DifferentialIn VivoActivities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata Isolates with and withoutFKSResistance Mutations

ABSTRACTWe recently observed that the micafungin MICs for someCandida glabrata fkshot spot mutant isolates are less elevated than those for the other echinocandins, suggesting that the efficacy of micafungin may be differentially dependent on such mutations. Three clinicalC. glabrataisolates with or without (S3)fkshot spot mutations R83 (Fks2p-S663F) and RR24 (Fks1p-S629P) and low, medium, and high echinocandin MICs, respectively, were evaluated to assess thein vivoefficacy in an immunocompetent mouse model using three doses of each echinocandin. Drug concentrations were determined in plasma and kidneys by high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic mathematical model was used to define the area under the concentration-time curve (AUC) that produced half- and near-maximal activity. Micafungin was equally efficacious against the S3 and R83 isolates. The estimates for the AUCs of each echinocandin that induced half-maximal effect (E50s) were 194.2 and 53.99 mg · h/liter, respectively. In contrast, the maximum effect (Emax) for caspofungin was higher against S3 than R83, but the estimates for E50were similar (187.1 and 203.5 mg · h/liter, respectively). Anidulafungin failed to induce a ≥1-log reduction for any of the isolates (AUC range, 139 to 557 mg · h/liter). None of the echinocandins were efficacious in mice challenged with the RR24 isolate despite lower virulence (reduced maximal growth, prolonged lag phase, and lower kidney burden). The AUC associated with half-maximal effect was higher than the average human exposure for all drug-dose-bug combinations except micafungin and the R83 isolate. In conclusion, differences in micafungin MICs are associated with differential antifungal activities in the animal model. This study may have implications for clinical practice and echinocandin breakpoint determination, and further studies are warranted.

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Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00453-11 ◽

2011 ◽

Vol 55 (11) ◽

pp. 5325-5330 ◽

Cited By ~ 38

Author(s):

Yan Q. Xiong ◽

Wessam Abdel Hady ◽

Antoine Deslandes ◽

Astrid Rey ◽

Laurent Fraisse ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Maximum Effect ◽

Peptide Antibiotic ◽

Time Curve ◽

Cationic Antimicrobial Peptide ◽

Unbound Fraction ◽

Methicillin Resistant ◽

Content Type ◽

Conventional Antibiotics

ABSTRACTCationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungusPseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) thein vivopharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) thein vivoefficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistantStaphylococcus aureus(MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin (P< 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. Thesein vivoefficacies were equivalent and significantly correlated with three PK indices investigated:fCmax/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC),fAUC/MIC (where AUC is the area under the concentration-time curve), andf%T>MIC(%T>MICis the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (Emax) model (R2> 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.

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Pharmacodynamics of Imipenem in Combination with β-Lactamase Inhibitor MK7655 in a Murine Thigh Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03706-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 790-795 ◽

Cited By ~ 25

Author(s):

Eleftheria Mavridou ◽

Ria J. B. Melchers ◽

Anita C. H. A. M. van Mil ◽

E. Mangin ◽

Mary R. Motyl ◽

...

Keyword(s):

