netilmicin and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Aminoglycosides are recommended for the treatment of Enterococcus faecalis infections, especially in severe and bacteremic infection. However, the optimal aminoglycoside or the optimal dosage remains uncertain. This study aimed to compare the activity of four aminoglycosides against E. faecalis (gentamicin, netilmicin, tobramycin, and amikacin) and two dosages of gentamicin. One clinical strain of E. faecalis was used to induce aortic endocarditis in the study rabbits. Each aminoglycoside was infused daily over 3 days with a computer-regulated flow simulating human pharmacokinetics of 15 mg/kg/day for amikacin, 6 mg/kg/day for netilmicin, and 3 mg/kg/day for gentamicin and tobramycin. Additionally, two dosages of gentamicin (simulating 3 or 6 mg/kg/day) were compared over 1 or 3 days of treatment. The in vivo efficacy was assessed according to the bacterial count in vegetations, in comparison with a control group. Of the four aminoglycosides tested, only gentamicin and netilmicin showed significant antibacterial efficacy after 3 days of treatment. After only 1 day of treatment, the high dosage of gentamicin (6 mg/kg/day) was more effective than the standard dosage (3 mg/kg/day). Among the tested aminoglycosides, gentamicin showed the best efficacy, with the best results after 24 h of treatment for the highest dosage.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Bacterial Load; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Endocarditis, Bacterial; Enterococcus faecalis; Female; Gentamicins; Gram-Positive Bacterial Infections; Netilmicin; Rabbits; Time Factors; Tobramycin

First, we studied the effect of the following variables used for netilmicin- and vancomycin-impregnation of cancellous bone: a) antibiotic concentration of the impregnation fluid, b) time used for impregnation, c) pH of the impregnation fluid, d) the degree of bone morselizing and e) antibiotic combination. An increase in the antibiotic concentration of the impregnation fluid increased the amount of antibiotics released from bone. In addition, the amount of vancomycin eluted was also dependent on the time used for impregnation. The fraction of the total amount of netilmicin and vancomycin released after 24 h was 80% and 30%, respectively. More netilmicin and vancomycin were eluted from bone impregnated with antibiotics at pH 7 than the amount eluted from bone impregnated at pH 3. More netilmicin was eluted from fine morselized bone than from coarse morselized bone. By combining netilmicin and vancomycin in the impregnation fluid, the release of vancomycin was reduced. Secondly, we analyzed if the release of antibiotics from bone was complete: 99.9% of the total amount of netilmicin adsorbed to the bone was released by elution during 6 weeks. Finally, after implantation of netilmicin-impregnated bone in rabbit femur condyle, we measured netilmicin and vancomycin in serum: peak serum values of netilmicin were 4.2 (3.7-4.7) mg/L 2-3 h postoperatively.

Topics: Animals; Anti-Bacterial Agents; Bony Callus; Disease Models, Animal; Femur; Gentamicins; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Netilmicin; Rabbits; Time Factors; Vancomycin

Two combinations of antibiotics, clindamycin with rifampicin and cloxacillin with netilmicin, were investigated for their activity against two strains of Staphylococcus aureus (a sensitive reference strain and a methicillin-resistant clinical isolate) by means of the in vitro checkerboard technique and an in vivo infected mouse model. The mouse model allowed drug interactions to be evaluated both from the changes in the number of bacteria surviving treatment and from the measured exposure to antibiotics at the site of infection. Specimens from the latter were evaluated twice (day 0 and day 2) in each experiment. The combination of cloxacillin and netilmicin exhibited a synergistic effect against the reference strain both in vitro and in vivo, whereas synergism was obtained under in vitro conditions only against the methicillin-resistant strain. The clindamycin and rifampicin combination acted synergistically or indifferently against both strains in vitro and at day 0 of the in vivo experiments. In contrast, on day 2 of infection, this combination had significantly greater bactericidal effect (synergism) compared to the combination of cloxacillin and netilmicin. These results illustrate the difficulties of interpreting in vitro results for clinical use.

Topics: Animals; Clindamycin; Cloxacillin; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Female; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Netilmicin; Rifampin; Staphylococcal Infections; Staphylococcus aureus

The object of this work is to study in neutropenic mice the in vivo postantibiotic effect (PAE) of isepamicin, a new aminoglycoside, gentamicin and netilmicin on Staphylococcus aureus and Escherichia coli and in vivo killing kinetics using two different schedules (A and B) of isepamicin and gentamicin administration against S. aureus: (A) at time zero and every hour up to the 7th or 9th hour and (B) two doses only, at time zero and at the end of the PAE. The PAE of the three aminoglycosides was long (3-5 h), showing that of isepamicin to be the largest, especially on S. aureus. Both A and B treatment models show the same effectiveness for the two tested drugs. These results support the idea that the major significance of the PAE is in its application to dosing regimens.

