scholarly journals Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jian Zhou ◽  
Kimberly R. Ledesma ◽  
Kai-Tai Chang ◽  
Henrietta Abodakpi ◽  
Song Gao ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Dose Linearity ◽  
Unit Reduction ◽  
The Relationship

ABSTRACT Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0–24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0–24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r 2 = 0.81). The required AUCELF,0–24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted.

scholarly journals Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

2015 ◽  
Vol 59 (6) ◽  
pp. 3252-3256 ◽  
Author(s):  
Liana C. Chan ◽  
Li Basuino ◽  
Etyene C. Dip ◽  
Henry F. Chambers
Keyword(s):  
Staphylococcus Aureus ◽  
Rabbit Model ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Dose Ranging

ABSTRACTTedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid againstStaphylococcus aureusin vitro. Thein vivoefficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistantS. aureusstrain COL (infection inoculum of 107CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P= 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P= 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (108CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0–24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0–24for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin.

scholarly journals Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Jeffrey P. Hammel ◽  
Elizabeth A. Lakota ◽  
M. Courtney Safir ◽  
Brian D. VanScoy ◽  
...  
Keyword(s):  
Compartment Model ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Total Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PK­PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

scholarly journals In VitroandIn VivoActivities of E-101 Solution against Acinetobacter baumannii Isolates from U.S. Military Personnel

2011 ◽  
Vol 55 (7) ◽  
pp. 3603-3608 ◽  
Author(s):  
G. A. Denys ◽  
J. C. Davis ◽  
P. D. O'Hanley ◽  
J. T. Stephens
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
Military Personnel ◽  
Multidrug Resistant ◽  
Full Thickness ◽  
Content Type ◽  
Full Thickness Excision ◽  
Time Kill

ABSTRACTWe evaluated thein vitroandin vivoactivity of a novel topical myeloperoxidase-mediated antimicrobial, E-101 solution, against 5 multidrug-resistantAcinetobacter baumanniiisolates recovered from wounded American soldiers. Time-kill studies demonstrated rapid bactericidal activity against allA. baumanniistrains tested in the presence of 3% blood. Thein vitrobactericidal activity of E-101 solution againstA. baumanniistrains was confirmed in a full-thickness excision rat model. Additionalin vivostudies appear warranted.

scholarly journals Use of Carbapenems against Clinical, Nontyphoid Salmonella Isolates: Results fromIn VitroandIn VivoAnimal Studies

2012 ◽  
Vol 56 (6) ◽  
pp. 2916-2922 ◽  
Author(s):  
Hung-Jen Tang ◽  
Chi-Chung Chen ◽  
Chun-Cheng Zhang ◽  
Kuo Chen Cheng ◽  
Shyh-Ren Chiang ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Survival Rates ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Percent Time ◽  
Clinical Investigations

ABSTRACTThe emergence of multidrug-resistantSalmonellaisolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoidSalmonella(NTS) isolatesin vitroandex vivo. Subsequently, the efficacy of carbapenem treatment against selectedSalmonellaisolatesin vivowas assessed using a murine peritonitis model. The MIC50and MIC90for doripenem, ertapenem, imipenem, and meropenem against 126 NTS isolates were found to be 0.062 and 0.062, 0.015 and 0.015, 0.5 and 1, and 0.031 and 0.031 μg/ml, respectively. The intracellular killing effect of ertapenem was sustained for 24 h and was superior to that of imipenem, meropenem, and doripenem; its effect was comparable to that of ceftriaxone. Ertapenem demonstrated an excellent pharmacokinetic profile with a percent time above the MIC of 75.5% and an area under the concentration-time curve/MIC ratio of 20,733. When peritoneal exudate cells were examined directlyex vivofrom mice withSalmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 102- to 104-fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 × 105and 106CFU of a ceftriaxone-susceptibleSalmonellaisolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 × 104and 105CFU of a ceftriaxone-resistant and ciprofloxacin-resistantSalmonellaisolate, mice treated with ertapenem had a higher survival rate than mice treated with ceftriaxone (70% versus 0% and 50% versus 0%, respectively;P< 0.001). Our results suggest that ertapenem is at least as effective as ceftriaxone in treating murineSalmonellainfections and show that further clinical investigations on the potential use of ertapenem in treatment of humanSalmonellainfections are warranted.

scholarly journals Novel Phage Lysin Capable of Killing the Multidrug-Resistant Gram-Negative Bacterium Acinetobacter baumannii in a Mouse Bacteremia Model

2015 ◽  
Vol 59 (4) ◽  
pp. 1983-1991 ◽  
Author(s):  
Rolf Lood ◽  
Benjamin Y. Winer ◽  
Adam J. Pelzek ◽  
Roberto Diez-Martinez ◽  
Mya Thandar ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Genomic Library ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Genes Encoding

