Early Bactericidal Activity of Delpazolid (LCB01-0371) in Patients with Pulmonary Tuberculosis

Delpazolid, an oxazolidinone, has been studied in non-clinical studies of efficacy and toxicity and Phase 1 clinical studies. Delpazolid has in vitro activity against gram-positive bacteria, including Mycobacterium tuberculosis . This study evaluated the bactericidal activity, safety, and pharmacokinetics of delpazolid in patients with pulmonary tuberculosis (TB). Seventy-nine subjects, aged 19 to 75 years with newly diagnosed smear-positive TB with no prior treatment for the current episode and no confirmed resistance to rifampin or isoniazid, were randomized to receive delpazolid 800 mg once a day (QD), 400 mg twice a day (BID), 800 mg BID or 1200 mg QD or an active control of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) or linezolid 600 mg BID. The primary endpoint was the average daily reduction in log transformed bacterial load, assessed on 7H11 solid-media culture, from days 0 to 14. The average daily decline in log-cfu was 0.044±0.016, 0.053±0.017, 0.043±0.016, and 0.019±0.017, for the delpazolid 800 mg QD, 400 mg BID, 800 mg BID and the 1200 mg QD groups, respectively. The average daily decline in log-cfu was 0.192±0.028 for the HRZE group and 0.154±0.023 for the linezolid 600 mg BID group. Three serious adverse events (SAE) were reported, one each in the delpazolid 400 mg BID group (death due to worsening of TB at day 2), the HRZE group (hospitalization due to pleural effusion) and the linezolid group (hyperkalemia); none of the SAEs were assessed as related to study drugs. This study has been registered at ClinicalTrials.gov with registration number NCT02836483.

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Early Bactericidal Activity and Pharmacokinetics of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01204-07 ◽

2008 ◽

Vol 52 (8) ◽

pp. 2831-2835 ◽

Cited By ~ 175

Author(s):

R. Rustomjee ◽

A. H. Diacon ◽

J. Allen ◽

A. Venter ◽

C. Reddy ◽

...

Keyword(s):

Pulmonary Tuberculosis ◽

Bactericidal Activity ◽

Dose Range ◽

Study Drug ◽

First Line ◽

Serious Adverse Events ◽

Once Daily ◽

Smear Positive Pulmonary Tuberculosis

ABSTRACT Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log10 decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log10 CFU counts (± standard deviation) from baseline to day 7 were 0.04 ± 0.46 for 25 mg TMC207 (n = 14), 0.26 ± 0.64 for 100 mg TMC207 (n = 14), 0.77 ± 0.58 for 400 mg TMC207 (n = 14), 1.88 ± 0.74 for INH (n = 11), and 1.70 ± 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.

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Early Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01163-16 ◽

2016 ◽

Vol 60 (11) ◽

pp. 6591-6599 ◽

Cited By ~ 10

Author(s):

Jennifer J. Furin ◽

Jeannine Du Bois ◽

Elana van Brakel ◽

Phalkun Chheng ◽

Amour Venter ◽

...

Keyword(s):

Pulmonary Tuberculosis ◽

Bactericidal Activity ◽

Positive Culture ◽

Rate Of Change ◽

Sputum Smear ◽

Serious Adverse Events ◽

Once Daily ◽

Content Type ◽

The Mean

ABSTRACTAZD5847 is an oxazolidinone antibiotic within vitroactivity againstMycobacterium tuberculosis. The objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive AZD5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily standard chemotherapy. The primary efficacy endpoint was the mean daily rate of change in the log10number of CFU ofM. tuberculosisper milliliter of sputum, expressed as the change in log10number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (−0.163 log10CFU/ml sputum/day; 95% confidence interval [CI], −0.193, −0.133 log10CFU/ml sputum/day) was consistent with that found in previous studies. AZD5847 at 500 mg twice daily significantly decreased the number of CFU on solid medium (−0.039; 95% CI, −0.069, −0.009;P= 0.0048). No bactericidal activity was detected at doses of AZD5847 of 500 mg once daily (mean early bactericidal activity [EBA], 0.02 [95% CI, −0.01, 0.05]), 1,200 mg once daily (mean EBA, 0.02 [95% CI, −0.01, 0.05]), and 800 mg twice daily (mean EBA, 0.02 [95% CI, −0.01, 0.05]). AZD5847 at doses of both 500 mg and 800 mg twice daily also showed an increase in the time to a positive culture in MGIT liquid culture medium. Two serious adverse events (grade 4 thrombocytopenia and grade 4 hyperbilirubinemia) occurred in patients receiving AZD5847 at higher doses. AZD5847 dosed twice daily kills tubercle bacilli in the sputum of patients with pulmonary tuberculosis and has modest early bactericidal activity. (This study has been registered at ClinicalTrials.gov under registration no. NCT01516203.)