Dose Fractionation ◽

Maximum Effect ◽

Significant Activity ◽

Beta Lactamase ◽

Time Curve ◽

Unbound Fraction ◽

Content Type ◽

Concentration Time ◽

Lactamase Inhibitor

ABSTRACTMK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed against several beta-lactamase producingPseudomonas aeruginosaandKlebsiella pneumoniaestrains to determine its effectin vitroandin vivo. Neutropenic mice were infected in each thigh 2 h before treatment with an inoculum of approximately 5 × 106CFU. They were treated with IMP/C alone (every 2 hours [q2h], various doses) or in combination with MK7655 in either a dose fractionation study or q2h for 24 h and sacrificed for CFU determinations. IMP/MK7655 decreased MICs regarding IMP MIC. The PK profiles of IMP/C and MK7655 were linear over the dosing range studied and comparable with volumes of distribution (V) of 0.434 and 0.544 liter/kg and half-lives (t1/2) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect (Emax) model was fit to the PK/PD index responses. The effect of the inhibitor was not related to the maximum concentration of drug in serum (Cmax)/MIC, and model fits forT>MICand area under the concentration-time curve (AUC)/MIC were comparable (R2of 0.7 and 0.75), but there appeared to be no significant relationship of effect with dose frequency. Escalating doses of MK7655 and IMP/C showed that the AUC of MK7655 required for a static effect was dependent on the dose of IMP/C and the MIC of the strain, with a mean area under the concentration-time curve for the free, unbound fraction of the drug (fAUC) of 26.0 mg · h/liter. MK7655 shows significant activityin vivoand results in efficacy of IMP/C in otherwise resistant strains. The exposure-response relationships found can serve as a basis for establishing dosing regimens in humans.

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In Vivo Comparison of the Pharmacodynamic Targets for Echinocandin Drugs against Candida Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01584-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2497-2506 ◽

Cited By ~ 147

Author(s):

D. Andes ◽

D. J. Diekema ◽

M. A. Pfaller ◽

J. Bohrmuller ◽

K. Marchillo ◽

...

Keyword(s):

Candida Glabrata ◽

Candida Parapsilosis ◽

Free Drug ◽

Response Relationship ◽

Time Curve ◽

Exposure Response ◽

Concentration Time ◽

Drug Concentrations ◽

Good Descriptor

ABSTRACT Previous pharmacodynamic studies using in vivo candidiasis models have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC is a good descriptor of the echinocandin exposure-response relationship. Further studies investigating the 24-h AUC/MIC target for a stasis endpoint identified free-drug 24-h AUC/MIC against Candida albicans and were similar for two echinocandins, anidulafungin and micafungin. The current studies expand investigation of a third echinocandin (caspofungin) and compare the pharmacodynamic target among C. albicans, Candida glabrata, and Candida parapsilosis. Treatment studies were conducted with six C. albicans, nine C. glabrata, and 15 C. parapsilosis strains with various MICs (anidulafungin, 0.015 to 4.0 μg/ml; caspofungin, 0.03 to 4.0 μg/ml; and micafungin, 0.008 to 1.0 μg/ml). Efficacy was closely tied to MIC and the 24-h AUC/MIC. Therapy against C. parapsilosis required more of each echinocandin on a mg/kg basis. Caspofungin required less drug on a mg/kg basis for efficacy against all of the organisms than did the other two drugs. However, the 24-h AUC/MIC targets were similar among the echinocandins when free drug concentrations were considered, suggesting the relevance of protein binding. The targets for C. parapsilosis (mean, 7) and C. glabrata (mean, 7) were significantly lower than those for C. albicans (mean, 20) for each echinocandin. The results suggest that current susceptibility breakpoints and the consideration of organism species in these determinations should be reexplored.

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Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01303-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5916-5922 ◽

Cited By ~ 33

Author(s):

Alexander J. Lepak ◽

Karen Marchillo ◽

Solen Pichereau ◽

William A. Craig ◽

David R. Andes

Keyword(s):

