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 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 Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Lung Model ◽  
Maximum Effect ◽  
Pharmacokinetic Data ◽  
Time Curve ◽  
Content Type ◽  
Infection Models

ABSTRACT The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four Staphylococcus aureus strains were included. The telavancin MIC ranged from 0.06 to 0.25 mg/liter, and the vancomycin MIC ranged from 1 to 4 mg/liter. The plasma pharmacokinetics of escalating doses (1.25, 5, 20, and 80 mg/kg of body weight) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed that penetration into the ELF mirrored the percentage of the free fraction (the fraction not protein bound) in plasma for each drug. Telavancin (0.3125 to 80 mg/kg/6 h) and vancomycin (0.3125 to 1,280 mg/kg/6 h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity against all four strains was observed in both models. A sigmoid maximum-effect model was used to determine the area under the concentration-time curve (AUC)/MIC exposure associated with net stasis and 1-log10 kill relative to the burden at the start of therapy. The 24-h plasma free drug AUC (fAUC)/MIC values associated with stasis and 1-log kill were remarkably congruent. Net stasis for telavancin was noted at fAUC/MIC values of 83 and 40.4 in the thigh and lung, respectively, and 1-log kill was noted at fAUC/MIC values of 215 and 76.4, respectively. For vancomycin, the fAUC/MIC values for stasis were 77.9 and 45.3, respectively, and those for 1-log kill were 282 and 113, respectively. The 24-h ELF total drug AUC/MIC targets in the lung model were very similar to the 24-h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, the results of the MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus infections.

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 Pharmacodynamics of Isavuconazole in a DynamicIn VitroModel of Invasive Pulmonary Aspergillosis

2015 ◽  
Vol 60 (1) ◽  
pp. 278-287 ◽  
Author(s):  
Helen Box ◽  
Joanne Livermore ◽  
Adam Johnson ◽  
Laura McEntee ◽  
Timothy W. Felton ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Pathogenic Fungi ◽  
Time Profile ◽  
Wild Type ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Target Values ◽  
Maximal Suppression

ABSTRACTIsavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamicin vitromodel of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates ofAspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.

scholarly journals Comparative Pharmacodynamics of Posaconazole in Neutropenic Murine Models of Invasive Pulmonary Aspergillosis and Mucormycosis

2014 ◽  
Vol 58 (11) ◽  
pp. 6767-6772 ◽  
Author(s):  
Russell E. Lewis ◽  
Nathaniel D. Albert ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Rhizopus Oryzae ◽  
Invasive Pulmonary Aspergillosis ◽  
High Dose ◽  
Murine Models ◽  
Total Drug ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Content Type ◽  
Pulmonary Mucormycosis ◽  
Concentration Time

ABSTRACTWe used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice withAspergillus fumigatusstrain 293 (posaconazole MIC, 0.5 mg/liter) orRhizopus oryzaestrain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar forA. fumigatusandR. oryzaewhen indexed to pathogen MICs.

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 Isavuconazole Pharmacodynamic Target Determination for Candida Species in anIn VivoMurine Disseminated Candidiasis Model

2013 ◽  
Vol 57 (11) ◽  
pp. 5642-5648 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
Daniel Diekema ◽  
David R. Andes
Keyword(s):  
Body Weight ◽  
Dose Range ◽  
Clinical Trial Data ◽  
Free Drug ◽  
Time Curve ◽  
Content Type ◽  
Disseminated Candidiasis ◽  
Elimination Half ◽  
The Mean ◽  
Species Specific

ABSTRACTPharmacodynamic (PD) studies with triazoles in the neutropenic murine disseminated candidiasis model have been performed extensively forCandida albicans. They have consistently shown that the pharmacodynamic index most closely correlated with efficacy is the ratio of the 24-h area under the concentration-time curve (AUC) to the MIC, and a target 24-h free-drug AUC/MIC ratio near 25 is associated with 50% of maximal microbiologic efficacy. We utilized this model to investigate the pharmacodynamics of isavuconazole. Isavuconazole pharmacokinetics were linear over the dose range studied. Oral-gastric doses of 640, 160, 40, and 10 mg of prodrug/kg of body weight produced peak levels of 0.51 to 25.4 mg/liter, an elimination half-life of 1 to 5 h, and an AUC from 0 h to infinity (AUC0-∞) of 0.9 to 287 mg · h/liter. The AUC/MIC ratio was the pharmacodynamic index that correlated best with efficacy (R2, 0.84). Pharmacodynamic target studies were performed using 4C. albicansisolates with both a 24-h and a 96-h treatment duration. The strains were chosen to include previously characterized fluconazole-resistant strains. The mean 50% effective doses (ED50) (expressed in mg/kg of body weight/12 h) and associated 24-h free-drug AUC/MIC ratios were 89.3 ± 46.7 and 67.7 ± 35 for the 24-h treatment and 59.6 ± 22 and 33.3 ± 25.5 for the 96-h treatment. These differences were not statistically significant. Pharmacodynamic targets for two non-albicans Candidaspecies were also explored. The mean ED50(expressed in mg/kg/12 h) and associated 24-h free-drug AUC/MIC ratios were 31.2 and 6.2 forCandida tropicalis(n= 1) and 50.5 and 1.6 forCandida glabrata(n= 2). These PD targets were significantly different fromC. albicanstargets (P, 0.04). Isavuconazole PD targets forC. albicansare similar to those observed in this model with other triazoles. However, the PD targets for non-albicans Candidaspecies were more than 10-fold lower than those forC. albicans(P, 0.04). This difference is similar to the species-specific PD relationships for the echinocandins. The lower PD targets for these species in this model will be important to consider in the analysis of clinical trial data and during the development of susceptibility breakpoints.