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In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK)

Investigational New Drugs ◽

10.1007/s10637-021-01156-9 ◽

2021 ◽

Author(s):

Georgina Meneses-Lorente ◽

Stephen Fowler ◽

Elena Guerini ◽

Karey Kowalski ◽

Edna Chow-Maneval ◽

...

Keyword(s):

Single Dose ◽

Clinical Studies ◽

Healthy Subjects ◽

Phase 1 ◽

Anaplastic Lymphoma ◽

P Glycoprotein ◽

Cyp3a4 Inducer ◽

Cyp3a4 Substrate ◽

Registration Number

AbstractBackground Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC50 2 μM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC50 1.33 μM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib Cmax and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib Cmax and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although Cmax decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased Cmax by 21%. Single dose entrectinib increased digoxin AUC and Cmax by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered.

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NE-180, a Novel glycoPEGylated Erythropoietin Demonstrates Dose-Dependent Activity in a Phase 1 Single Dose, Dose Escalating Study in Normal Human Volunteers (NHV).

Blood ◽

10.1182/blood.v108.11.1149.1149 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1149-1149

Author(s):

Bruce A. Wallin ◽

Denise Ramjit ◽

Michael Seiberling ◽

David Zopf

Keyword(s):

Adverse Events ◽

Animal Studies ◽

Phase 1 ◽

Stopping Rules ◽

Open Label ◽

Serious Adverse Events ◽

Maximal Increase ◽

The Mean ◽

Dose Dependent

Abstract NE-180 is a glycoPEGylated recombinant human erythropoietin that binds to and activates the erythropoietin (EPO) receptor. It has demonstrated in vitro activities comparable to EPO and an extended serum half-life in animal studies. This may allow less frequent dosing in patients being treated with chronic anemia. METHODS: A single center, open-label study of NE-180, administered as single escalating doses given by the SC or IV route, was conducted to assess the safety, tolerability, PK and PD. Subjects (male or female NHV) were planned to be assigned to one of 4 dose groups, 10 subjects per dose with 5 SC and 5 IV subjects per group: 0.5, 1.5, 3, or 4.5 mg/kg. Each dose group was planned to be initiated in an ascending, sequential fashion unless or until stopping rules were met. RESULTS: 25 NHV (16 females) were enrolled in the first two dose cohorts and have completed 56 day follow-up. The 1.5 mg/kg IV cohort met the protocol-specified Hb rate of rise stopping rule (change in Hb greater than 1 g/dL during any 14 day period). Injections were generally well tolerated with no discontinuations for adverse events or serious adverse events. Reticulocyte increases were dose proportional. Average reticulocyte count at baseline was 1.0±0.3%. The maximal increase occurred at day 7. The mean change from baseline for the 0.5 and 1.5 mg/kg SC group was: 0.9±0.4% and 2.2±0.9%, respectively. The mean change from baseline for the 0.5 and 1.5 mg/kg IV group was: 1.7±0.8% and 2.3±0.8%, respectively. PK data will be presented. CONCLUSIONS: Single doses up to 1.5 mg/kg of NE-180 administered to NHV were generally well tolerated and demonstrated potent dose-dependent erythropoietic activity.

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THE GROWTH RATE PHENOTYPIC PROPERTY OF MYCOBACTERIUM TUBERCULOSIS CLINICAL STRAINS: DEPENDENCE ON TUBERCULOSIS LOCALIZATION, TREATMENT, DRUG SUSCEPTIBILITY

Russian Journal of Infection and Immunity ◽

10.15789/2220-7619-2018-2-175-186 ◽

2018 ◽

Vol 8 (2) ◽

pp. 175-186

Author(s):

O. A. Manicheva ◽

M. Z. Dogonadze ◽

N. N. Melnikova ◽

B. I. Vishnevskiy ◽

S. A. Manichev

Keyword(s):