Staphylococcus Aureus ◽

Dose Range ◽

Active Form ◽

Maximum Effect ◽

Time Curve ◽

Content Type ◽

Dosing Regimens ◽

Staphylococcus Aureus Pneumonia ◽

Unit Reduction

ABSTRACTTedizolid phosphate (TR-701) is a novel oxazolidinone prodrug (converted to the active form tedizolid [TR-700]) with potentStaphylococcus aureusactivity. The current studies characterized and compared thein vivopharmacokinetic/pharmacodynamic (PD) characteristics of TR-701/TR-700 and linezolid against methicillin-susceptibleS. aureus(MSSA) and methicillin-resistantS. aureus(MRSA) in the neutropenic murine pneumonia model. The pharmacokinetic properties of both drugs were linear over a dose range of 0.625 to 40 mg/kg of body weight. Protein binding was 30% for linezolid and 85% for TR-700. Mice were infected with one of 11 isolates ofS. aureus, including MSSA and community- and hospital-acquired MRSA strains. Each drug was administered by oral-gastric gavage every 12 h (q12h). The dosing regimens ranged from 1.25 to 80 mg/kg/12 h for linezolid and 0.625 to 160 mg/kg/12 h for TR-701. At the start of therapy, mice had 6.24 ± 0.40 log10CFU/lungs, which increased to 7.92 ± 1.02 log10CFU/lungs in untreated animals over a 24-h period. A sigmoid maximum-effect (Emax) model was used to determine the antimicrobial exposure associated with net stasis (static dose [SD]) and 1-log-unit reduction in organism relative to the burden at the start of therapy. The static dose pharmacodynamic targets for linezolid and TR-700 were nearly identical, at a free drug (non-protein-bound) area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) of 19 and 20, respectively. The 1-log-unit kill endpoints were also similar, at 46.1 for linezolid and 34.6 for TR-700. The exposure targets were also comparable for both MSSA and MRSA isolates. These dosing goals support further clinical trial examination of TR-701 in MSSA and MRSA pneumonia.

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Pharmacodynamic Target Evaluation of a Novel Oral Glucan Synthase Inhibitor, SCY-078 (MK-3118), Using anIn VivoMurine Invasive Candidiasis Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04445-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 1265-1272 ◽

Cited By ~ 47

Author(s):

Alexander J. Lepak ◽

Karen Marchillo ◽

David R. Andes

Keyword(s):

Invasive Candidiasis ◽

Target Identification ◽

Dose Range ◽

Time Curve ◽

Glucan Synthase ◽

Content Type ◽

First Line Therapy ◽

Drug Concentrations ◽

Synthase Inhibitor

ABSTRACTEchinocandins inhibit the synthesis of β-1,3-d-glucan inCandidaand are the first-line therapy in numerous clinical settings. Their use is limited by poor oral bioavailability, and they are available only as intravenous therapies. Derivatives of enfumafungin are novel orally bioavailable glucan synthase inhibitors. We performed anin vivopharmacodynamic (PD) evaluation with a novel enfumafungin derivative, SCY-078 (formerly MK-3118), in a well-established neutropenic murine model of invasive candidiasis againstC. albicans,C. glabrata, andC. parapsilosis. The SCY-078 MICs varied 8-fold. Oral doses of 3.125 to 200 mg/kg SCY-078 salt in sterile water produced peak levels of 0.04 to 2.66 μg/ml, elimination half-lives of 5.8 to 8.5 h, areas under the concentration-time curve from 0 to 24 h (AUC0–24 h) of 0.61 to 41.10 μg · h/ml, and AUC from 0 to infinity (AUC0—∞) values of 0.68 to 40.31 μg · h/ml. The pharmacokinetics (PK) were approximately linear over the dose range studied. Maximum response (Emax) and PK/PD target identification studies were performed with 4C. albicans, 4C. glabrata, and 3C. parapsilosisisolates. The PD index AUC/MIC was explored by using total (tAUC) and free (fAUC) drug concentrations. The maximum responses were 4.0, 4.0, and 4.3 log10CFU/kidney reductions forC. albicans,C. glabrata, andC. parapsilosis, respectively. The AUC/MIC was a robust predictor of efficacy (R2, 0.53 to 0.91). The 24-h PD targets were a static dose of 63.5 mg/kg, atAUC/MIC of 500, and anfAUC/MIC of 1.0 forC. albicans; a static dose of 58.4 mg/kg, atAUC/MIC of 315, and anfAUC/MIC of 0.63 forC. glabrata; and a static dose of 84.4 mg/kg, atAUC/MIC of 198, and anfAUC/MIC of 0.40 forC. parapsilosis. The meanfAUC/MIC values associated with a 1-log kill endpoint against these species were 1.42, 1.26, and 0.91 forC. albicans,C. glabrata, andC. parapsilosis, respectively. The static and 1-log kill endpoints were measured relative to the burden at the start of therapy. The static and 1-log kill doses, as well as the total and free drug AUC/MIC PD targets, were not statistically different between species but were numerically lower than those observed for echinocandins. SCY-078 is a promising novel oral glucan synthase inhibitor againstCandidaspecies, and further investigation is warranted.

