organs at escalating doses. In the brain, ABCD or AmBi at 5 or 10 mg/kg or ABLC at 10 mg/kg was more effective than Fungizone at 1 mg/kg or no treatment, while ABCD or AmBi at 1 mg/kg was as effective as ABLC at 10 mg/kg. Similar results were obtained for the kidneys and lungs. In the spleen, ABCD at 10 mg/kg cured all mice of infection and was superior to all other regimens. In the liver, AmBi at 5 mg/kg was superior to an equal dose of ABCD or ABLC. Overall, the efficacies of ABCD and AmBi were equal to that of Fungizone at 1 mg/kg and were about 10-fold better than that of ABLC, particularly in the brain; a comparative rank order of efficacies was ABCD ≅ AmBi > ABLC ≫ Fungizone. This is the first study that compared all four amphotericin B formulations.
Synthesis and Antibacterial Evaluation of Novel Water-Soluble Organic Peroxides
Authors: Liu Wenqiu , Liu Xuejun , Knaebel David , Luck Linda , Li Yuzhou 
Published: October 2018

ABSTRACT

A set of new water-soluble organic peroxides has been synthesized and evaluated for in vitro antibacterial activity as part of an effort to develop new antibacterial agents for the treatment of acne vulgaris. The water solubility of these new dialkyl peroxides and peroxyesters was achieved by incorporating either a quaternary ammonium group or a polyethylene glycol moiety. These peroxides are effective against both gram-positive and gram-negative bacteria and have a prolonged activity compared to that of benzoyl peroxide and other peroxide-type antiseptic agents. Among them 4-[[(
tert
-butylperoxy)carbonyl]benzyl]triethylammonium chloride and [10-(
tert
-butylperoxy)decyl]trimethylammonium bromide have the broadest antimicrobial spectrums. We have shown that the oxidizing properties of the dioxy group of these compounds are responsible for their antibacterial activities.
Effects of Slime Produced by Clinical Isolates of Coagulase-Negative Staphylococci on Activities of Various Antimicrobial Agents
Authors: Souli Maria , Giamarellou Helen 
Published: October 2018

ABSTRACT
A novel in vitro semiquantitative method was developed to investigate the influence of staphylococcal slime on the activities of 22 antimicrobial agents. Pefloxacin, teicoplanin, and vancomycin demonstrated remarkable decreases in efficacy: 30, 52, and 63%, respectively. The activity of rifampin was not significantly reduced (0.99%), whereas all other agents tested were modestly affected (<15% decrease). These data could be influential in the treatment of implant-associated infections caused by slime-producing staphylococci.
Determination of Activities of Levofloxacin, Alone and Combined with Gentamicin, Ceftazidime, Cefpirome, and Meropenem, against 124 Strains of
Pseudomonas aeruginosa
by Checkerboard and Time-Kill Methodology
Authors: Visalli Melissa A. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT

A total of 124
Pseudomonas aeruginosa
strains were tested for synergy between levofloxacin and cefpirome, ceftazidime, gentamicin, and meropenem. Checkerboards yielded synergistic fractional inhibitory concentration (FIC) indices (≤0.5) with 25 of 496 possible combinations. All other FIC indices were >0.5 to 2 (additive or indifferent), with no antagonism. Time-kill studies with 12 strains showed that levofloxacin (0.06 to 0.5 μg/ml) was synergistic with cefpirome, ceftazidime, gentamicin, and meropenem in 10, 9, 4, and 11 strains, respectively.
Killing of
Staphylococcus aureus
by C-8-Methoxy Fluoroquinolones
Authors: Zhao Xilin , Wang Jian-Ying , Xu Chen , Dong Yuzhi , Zhou Jianfeng , Domagala John , Drlica Karl 
Published: October 2018

ABSTRACT

C-8-methoxy fluoroquinolones were more lethal than C-8-bromine, C-8-ethoxy, and C-8-H derivatives for
Staphylococcus aureus
, especially when topoisomerase IV was resistant. The methoxy group also increased lethality against wild-type cells when protein synthesis was inhibited. These properties encourage refinement of C-8-methoxy fluoroquinolones to kill staphylococci.