scholarly journals Isavuconazole (BAL4815) Pharmacodynamic Target Determination in anIn VivoMurine Model of Invasive Pulmonary Aspergillosis against Wild-Type andcyp51Mutant Isolates of Aspergillus fumigatus

2013 ◽  
Vol 57 (12) ◽  
pp. 6284-6289 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Dose Range ◽  
Invasive Pulmonary Aspergillosis ◽  
Mortality Rates ◽  
Free Drug ◽  
Lung Homogenate ◽  
Infection Model ◽  
Wild Type ◽  
Pulmonary Aspergillosis ◽  
Content Type ◽  
Target Determination

ABSTRACTInvasive pulmonary aspergillosis (IPA) continues to rise in concert with increasing numbers of immune suppression techniques to treat other medical conditions and transplantation. Despite these advances, morbidity and mortality rates remain unacceptably high. One strategy used to optimize outcomes is antifungal pharmacodynamic (PD) examination. We explored the pharmacodynamics of a new triazole in development, isavuconazole, in a murine neutropenic IPA model. TenA. fumigatusisolates were used, including four wild-type isolates and sixcyp51mutants. The MIC range was 0.125 to 8 mg/liter. Following infection, groups of mice were treated orally with the prodrug (BAL8557) at 40 to 640 mg/kg/12 h for 7 days. Efficacy was determined by quantitative PCR of lung homogenates. At the start of therapy, mice had 4.97 log10conidial equivalents (CE)/ml of lung homogenate, and this increased to 6.82 log10CE/ml of lung homogenate in untreated animals. The infection model was uniformly lethal in untreated control mice. The PD target endpoints examined included the static-dose AUC/MIC ratio and the 1-log10killing AUC/MIC ratio. A stasis endpoint was achieved for all isolates with an MIC of ≤1 mg/liter and 1-log10killing in all isolates with an MIC of ≤0.5 mg/liter, regardless of the presence or absence of thecyp51mutation. The static-dose range was 65 to 617 mg/kg/12 h. The corresponding median free-drug AUC/MIC ratio was near 5. The 1-log10killing dose range was 147 to 455 mg/kg/12 h, and the corresponding median free-drug AUC/MIC ratio was 11.1. These values are similar to those previously reported for other triazoles.

scholarly journals Posaconazole Pharmacodynamic Target Determination against Wild-Type andCyp51Mutant Isolates of Aspergillus fumigatus in anIn VivoModel of Invasive Pulmonary Aspergillosis

2012 ◽  
Vol 57 (1) ◽  
pp. 579-585 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jaimie VanHecker ◽  
David R. Andes
Keyword(s):  
Dose Range ◽  
Invasive Pulmonary Aspergillosis ◽  
Free Drug ◽  
Lung Homogenate ◽  
Study Endpoint ◽  
Pharmacokinetic Data ◽  
Wild Type ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Content Type

ABSTRACTInvasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explored the PD target of posaconazole in an immunocompromised murine model of IPA against 10A. fumigatusisolates, including 4Cyp51wild-type isolates and 6 isolates carryingCyp51mutations conferring azole resistance. The posaconazole MIC range was 0.25 to 8 mg/liter. Following infection, mice were given 0.156 to 160 mg/kg of body weight of oral posaconazole daily for 7 days. Efficacy was assessed by quantitative PCR (qPCR) of lung homogenate and survival. At the start of therapy, mice had 5.59 ± 0.19 log10Aspergillusconidial equivalents (CE)/ml of lung homogenate, which increased to 7.11 ± 0.29 log10CE/ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to the study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug area under the concentration-time curve (AUC)/MIC and qPCR lung burden. The static dose range was 1.09 to 51.9 mg/kg/24 h. The free drug AUC/MIC PD target was 1.09 ± 0.63 for the group of strains. The 1-log kill free drug AUC/MIC was 2.07 ± 1.02. The PD target was not significantly different for the wild-type and mutant organism groups. Mortality mirrored qPCR results, with the greatest improvement in survival noted at the same dosing regimens that produced static or cidal activity. Consideration of human pharmacokinetic data and the current static dose PD target would predict a clinical MIC threshold of 0.25 to 0.5 mg/liter.

scholarly journals Impact ofIn VivoTriazole and Echinocandin Combination Therapy for Invasive Pulmonary Aspergillosis: Enhanced Efficacy againstCyp51Mutant Isolates