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Characterization ofIn VitroResistance Development to the Novel Echinocandin CD101 in Candida Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00620-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 6100-6107 ◽

Cited By ~ 28

Author(s):

Jeffrey B. Locke ◽

Amanda L. Almaguer ◽

Douglas E. Zuill ◽

Ken Bartizal

Keyword(s):

Drug Exposure ◽

Hot Spot ◽

Serial Passage ◽

Single Step ◽

Cross Resistance ◽

Time Curve ◽

Resistance Development ◽

Content Type ◽

Development Of Resistance

ABSTRACTCD101 is a novel echinocandin with a long half-life undergoing clinical development for treatment of candidemia/invasive candidiasis and vulvovaginal candidiasis. The potential for and mechanisms underlying the development of resistance to CD101 inCandidaspecies were investigated by using spontaneous resistance and serial passage selection methodologies. FourCandidaspp. (C. albicans,C. glabrata,C. parapsilosis, andC. krusei) were chosen for resistance characterization with CD101, anidulafungin, and caspofungin. The frequency of spontaneous, single-step mutations conferring reduced susceptibility to CD101 at 1× the agar growth inhibition concentration was low across all species, with median frequencies ranging from 1.35 × 10−8to 3.86 × 10−9, similar to ranges generated for anidulafungin and caspofungin. Serial passage ofCandidaspp. on agar plates containing drug gradients demonstrated a low potential for resistance development, with passage 20 CD101-selected strains possessing increases in MICs equivalent to or lower than those for the majority of strains generated under selection with anidulafungin and caspofungin. A total of 12fks“hot spot” mutations were identified, typically in strains with the highest MIC shifts. Cross-resistance was broadly observed among the 3 echinocandins evaluated, with no CD101-selected mutants (with or withoutfkshot spot mutations) exhibiting reduced susceptibility to CD101 but not also to anidulafungin and/or caspofungin. Consistent with currently approved echinocandins, CD101 demonstrates a low potential for resistance development, which could be further enhancedin vivoby the high maximum concentration of drug in serum (Cmax)/area under the concentration-time curve (AUC) plasma drug exposure achieved with once-weekly dosing of CD101.

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Optimizing Echinocandin Dosing and Susceptibility Breakpoint Determination viaIn VivoPharmacodynamic Evaluation against Candida glabrata with and withoutfksMutations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01102-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5875-5882 ◽

Cited By ~ 30

Author(s):

Alexander Lepak ◽

Mariana Castanheira ◽

Daniel Diekema ◽

Michael Pfaller ◽

David Andes

Keyword(s):

Invasive Candidiasis ◽

Candida Glabrata ◽

Pharmacokinetic Data ◽

Time Curve ◽

Content Type ◽

Broad Spectrum Resistance ◽

Breakpoint Determination ◽

Susceptibility Breakpoint ◽

Genetic Mutants

ABSTRACTEchinocandins are a preferred therapy for invasive candidiasis due to their potency and broad spectrum. Resistance, especially inCandida glabrata, is an emerging threat to their use. Pharmacodynamic (PD) studies examining reduced susceptibility secondary tofksmutations inC. glabrataare lacking. The current study explored PD targets for anidulafungin, caspofungin, and micafungin in anin vivoinvasive candidiasis model against 11C. glabrataisolates with known or putativefksmutations. The PD targets were compared to those of 8 wild-type (WT) isolates. The MIC ranges in the WT group were 0.03 to 0.25 mg/liter for anidulafungin, 0.03 to 0.25 mg/liter for caspofungin, and 0.01 to 0.06 mg/liter for micafungin. The MIC ranges for mutants were 0.06 to 4, 0.25 to 16, and 0.13 to 8 mg/liter for the same compounds, respectively. The mean free drug 24-h area under the concentration-time curve (AUCf)/MIC ratio associated with a stasis endpoint for the WT group was 13.2 for anidulafungin, 2.04 for caspofungin, and 6.78 for micafungin. Comparative values for mutants were 3.43, 2.67, and 0.90, respectively. Pharmacokinetic data from patients suggest that theC. glabrataPD targets needed for success in this model could be achieved based on MIC values of 0.25 mg/liter for anidulafungin, 2 mg/liter for caspofungin, and 0.5 mg/liter for micafungin. These values are higher than recently identified epidemiology cutoff values (ECVs). The results suggest that drug-specific MIC breakpoints could be increased for caspofungin and micafungin againstC. glabrataand could include organisms with mutations infks-1andfks-2. While identification of genetic mutants is epidemiologically important, the phenotype (MIC) provides a better predictor of therapeutic efficacy.