Growth Rate ◽

Pulmonary Tuberculosis ◽

Bacterial Load ◽

Phenotypic Properties ◽

Extra Pulmonary Tuberculosis ◽

Mean Values ◽

Clinical Strains ◽

The Mean ◽

Strain H37rv

The phenotypic properties of the M. tuberculosis strains obtained from patients with pulmonary or extra-pulmonary tuberculosis are determined by a complex set of factors: the genetic characteristics of the pathogen, its ability to adapt in vivo and in vitro, the influence of the host’s immune system and chemotherapy. The growth rate as the phenotypic property is the most accessible for the study of the host-pathogen relationships at the level of host/strain population interactions. The aim of the study is to assess in vitro of the growth rate of M. tuberculosis strains isolated from patients with pulmonary and extra-pulmonary tuberculosis: untreated and treated (with surgical and non-surgical treatment) and also sensitive and resistant isolates in comparison with the reference strain H37Rv. To estimate the growth rate of 116 clinical isolates we have used the modified method originally developed by von Groll and co-authors: to get the bacteria growth curve the fluorescence intensity of growing strains (with indicator resazurin) has been measured daily for 8 days in 96- well plate. The growth rate is determined as the slope of the growth curve. The mean values of the growth rate have been calculated in the following groups of patients: 1 — untreated patients with pulmonary tuberculosis (PT), respiratory material; 2 — non-surgical treated PT patients, respiratory material; 3 — surgical treated PT patients (mainly with chronic and hyperchronic process), respiratory material; 4 — patients like in 3rd group, surgical material; 5 — bone and joint tuberculosis (BJT), surgical material. In addition, groups of sensitive and resistant strains have been examined, but there are no significant differences in growth rates. It has been obtained that the growth rate of strains isolated from the PT patients is higher than in BJT patients: it can be explained less favorable conditions for the pathogen vegetation in the BJT. In the case of a closed tuberculous lesion where the pathogen transmission to another host is impossible, then the selection of strains with the property to survive in the tissues of the osteoarticular system is impossible too, therefor it should be observed only an adaptation of the pathogen strain population to the individual host. The growth rate of isolates from untreated PT patients is higher than that of the treated ones. Comparison of the growth parameters of only MDR strains 1–5 groups to eliminate the influence of the sensitivity/resistance has resulted in the same conclusions. We suggest that the decrease in the growth rate of strains from the treated PT patients is in not only result of the treatment, but also is conditioned by adaptation of the pathogen to its external environment, which is the internal environment of the macroorganism. To confirm this assumption, the bacterial load of 1,083 diagnostic specimens grouped in a similar manner has been estimated, taking into account only MDR/XDR strains. In the group of treated patients the frequency of high bacterial load (CFU ≥ 100) reached 52.5–63.8% that shows the conserved fitness of bacteria in such patients. The mean values of the growth rate of the strain H37Rv non-adapted to the macroorganism (due to numerous passages on artificial media) are higher than in all groups of clinical strains. Thus, heterogeneity of phenotypic properties of M. tuberculosis clinical strains on the basis of growth rate has been obtained. The growth rate of M. tuberculosis clinical strains is depended on the tuberculosis localization (PT, BJT) and on the joint effect of patient treatment and pathogen adaptation to the host.

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First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01208-21 ◽

2021 ◽

Author(s):

Angela K. Talley ◽

Archie Thurston ◽

Grayson Moore ◽

Vipul K. Gupta ◽

Myriah Satterfield ◽

...

Keyword(s):

Adverse Events ◽

Phase 1 ◽

Human Study ◽

Dna Gyrase ◽

Plasma Exposure ◽

Serious Adverse Events ◽

Double Blind ◽

Bacterial Dna ◽

Elimination Pathway

SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria in vitro and in murine and hollow fiber infection models. This Phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 mg to 2000 mg, or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. The median SPR719 T max ranged from 2.8 to 8.0 hours across cohorts, and the t 1/2 ranged from 2.9 to 4.5 hours and was shown to be dose-independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC 0-24 was comparable between Days 7 and 14. Results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720.

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Modulation of Endolysin LysECD7 Bactericidal Activity by Different Peptide Tag Fusion

Biomolecules ◽

10.3390/biom10030440 ◽

2020 ◽

Vol 10 (3) ◽

pp. 440 ◽

Cited By ~ 2

Author(s):

Nataliia P. Antonova ◽

Daria V. Vasina ◽

Evgeny O. Rubalsky ◽

Mikhail V. Fursov ◽

Alina S. Savinova ◽

...

Keyword(s):

Bactericidal Activity ◽

Lytic Enzyme ◽

Antibiotic Resistant ◽

Gram Positive Bacteria ◽

Highly Active ◽

Different Types ◽

Peptide Tags ◽

Resistant Strains ◽

Bacterial Outer Membrane

The use of recombinant endolysins is a promising approach for antimicrobial therapy capable of counteracting the spread of antibiotic-resistant strains. To obtain the necessary biotechnological product, diverse peptide tags are often fused to the endolysin sequence to simplify enzyme purification, improve its ability to permeabilize the bacterial outer membrane, etc. We compared the effects of two different types of protein modifications on endolysin LysECD7 bactericidal activity in vitro and demonstrated that it is significantly modulated by specific permeabilizing antimicrobial peptides, as well as by widely used histidine tags. Thus, the tags selected for the study of endolysins and during the development of biotechnological preparations should be used with the appropriate precautions to minimize false conclusions about endolysin properties. Further, modifications of LysECD7 allowed us to obtain a lytic enzyme that was largely devoid of the disadvantages of the native protein and was active over the spectra of conditions, with high in vitro bactericidal activity not only against Gram-negative, but also against Gram-positive, bacteria. This opens up the possibility of developing effective antimicrobials based on N-terminus sheep myeloid peptide of 29 amino acids (SMAP)-modified LysECD7 that can be highly active not only during topical treatment but also for systemic applications in the bloodstream and tissues.