2013 ◽  
Vol 57 (11) ◽  
pp. 5438-5447 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Combination Therapy ◽  
Wild Type Strain ◽  
Invasive Pulmonary Aspergillosis ◽  
Area Under The Curve ◽  
Free Drug ◽  
Target Area ◽  
Synergistic Activity ◽  
Wild Type ◽  
Pulmonary Aspergillosis ◽  
Content Type

ABSTRACTPrevious studies examining combination therapy for invasive pulmonary aspergillosis (IPA) have revealed conflicting results, including antagonism, indifference, and enhanced effects. The most commonly employed combination for this infection includes a mold-active triazole and echinocandin. Few studies have evaluated combination therapy from a pharmacodynamic (PD) perspective, and even fewer have examined combination therapy against both wild-type and azole-resistantCyp51mutant isolates. The current studies aim to fill this gap in knowledge. FourAspergillus fumigatusisolates were utilized, including a wild-type strain, anFks1mutant (posaconazole susceptible and caspofungin resistant), and twoCyp51mutants (posaconazole resistant). A neutropenic murine model of IPA was used for the treatment studies. The dosing design included monotherapy with posaconazole, monotherapy with caspofungin, and combination therapy with both. Efficacy was determined using quantitative PCR, and results were normalized to known quantities of conidia (conidial equivalents [CE]). The static dose, 1-log kill dose, and associated PD target area under the curve (AUC)/MIC ratio were determined for monotherapy and combination therapy. Monotherapy experiments revealed potent activity for posaconazole, with reductions of 3 to 4 log10AspergillusCE/ml with the two “low”-MIC isolates. Posaconazole alone was less effective for the two isolates with higher MICs. Caspofungin monotherapy did not produce a significant decrease in fungal burden for any strain. Combination therapy with the two antifungals did not enhance efficacy for the two posaconazole-susceptible isolates. However, the drug combination produced synergistic activity against both posaconazole-resistant isolates. Specifically, the combination resulted in a 1- to 2-log10decline in burden that would not have been predicted based on the monotherapy results for each drug. This corresponded to a reduction in the free-drug posaconazole AUC/MIC ratio needed for stasis of up to 17-fold. The data suggest that combination therapy using a triazole and an echinocandin may be a beneficial treatment strategy for triazole-resistant isolates.

scholarly journals In VivoPharmacodynamic Target Investigation of Two Bacterial Topoisomerase Inhibitors, ACT-387042 and ACT-292706, in the Neutropenic Murine Thigh Model against Streptococcus pneumoniae and Staphylococcus aureus

2016 ◽  
Vol 60 (6) ◽  
pp. 3626-3632 ◽  
Author(s):  
A. J. Lepak ◽  
P. Seiler ◽  
J. P. Surivet ◽  
D. Ritz ◽  
C. Kohl ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Dose Range ◽  
Free Drug ◽  
Infection Model ◽  
Topoisomerase Inhibitors ◽  
Time Curve ◽  
Content Type ◽  
Phenotypic Resistance

ACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad-spectrum activity against Gram-positive and -negative bacteria, including methicillin-resistantStaphylococcus aureusand penicillin- and fluoroquinolone-resistantStreptococcus pneumoniae. We used the neutropenic murine thigh infection model to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of these investigational compounds against a group of 10S. aureusandS. pneumoniaeisolates with phenotypic resistance to beta-lactams and fluoroquinolones. Thein vitroactivities of the two compounds were very similar (MIC range, 0.03 to 0.125 mg/liter). Plasma pharmacokinetics were determined for each compound by using four escalating doses administered by the subcutaneous route. In treatment studies, mice had 107.4to 108CFU/thigh at the start of therapy with ACT-387042 and 106.7to 108.3CFU/thigh at the start of therapy with ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3 to 4 log10CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) and therapeutic efficacy in the model (R2, 0.63 to 0.82). The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-387042 againstS. aureusandS. pneumoniaewere 43 and 10, respectively. The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-292706 againstS. aureusandS. pneumoniaewere 69 and 25, respectively. The stasis PD targets were significantly lower forS. pneumoniae(P< 0.05) for both compounds. The 1-log-kill AUC/MIC ratio targets were ∼2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. These results should be helpful in the design of clinical trials for topoisomerase inhibitors.

scholarly journals In Vivo Pharmacokinetic and Pharmacodynamic Profiles of Antofloxacin against Klebsiella pneumoniae in a Neutropenic Murine Lung Infection Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Yu-Feng Zhou ◽  
Meng-Ting Tao ◽  
Wei Huo ◽  
Xiao-Ping Liao ◽  
Jian Sun ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bacterial Species ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Dose Fractionation ◽  
Infection Model ◽  
Content Type ◽  
Murine Lung ◽  
Tract Infections