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In VivoPharmacokinetics and Pharmacodynamics of APX001 againstCandidaspp. in a Neutropenic Disseminated Candidiasis Mouse Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02542-17 ◽

2018 ◽

Vol 62 (4) ◽

Cited By ~ 25

Author(s):

Miao Zhao ◽

Alexander J. Lepak ◽

Brian VanScoy ◽

Justin C. Bader ◽

Karen Marchillo ◽

...

Keyword(s):

Dose Fractionation ◽

Coefficient Of Determination ◽

Maximum Effect ◽

Pharmacokinetic Studies ◽

Maximum Plasma ◽

Time Curve ◽

Content Type ◽

Disseminated Candidiasis

ABSTRACTAPX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model forCandida albicans(n= 5),C. glabrata(n= 5), andC. auris(n= 4). MIC values ranged from 0.002 to 0.03 mg/liter forC. albicans, from 0.008 to 0.06 mg/liter forC. glabrata, and from 0.004 to 0.03 mg/liter forC. auris. Plasma APX001A pharmacokinetic measurements were performed in mice after oral administration of 4, 16, 64, and 256 mg/kg of body weight APX001. Single-dose pharmacokinetic studies exhibited maximum plasma concentration (Cmax) values of 0.46 to 15.6 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC0–inf) values of 0.87 to 70.0 mg · h/liter, and half-lives of 1.40 to 2.75 h. A neutropenic murine disseminated candidiasis model was utilized for all treatment studies, and drug dosing was by the oral route. Dose fractionation was performed againstC. albicansK1, with total doses ranging from 4 to 1,024 mg/kg/day of APX001 fractionated into regimens of dosing every 3, 6, 8, and 12 h for a 24-h treatment duration. Nonlinear regression analysis was used to determine which PK/PD index best correlated with efficacy on the basis of the reduction in the number of CFU/kidney at 24 h. The 24-h free-drug AUC/MIC ratio (fAUC0–24/MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [R2] = 0.88). Treatment studies with the remaining strains utilized regimens of 1 to 256 mg/kg of APX001 administered every 6 h for a 24-h duration withC. albicansand a 96-h study duration withC. glabrataandC. auris. The dose required to achieve 50% of the maximum effect (ED50) and stasisfAUC/MIC targets were as follows: forC. albicans, 3.67 ± 3.19 and 20.60 ± 6.50, respectively; forC. glabrata, 0.38 ± 0.21 and 1.31 ± 0.27, respectively; and forC. auris, 7.14 ± 4.54 and 14.67 ± 8.30, respectively. The present studies demonstratedin vitroandin vivoAPX001A and APX001 potency, respectively, againstC. albicans,C. glabrata, andC. auris.These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target forC. glabratasuggests that species-specific susceptibility breakpoints should be explored.