ABSTRACTAcinetobacter baumannii, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13A. baumanniistrains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killingA. baumannii. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all testedA. baumanniiclinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilmA. baumanniibothin vitroandin vivo. Finally, PlyF307 rescued mice from lethalA. baumanniibacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found inAcinetobacterphage.

scholarly journals Characterizing the Antimicrobial Activity of N2,N4-Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Renee Fleeman ◽  
Kurt S. Van Horn ◽  
Megan M. Barber ◽  
Whittney N. Burda ◽  
David L. Flanigan ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Acinetobacter Baumannii ◽  
Alkyl Substituent ◽  
Fold Increase ◽  
Multidrug Resistant ◽  
Antibiofilm Activity ◽  
Gram Negative ◽  
Content Type

ABSTRACT We previously reported a series of N 2,N 4-disubstituted quinazoline-2,4-diamines as dihydrofolate reductase inhibitors with potent in vitro and in vivo antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. In this work, we extended our previous study to the Gram-negative pathogen Acinetobacter baumannii. We determined that optimized N 2,N 4-disubstituted quinazoline-2,4-diamines are strongly antibacterial against multidrug-resistant A. baumannii strains when the 6-position is replaced with a halide or an alkyl substituent. Such agents display potent antibacterial activity, with MICs as low as 0.5 μM, while proving to be strongly bactericidal. Interestingly, these compounds also possess the potential for antibiofilm activity, eradicating 90% of cells within a biofilm at or near MICs. Using serial passage assays, we observed a limited capacity for the development of resistance toward these molecules (4-fold increase in MIC) compared to existing folic acid synthesis inhibitors, such as trimethoprim (64-fold increase) and sulfamethoxazole (128-fold increase). We also identified limited toxicity toward human cells, with 50% lethal doses (LD50s) of ≤23 μM for lead agents 4 and 5. Finally, we demonstrated that our lead agents have excellent in vivo efficacy, with lead agent 5 proving more efficacious than tigecycline in a murine model of A. baumannii infection (90% survival versus 66%), despite being used at a lower dose (2 versus 30 mg kg−1). Together, our results demonstrate that N 2,N 4-disubstituted quinazoline-2,4-diamines have strong antimicrobial and antibiofilm activities against both Gram-positive organisms and Gram-negative pathogens, suggesting strong potential for their development as antibacterial agents.

Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo

1994 ◽  
Vol 80 (3) ◽  
pp. 527-534 ◽  
Author(s):  
Yasuhiro Matsuda ◽  
Keiichi Kawamoto ◽  
Katsuzo Kiya ◽  
Kaoru Kurisu ◽  
Kazuhiko Sugiyama ◽  
...  
Keyword(s):  
Marked Reduction ◽  
Tumor Volume ◽  
Collagen Gel ◽  
Antitumor Effects ◽  
Histological Changes ◽  
Content Type ◽  
The Relationship ◽  
Fine Print

✓ The presence of the progesterone receptor (PR) in meningioma tissue has been confirmed by previous investigations. Studies have shown that the antiprogesterone drug, mifepristone, is a potent agent that inhibits the growth of cultured meningioma cells and reduces the size of meningiomas in experimental animal models and humans. However, these studies have not fully examined the relationship between the antitumor effects of an antiprogesterone agent and the expression of the PR. The present study examined the antitumor effects of mifepristone and a new potent antiprogesterone agent, onapristone; a correlation between the antitumor effects of these antiprogesterones and the presence of PR's in meningiomas in vitro and in vivo was also investigated. Meningioma tissue surgically removed from 13 patients was used in this study. In the in vitro arm of the study, mifepristone and onapristone exhibited cytostatic and cytocidal effects against cultured meningioma cells, regardless of the presence or absence of PR's; however, three PR-negative meningiomas showed no response to any dose of mifepristone and/or onapristone. In the in vivo arm, meningioma cells, embedded in a collagen gel, were implanted into the renal capsules of nude mice. Antiprogesterone treatment resulted in a marked reduction of the tumor volume regardless of the presence or absence of PR's. No histological changes in the meningioma cells suggestive of necrosis or apoptosis were detected in any of the mice treated with antiprogesterones. These findings suggest that mifepristone and onapristone have an antitumor effect against meningioma cells via the PR's and/or another receptor, such as the glucocorticoid receptor.

scholarly journals Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Elizabeth A. Lakota ◽  
Justin C. Bader ◽  
Voon Ong ◽  
Ken Bartizal ◽  
Lynn Miesel ◽  
...  
Keyword(s):  
Time Course ◽  
Fungicidal Activity ◽  
Control Group ◽  
Time Curve ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Treatment Control Group ◽  
Pharmacological Basis