ABSTRACT Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven Klebsiella pneumoniae isolates by using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic (PK) studies were conducted at single subcutaneous doses of 2.5, 10, 40, and 160 mg/kg of body weight. Mice were infected intratracheally with K. pneumoniae and treated using 2-fold-increasing total doses of antofloxacin ranging from 2.5 to 160 mg/kg/24 h administered in 1, 2, 3, or 4 doses. The E max Hill equation was used to model the dose-response data. Antofloxacin could penetrate the lung epithelial lining fluid (ELF) with pharmacokinetics similar to those in plasma with linear elimination half-lives over the dose range. All study strains showed a 3-log10 or greater reduction in bacterial burden and prolonged postantibiotic effects (PAEs) ranging from 3.2 to 5.3 h. Dose fractionation response curves were steep, and the free-drug area under the concentration-time curve over 24 h (AUC0–24)/MIC ratio was the PD index most closely linked to efficacy (R 2 = 0.96). The mean free-drug AUC0–24/MIC ratios required to achieve net bacterial stasis, a 1-log10 kill, and a 2-log10 kill for each isolate were 52.6, 89.9, and 164.9, respectively. When integrated with human PK data, these PD targets could provide a framework for further optimization of dosing regimens. This could make antofloxacin an attractive option for the treatment of respiratory tract infections involving K. pneumoniae.

scholarly journals Pharmacokinetic/Pharmacodynamic Evaluation of a Novel Aminomethylcycline Antibiotic, KBP-7072, in the Neutropenic Murine Pneumonia Model against Staphylococcus aureus and Streptococcus pneumoniae

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Qingmei Liu ◽  
Ping Wang ◽  
Yanli Wang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Rational Design ◽  
Dose Range ◽  
Free Drug ◽  
Pharmacokinetic Parameters ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Drug Concentrations

ABSTRACT KBP-7072 is a novel aminomethylcycline antibiotic in clinical development for community-acquired pneumonia. The goal of present studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter magnitude correlated with efficacy in the murine pneumonia infection model against Staphylococcus aureus and Streptococcus pneumoniae. KBP-7072 pharmacokinetic measurements were performed in plasma and epithelial lining fluid (ELF) at 4-fold-increasing doses from 1 to 256 mg/kg of body weight subcutaneously. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 82% to 238% comparing ELF drug concentrations to plasma free drug concentrations. Twenty-four-hour dose-ranging efficacy studies were then performed in the neutropenic murine pneumonia model against 5 S. aureus (3 methicillin-resistant and 2 methicillin-susceptible) and 6 S. pneumoniae (2 Tetr and 2 Penr) strains. KBP-7072 demonstrated potent in vivo activity resulting in a 3- to 5-log10 kill in CFU burden compared to the start of therapy for all strains. The PK/PD index area under the concentration-time curve (AUC)/MIC corelated well with efficacy (R2, 0.80 to 0.89). Net stasis was achieved at plasma 24-h free drug AUC/MIC values of 1.13 and 1.41 (24-h ELF AUC/MIC values of 2.01 and 2.50) for S. aureus and S. pneumoniae, respectively. A 1-log10 kill was achieved at 24-h plasma AUC/MIC values of 2.59 and 5.67 (24-h ELF AUC/MIC values of 4.22 and 10.08) for S. aureus and S. pneumoniae, respectively. A 2-log10 kill was achieved at 24-h plasma AUC/MIC values of 7.16 and 31.14 (24-h ELF AUC/MIC values of 8.37 and 42.92) for S. aureus and S. pneumoniae, respectively. The results of these experiments will aid in the rational design of dose-finding studies for KBP-7072 in patients with community-acquired bacterial pneumonia (CAP).

scholarly journals In Vivo Pharmacodynamic Target Determination for Delafloxacin against Klebsiella pneumoniae and Pseudomonas aeruginosa in the Neutropenic Murine Pneumonia Model

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
David R. Andes
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Area Under The Curve ◽  
Lung Infection ◽  
Free Drug ◽  
Infection Model ◽  
Phase 3 ◽  
Content Type ◽  
Target Determination