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Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02734-16 ◽

2017 ◽

Vol 61 (4) ◽

Cited By ~ 6

Author(s):

Vien T. M. Le ◽

Hoan N. Le ◽

Marcos Gabriel Pinheiro ◽

Kenneth J. Hahn ◽

Mary L. Dinh ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bacterial Production ◽

Protective Efficacy ◽

Survival Rates ◽

Rabbit Model ◽

Rank Test ◽

Necrotizing Pneumonia ◽

Time Curve ◽

Content Type

ABSTRACT The protective efficacy of tedizolid phosphate, a novel oxazolidinone that potently inhibits bacterial protein synthesis, was compared to those of linezolid, vancomycin, and saline in a rabbit model of Staphylococcus aureus necrotizing pneumonia. Tedizolid phosphate was administered to rabbits at 6 mg/kg of body weight intravenously twice daily, which yielded values of the 24-h area under the concentration-time curve approximating those found in humans. The overall survival rate was 83% for rabbits treated with 6 mg/kg tedizolid phosphate twice daily and 83% for those treated with 50 mg/kg linezolid thrice daily (P = 0.66 by the log-rank test versus the results obtained with tedizolid phosphate). These survival rates were significantly greater than the survival rates of 17% for rabbits treated with 30 mg/kg vancomycin twice daily (P = 0.003) and 17% for rabbits treated with saline (P = 0.002). The bacterial count in the lungs of rabbits treated with tedizolid phosphate was significantly decreased compared to that in the lungs of rabbits treated with saline, although it was not significantly different from that in the lungs of rabbits treated with vancomycin or linezolid. The in vivo bacterial production of alpha-toxin and Panton-Valentine leukocidin, two key S. aureus-secreted toxins that play critical roles in the pathogenesis of necrotizing pneumonia, in the lungs of rabbits treated with tedizolid phosphate and linezolid was significantly inhibited compared to that in the lungs of rabbits treated with vancomycin or saline. Taken together, these results indicate that tedizolid phosphate is superior to vancomycin for the treatment of S. aureus necrotizing pneumonia because it inhibits the bacterial production of lung-damaging toxins at the site of infection.

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Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04875-14 ◽

2015 ◽

Vol 59 (6) ◽

pp. 3501-3508 ◽

Cited By ~ 11

Author(s):

Gina S. El-Feky ◽

Wael S. Mohamed ◽

Hanaa E. Nasr ◽

Naglaa M. El-Lakkany ◽

Sayed H. Seif el-Din ◽

...

Keyword(s):

Schistosoma Mansoni ◽

Rate Constant ◽

Elimination Rate ◽

New Drugs ◽

Egg Load ◽

Potential Cost ◽

Time Curve ◽

Content Type ◽

Mmt Clay

ABSTRACTConsideration of existing compounds always simplifies and shortens the long and difficult process of discovering new drugs specifically for diseases of developing countries, an approach that may add to the significant potential cost savings. This study focused on improving the biological characteristics of the already-existing antischistosomal praziquantel (PZQ) by incorporating it into montmorillonite (MMT) clay as a delivery carrier to overcome its known bioavailability drawbacks. The oral bioavailability of a PZQ-MMT clay nanoformulation and itsin vivoefficacy againstSchistosoma mansoniwere investigated. The PZQ-MMT clay nanoformulation provided a preparation with a controlled release rate, a decrease in crystallinity, and an appreciable reduction in particle size. Uninfected and infected mice treated with PZQ-MMT clay showed 3.61- and 1.96-fold and 2.16- and 1.94-fold increases, respectively, in area under the concentration-time curve from 0 to 8 h (AUC0–8) and maximum concentration of drug in serum (Cmax), with a decrease in elimination rate constant (kel) by 2.84- and 1.35-fold and increases in the absorption rate constant (ka) and half-life (t1/2e) by 2.11- and 1.51-fold and 2.86- and 1.34-fold, respectively, versus the corresponding conventional PZQ-treated groups. This improved bioavailability has been expressed in higher efficacy of the drug, where the dose necessary to kill 50% of the worms was reduced by >3-fold (PZQ 50% effective dose [ED50] was 20.25 mg/kg of body weight for PZQ-MMT clay compared to 74.07 mg/kg for conventional PZQ), with significant reduction in total tissue egg load and increase in total immature, mature, and dead eggs in most of the drug-treated groups. This formulation showed better bioavailability, enhanced antischistosomal efficacy, and a safer profile despite the longer period of residence in the systemic circulation. Although the conventional drug's toxicity was not examined, animal mortality rates were not different between groups receiving the test PZQ-clay nanoformulation and conventional PZQ.

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