Topics: Animals; Bacterial Infections; Disease Models, Animal; Escherichia coli; Female; Gentamicins; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Netilmicin; Neutropenia; Staphylococcus aureus; Thigh; Time Factors

Pharmacokinetic profiles in small animals substantially differ from those observed in man. We hence devised a man adapted animal model to critically assess the impact of such differences on antimicrobial efficacy. We approximated in mice the human pharmacokinetic profiles of netilmicin, ticarcillin and ceftazidime. The CD50 (curative dose for 50% of lethally intra-peritoneally infected animals) against Pseudomonas aeruginosa was comparatively determined for murine versus man-adapted pharmacokinetic profiles. With netilmicin the man-adapted profile was significantly less efficacious than the murine profile. In contrast, a significant superiority of the man-adapted profile was found with the beta-lactam drugs. We conclude that determinations of antimicrobial activity in small animals may yield misleading results in respect to man. Depending on the drug in question, murine pharmacokinetics may lead to overestimation or underestimation of antimicrobial activity. Our findings are of particular importance for the interpretation of studies in small animals comparing different antimicrobial compounds or different dosage regimens.

Topics: Animals; Ceftazidime; Disease Models, Animal; Drug Administration Schedule; Female; Half-Life; Injections, Subcutaneous; Mice; Mice, Inbred ICR; Netilmicin; Peritonitis; Pseudomonas aeruginosa; Pseudomonas Infections; Random Allocation; Sepsis; Specific Pathogen-Free Organisms; Ticarcillin

A granulocytopenic mouse model was used to elucidate the impact of dose spacing on the activity of netilmicin against Pseudomonas aeruginosa. A thigh infection was produced and then treated with netilmicin combined with azlocillin. Netilmicin was injected subcutaneously at decreasing doses every 20 min to result in plasma-concentration-time curves similar to those observed in patients on intravenous netilmicin treatment. A once-daily regimen was simulated and compared to a simulated conventional schedule of every 8 h. Identical total amounts of drug were used in both groups of comparatively treated mice. Therapeutic efficacy was quantitated by repeated determinations of surviving organisms in thigh homogenates. Combination therapy was significantly more effective than azlocillin treatment alone. In combination regimens the simulated once-daily netilmicin schedule killed the target organisms faster than the simulated thrice-daily regimen and was significantly more efficacious by 24 and 32 h in two out of three strains of Pseudomonas aeruginosa tested. It is concluded that the results of combination therapy of severe Pseudomonas aeruginosa infections in the immunocompromised host might be improved by choosing an aminoglycoside dosage interval of 24 h instead of the conventional 8 h.

Topics: Animals; Azlocillin; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppression Therapy; Mice; Netilmicin; Neutropenia; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

Topics: Animals; Bacteria, Aerobic; Bacteria, Anaerobic; Clindamycin; Disease Models, Animal; Double-Blind Method; Drug Therapy, Combination; Netilmicin; Premedication; Random Allocation; Surgical Wound Infection

The efficacy of various dosage schedules of netilmicin against Pseudomonas aeruginosa has been compared using an in vivo model (normal and granulocytopenic mice). Bolus injections were at least as effective as simulated short infusions or simulated continuous infusions of identical total amounts of netilmicin.

Topics: Agranulocytosis; Animals; Delayed-Action Preparations; Disease Models, Animal; Gentamicins; Infusions, Parenteral; Injections, Intravenous; Mice; Netilmicin; Pseudomonas aeruginosa; Pseudomonas Infections

Moxalactam (LY127935) is a 1-oxa-beta-lactam which was active in vitro against the majority of 128 strains of gram-negative enteric bacilli isolated from meningitis in neonates. Pharmacokinetics and bacteriological efficacy of LY127935 were studied in a lapin meningitis model. The average penetration of this investigational oxa-cephalosporin into cerebrospinal fluid of infected rabbits was 23% compared with 25% for netilmicin and 11% for ampicillin. The cerebrospinal fluid concentrations of LY127935 produced median bactericidal titers of 1:64 to 1:128 against five coliform organisms (two Escherichia coli K1 strains, Klebsiella pneumoniae, Salmonella saint-paul, and Citrobacter diversus) used in these experiments compared with median titers of 1:2 to 1:8 for netilmicin and 1:2 to 1:4 for ampicillin. LY127935 was statistically significantly more effective than netilmicin or ampicillin in reducing cerebrospinal fluid bacterial colony counts and in sterilizing cerebrospinal fluid of experimentally infected rabbits. These results suggest that LY127935 has theoretical advantages over netilmicin and ampicillin for therapy of gram-negative bacillary meningitis.

Topics: Ampicillin; Animals; Bacteria; Bacterial Infections; Cephalosporins; Cephamycins; Disease Models, Animal; Gentamicins; Male; Meningitis; Moxalactam; Netilmicin; Rabbits; Species Specificity