ABSTRACT Delafloxacin is a broad-spectrum anionic fluoroquinolone that has completed a phase 3 study for community-acquired bacterial pneumonia. We investigated the pharmacodynamic target for delafloxacin against 12 Klebsiella pneumoniae and 5 Pseudomonas aeruginosa strains in the neutropenic murine lung infection model. The median 24-h free-drug area under the curve (fAUC)/MIC values associated with net stasis and 1-log kill were 28.6 and 64.1 for K. pneumoniae, respectively. The 24-h fAUC/MIC values associated with net stasis and 1-log kill for P. aeruginosa were 5.66 and 14.3, respectively.

scholarly journals Posaconazole Prophylaxis in Experimental Azole-Resistant Invasive Pulmonary Aspergillosis

2014 ◽  
Vol 59 (3) ◽  
pp. 1487-1494 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Johan W. Mouton ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Murine Model ◽  
Pulmonary Infection ◽  
Invasive Pulmonary Aspergillosis ◽  
Clinical Isolates ◽  
Wild Type ◽  
Breakthrough Infection ◽  
Pulmonary Aspergillosis ◽  
Content Type

ABSTRACTWe investigated the efficacy of posaconazole prophylaxis in preventing invasive aspergillosis due to azole-resistantAspergillus fumigatusisolates. Using a neutropenic murine model of pulmonary infection, posaconazole prophylaxis was evaluated using three isogenic clinical isolates, with posaconazole MICs of 0.063 mg/liter (wild type), 0.5 mg/liter (F219I mutation), and 16 mg/liter. A fourth isolate harboring TR34/L98H (MIC of 0.5 mg/liter) was also tested. Posaconazole prophylaxis was effective inA. fumigatuswith posaconazole MICs of ≤0.5 mg/liter, where 100% survival was reached. However, breakthrough infection was observed in mice infected with the isolate for which the posaconazole MIC was >16 mg/liter.

scholarly journals ThemtfATranscription Factor Gene Controls Morphogenesis, Gliotoxin Production, and Virulence in the Opportunistic Human Pathogen Aspergillus fumigatus

2014 ◽  
Vol 13 (6) ◽  
pp. 766-775 ◽  
Author(s):  
Timothy D. Smith ◽  
Ana M. Calvo
Keyword(s):  
Aspergillus Fumigatus ◽  
Protease Activity ◽  
Galleria Mellonella ◽  
Molecular Genetic ◽  
Colony Growth ◽  
Infection Model ◽  
Slight Reduction ◽  
Wild Type ◽  
Content Type ◽  
Factor Gene

ABSTRACTAspergillus fumigatusis the leading causative agent of invasive aspergillosis (IA). The number of cases is on the rise, with mortality rates as high as 90% among immunocompromised patients. Molecular genetic studies inA. fumigatuscould provide novel targets to potentially set the basis for antifungal therapies. In the current study, we investigated the role of the transcription factor genemtfAinA. fumigatus. Our results revealed thatmtfAplays a role in the growth and development of the fungus. Deletion or overexpression ofmtfAleads to a slight reduction in colony growth, as well as a reduction in conidiation levels, in the overexpression strain compared to the wild-type strain. Furthermore, production of the secondary metabolite gliotoxin increased whenmtfAwas overexpressed, coinciding with an increase in the transcription levels of the gliotoxin genesgliZandgliPwith respect to the wild type. In addition, our study showed thatmtfAis also necessary for normal protease activity inA. fumigatus; deletion ofmtfAresulted in a reduction of protease activity compared to wild-type levels. Importantly, the absence ofmtfAcaused a decrease in virulence in theGalleria mellonellainfection model, indicating thatmtfAis necessary forA. fumigatuswild-type pathogenesis.

scholarly journals In Vivo Bioluminescent Monitoring of Therapeutic Efficacy and Pharmacodynamic Target Assessment of Antofloxacin against Escherichia coli in a Neutropenic Murine Thigh Infection Model

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Yu-Feng Zhou ◽  
Meng-Ting Tao ◽  
Yu-Zhang He ◽  
Jian Sun ◽  
Ya-Hong Liu ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Subcutaneous Administration ◽  
Free Drug ◽  
Infection Model ◽  
Bioluminescent Imaging ◽  
Time Curve ◽  
Content Type ◽  
E Coli ◽  
Tract Infections