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Impact of Inoculum Size and Heterogeneous Vancomycin-Intermediate Staphylococcus aureus (hVISA) on Vancomycin Activity and Emergence of VISA in an In Vitro Pharmacodynamic Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01009-08 ◽

2008 ◽

Vol 53 (2) ◽

pp. 805-807 ◽

Cited By ~ 22

Author(s):

Warren E. Rose ◽

Steven N. Leonard ◽

Kerri L. Rossi ◽

Glenn W. Kaatz ◽

Michael J. Rybak

Keyword(s):

Staphylococcus Aureus ◽

Bactericidal Activity ◽

Bacterial Load ◽

Inoculum Size ◽

Pharmacodynamic Model ◽

High Inoculum ◽

High Bacterial Load

ABSTRACT The activity of vancomycin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) and non-hVISA isolates, using an in vitro pharmacodynamic model, was reduced in the presence of a high inoculum amount (108 CFU/ml). A high bacterial load of >105 CFU/ml persisted for all strains with doses up to 5 g every 12 h against high inoculum amounts. No change in the vancomycin MIC was detected in any isolate at a moderate inoculum amount (106 CFU/ml), and bactericidal activity occurred only against the non-hVISA isolate (time to 99% kill, 7.5 h; P = 0.001).

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Nav1.7 target modulation and efficacy can be measured in nonhuman primate assays

Science Translational Medicine ◽

10.1126/scitranslmed.aay1050 ◽

2021 ◽

Vol 13 (594) ◽

pp. eaay1050

Author(s):

Richard L. Kraus ◽

Fuqiang Zhao ◽

Parul S. Pall ◽

Dan Zhou ◽

Joshua D. Vardigan ◽

...

Keyword(s):

Plasma Concentration ◽

Clinical Studies ◽

Clinical Success ◽

Rhesus Macaques ◽

Phase 1 ◽

Analgesic Efficacy ◽

Loss Of Function ◽

Noxious Heat

Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.

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Efficacy of the New Lantibiotic NAI-107 in Experimental Infections Induced by Multidrug-Resistant Gram-Positive Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01288-10 ◽

2011 ◽

Vol 55 (4) ◽

pp. 1671-1676 ◽

Cited By ~ 85

Author(s):

Daniela Jabés ◽

Cristina Brunati ◽

GianPaolo Candiani ◽

Simona Riva ◽

Gabriella Romanó ◽

...

Keyword(s):

Bactericidal Activity ◽

Bacterial Load ◽

Severe Infection ◽

Multidrug Resistant ◽

Minimal Bactericidal Concentration ◽

Gram Positive ◽

Immunocompetent Mice ◽

Dose Proportional

ABSTRACTNAI-107 is a novel lantibiotic active against Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus(MRSA), glycopeptide-intermediateS. aureus(GISA), and vancomycin-resistant enterococci (VRE). The aim of this study was to evaluate thein vivoefficacy of NAI-107 in animal models of severe infection. In acute lethal infections induced with a penicillin-intermediateStreptococcus pneumoniaestrain in immunocompetent mice, or with MRSA, GISA, and VRE strains in neutropenic mice, the 50% effective dose (ED50) values of NAI-107 were comparable or lower than those of reference compounds, irrespective of the strain and immune status (0.51 to 14.2 mg/kg of body weight for intravenous [i.v.] NAI-107, 5.1 to 22.4 for oral linezolid, and 22.4 for subcutaneous [s.c.] vancomycin). Inthe granuloma pouch model induced in rats with a MRSA strain, intravenous NAI-107 showed a dose-proportional bactericidal activity that, at a single 40-mg/kg dose, compared with 2 20-mg/kg doses at a 12-h or 24-h interval, caused a 3-log10-CFU/ml reduction of viable MRSA in exudates that persisted for more than 72 h. Rat endocarditis was induced with a MRSA strain and treated for five consecutive days. In a first experiment, using 5, 10, or 20 mg/kg/day, and in a second experiment, when 10 mg/kg at 12-h intervals was compared to 20 mg/kg/day, intravenous NAI-107 was effective in reducing the bacterial load in heart vegetations in a dose-proportional manner. Trough plasma levels, as determined on days 2 and 5, were several times higher than the NAI-107 minimal bactericidal concentration (MBC). NAI-107 binding to rat and human serum ranges between 93% and 98.6%. The rapid bactericidal activity of NAI-107 observedin vitrowas thus confirmed by the efficacy in several models of experimental infection induced by Gram-positive pathogens, supporting further investigation of the compound.

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