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 VivoActivity of Cefquinome against Escherichia coli in the Thighs of Neutropenic Mice

2014 ◽  
Vol 58 (10) ◽  
pp. 5943-5946 ◽  
Author(s):  
Qi Shan ◽  
Chaoping Liang ◽  
Jing Wang ◽  
Jufeng Li ◽  
Zhenling Zeng
Keyword(s):  
Escherichia Coli ◽  
Dose Range ◽  
Serum Levels ◽  
Free Drug ◽  
Dose Fractionation ◽  
Maximum Effect ◽  
Time Curve ◽  
Content Type ◽  
E Coli ◽  
Liquid Chromatography Tandem Mass

ABSTRACTCefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against enteric Gram-negative bacilli such asEscherichia coli. We utilized a neutropenic mouse model of colibacillosis to examine the pharmacodynamic (PD) characteristics of cefquinome, as measured by organism number in homogenized thigh cultures after 24 h of therapy. Serum drug levels following 4-fold-escalating single doses of cefquinome were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic (PK) properties of cefquinome were linear over a dose range of 10 to 640 mg/kg of body weight. Serum half-lives ranged from 0.29 to 0.32 h. Dose fractionation studies over a 24-h dose range of 2.5 to 320 mg/kg were conducted every 3, 6, 12, or 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. The free percentage of the dosing interval that the serum levels exceed the MIC (fT>MIC) was the PK-PD index that best correlated with efficacy (R2= 73% forE. coli, compared with 13% for the maximum concentration of the free drug in serum [fCmax]/MIC and 45% for the free-drug area under the concentration-time curve from 0 to 24 h [fAUC0-24]/MIC). Subsequently, we employed a similar dosing strategy by using 4-fold-increasing total cefquinome doses administered every 4 h to treat animals infected with four additionalE. coliisolates. A sigmoid maximum-effect (Emax) model was used to estimate the magnitudes of the %fT>MICassociated with net bacterial stasis, a 1-log10CFU reduction from baseline, and a 2-log10CFU reduction from baseline; the corresponding values were 28.01% ± 2.27%, 37.23% ± 4.05%, and 51.69% ± 9.72%. The potent bactericidal activity makes cefquinome an attractive option for the treatment of infections caused byE. coli.

scholarly journals Azithromycin To Prevent Bronchopulmonary Dysplasia in Ureaplasma-Infected Preterm Infants: Pharmacokinetics, Safety, Microbial Response, and Clinical Outcomes with a 20-Milligram-per-Kilogram Single Intravenous Dose

2013 ◽  
Vol 57 (5) ◽  
pp. 2127-2133 ◽  
Author(s):  
Rose M. Viscardi ◽  
Ahmed A. Othman ◽  
Hazem E. Hassan ◽  
Natalie D. Eddington ◽  
Elias Abebe ◽  
...  
Keyword(s):  
Body Weight ◽  
Single Dose ◽  
Preterm Infants ◽  
Bronchopulmonary Dysplasia ◽  
Dose Range ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Open Label ◽  
Time Curve ◽  
Content Type

ABSTRACTUreaplasmarespiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicateUreaplasmaspp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)0.75[WT(kg)0.75indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)0.75; central volume of distribution (V), 1.97 liters × WT (kg); and peripheralV, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90(AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50of 1 μg/ml for this group ofUreaplasmaisolates for ≥96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%)Ureaplasma-positive subjects and three of six (50%)Ureaplasma-negative subjects developed physiologic BPD.Ureaplasmawas eradicated in all treatedUreaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

Sign in / Sign up

Export Citation Format

Share Document