ABSTRACT Antimicrobial resistance among uropathogens has increased the rates of infection-related morbidity and mortality. Antofloxacin is a novel fluoroquinolone with broad-spectrum antibacterial activity against urinary Gram-negative bacilli, such as Escherichia coli. This study monitored the in vivo efficacy of antofloxacin using bioluminescent imaging and determined pharmacokinetic (PK)/pharmacodynamic (PD) targets against E. coli isolates in a neutropenic murine thigh infection model. The PK properties were determined after subcutaneous administration of antofloxacin at 2.5, 10, 40, and 160 mg/kg of body weight. Following thigh infection, the mice were treated with 2-fold-increasing doses of antofloxacin from 2.5 to 80 mg/kg administered every 12 h. Efficacy was assessed by quantitative determination of the bacterial burdens in thigh homogenates and was compared with the bioluminescent density. Antofloxacin demonstrated both static and killing endpoints in relation to the initial burden against all study strains. The PK/PD index area under the concentration-time curve (AUC)/MIC correlated well with efficacy (R 2 = 0.92), and the dose-response relationship was relatively steep, as observed with escalating doses of antofloxacin. The mean free drug AUC/MIC targets necessary to produce net bacterial stasis and 1-log10 and 2-log10 kill for each isolate were 38.7, 66.1, and 147.0 h, respectively. In vivo bioluminescent imaging showed a rapid decrease in the bioluminescent density at free drug AUC/MIC exposures that exceeded the stasis targets. The integration of these PD targets combined with the results of PK studies with humans will be useful in setting optimal dosing regimens for the treatment of urinary tract infections due to E. coli.

scholarly journals In Vivo Pharmacodynamic Activity of the Glycopeptide Dalbavancin

2007 ◽  
Vol 51 (5) ◽  
pp. 1633-1642 ◽  
Author(s):  
David Andes ◽  
William A. Craig
Keyword(s):  
Half Life ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Infection Model ◽  
Gram Positive ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Dose Dependent

ABSTRACT Dalbavancin is a lipoglycopeptide antibiotic with broad-spectrum activity against gram-positive cocci and a markedly prolonged serum elimination half-life. We used the neutropenic murine thigh and lung infection models to characterize the pharmacodynamics of dalbavancin. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged elimination half-life which ranged from 7.6 to 13.1 h over the dose range of 2.5 to 80 mg/kg of body weight. The level of protein binding in mouse serum was 98.4%. The time course of in vivo activity of dalbavancin over the same dose range was examined in neutropenic ICR Swiss mice infected with a strain of either Streptococcus pneumoniae or Staphylococcus aureus by using the thigh infection model. The burden of organisms for S. pneumoniae was markedly reduced over the initial 24 h of study, and organism regrowth was suppressed in a dose-dependent fashion for up to the entire 96 h of study following dalbavancin doses of 2.5 mg/kg or greater. Dalbavancin doses of 20 mg/kg or greater resulted in less killing of S. aureus but were still followed by a prolonged suppression of regrowth. Multiple-dosing-regimen studies with the same organisms were used to determined which of the pharmacodynamic indices (maximum concentration in serum [C max]/MIC, area under the concentration-versus-time curve [AUC]/MIC, or the duration of time that levels in serum exceed the MIC) best correlated with treatment efficacy. These studies used a dose range of 3.8 to 480 mg/kg/6 days fractionated into 2, 4, 6, or 12 doses over the 144-h dosing period. Nonlinear regression analysis was used to examine the data fit with each pharmacodynamic index. Dalbavancin administration by the use of large, widely spaced doses was the most efficacious for both organisms. Both the 24-h AUC/MIC and the C max/MIC parameters correlated well with the in vivo efficacy of treatment against S. pneumoniae and S. aureus (for 24-h AUC/MIC, R 2 = 78 and 77%, respectively; for C max/MIC, R 2 = 90 and 57%, respectively). The free-drug 24-h AUC/MICs required for a bacteriostatic effect were 17 ± 7 for five S. pneumoniae isolates. A similar treatment endpoint for the treatment against five strains of S. aureus required a larger dalbavancin exposure, with a mean free-drug 24-h AUC/MIC of 265 ± 143. Beta-lactam resistance did not affect the pharmacodynamic target. The dose-response curves were relatively steep for both species; thus, the pharmacodynamic target needed to achieve organism reductions of 1 or 2 log10 in the mice were not appreciably larger (1.3- to 1.6-fold). Treatment was similarly efficacious in neutropenic mice and in the lung infection model. The dose-dependent efficacy and prolonged elimination half-life of dalbavancin support the widely spaced regimens used in clinical trials. The free-drug 24-h AUC/MIC targets identified in these studies should be helpful for discerning rational susceptibility breakpoints. The current MIC90 for the target gram-positive organisms would fall within this value.

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