ABSTRACT CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (∼133 h in humans, ∼70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no-treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0–168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens.

scholarly journals Assessment of Minocycline and Polymyxin B Combination against Acinetobacter baumannii

2015 ◽  
Vol 59 (5) ◽  
pp. 2720-2725 ◽  
Author(s):  
Dana R. Bowers ◽  
Henry Cao ◽  
Jian Zhou ◽  
Kimberly R. Ledesma ◽  
Dongxu Sun ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Clinical Utility ◽  
Efflux Pump ◽  
Polymyxin B ◽  
Intracellular Concentration ◽  
Bacterial Cells ◽  
Efflux Pump Inhibitor ◽  
Content Type

ABSTRACTAntimicrobial resistance amongAcinetobacter baumanniiis increasing worldwide, often necessitating combination therapy. The clinical utility of using minocycline with polymyxin B is not well established. In this study, we investigated the activity of minocycline and polymyxin B against 1 laboratory isolate and 3 clinical isolates ofA. baumannii. Minocycline susceptibility testing was performed with and without an efflux pump inhibitor, phenylalanine-arginine β-naphthylamide (PAβN). The intracellular minocycline concentration was determined with and without polymyxin B (0.5 μg/ml). Time-kill studies were performed over 24 h using approximately 106CFU/ml of each strain with clinically relevant minocycline concentrations (2 μg/ml and 8 μg/ml), with and without polymyxin B (0.5 μg/ml). Thein vivoefficacy of the combination was assessed in a neutropenic murine pneumonia model. Infected animals were administered minocycline (50 mg/kg), polymyxin B (10 mg/kg), or both to achieve clinically equivalent exposures in humans. A reduction in the minocycline MIC (≥4×) was observed in the presence of PAβN. The intracellular concentration andin vitrobactericidal effect of minocycline were both enhanced by polymyxin B. With 2 minocycline-susceptible strains, the bacterial burden in lung tissue at 24 h was considerably reduced by the combination compared to monotherapy with minocycline or polymyxin B. In addition, the combination prolonged survival of animals infected with a minocycline-susceptible strain. Polymyxin B increased the intracellular concentration of minocycline in bacterial cells and enhanced the bactericidal activity of minocycline, presumably due to efflux pump disruption. The clinical utility of this combination should be further investigated.

scholarly journals In VitroActivity of RX-P873 against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii

2015 ◽  
Vol 59 (4) ◽  
pp. 2280-2285 ◽  
Author(s):  
Robert K. Flamm ◽  
Paul R. Rhomberg ◽  
Ronald N. Jones ◽  
David J. Farrell
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Active Agent ◽  
Multidrug Resistant ◽  
Surveillance Program ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Bacterial Ribosome

ABSTRACTRX-P873 is a novel antibiotic from the pyrrolocytosine series which exhibits high binding affinity for the bacterial ribosome and broad-spectrum antibiotic properties. The pyrrolocytosines have shownin vitroactivity against multidrug-resistant Gram-negative and Gram-positive strains of bacteria known to cause complicated urinary tract, skin, and lung infections, as well as sepsis.Enterobacteriaceae(657),Pseudomonas aeruginosa(200), andAcinetobacter baumannii(202) isolates from North America and Europe collected in 2012 as part of a worldwide surveillance program were testedin vitroby broth microdilution using Clinical and Laboratory Standards Institute (CLSI) methodology. RX-P873 (MIC90, 0.5 μg/ml) was >32-fold more active than ceftazidime and inhibited 97.1% and 99.5% ofEnterobacteriaceaeisolates at MIC values of ≤1 and ≤4 μg/ml, respectively. There were only three isolates with an MIC value of >4 μg/ml (all were indole-positiveProtea). RX-P873 (MIC50/90, 2/4 μg/ml) was highly active againstPseudomonas aeruginosaisolates, including isolates which were nonsusceptible to ceftazidime or meropenem. RX-P873 was 2-fold less active againstP. aeruginosathan tobramycin (MIC90, 2 μg/ml; 91.0% susceptible) and colistin (MIC90, 2 μg/ml; 99.5% susceptible) and 2-fold more potent than amikacin (MIC90, 8 μg/ml; 93.5% susceptible) and meropenem (MIC90, 8 μg/ml; 76.0% susceptible). RX-P873, the most active agent againstAcinetobacter baumannii(MIC90, 1 μg/ml), was 2-fold more active than colistin (MIC90, 2 μg/ml; 97.0% susceptible) and 4-fold more active than tigecycline (MIC90, 4 μg/ml). This novel agent merits further exploration of its potential against multidrug-resistant Gram-negative bacteria.

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