Penetration of Netilmicin in the Lower Respiratory Tract after Once-Daily Dosing

Valcke, Y.; Vogelaers, Dirk; Colardyn, Francis; Pauwels, Romain

doi:10.1378/chest.101.4.1028

Cited by 38 publications

(23 citation statements)

References 24 publications

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“…1). To compare our data with already published evidence, we performed a systematic literature search on aminoglycoside (amikacin [8,12,17,20,23], tobramycin [5,7,9,17,19,20], gentamicin [21,22], and netilmicin [26]) quantification in BAL fluid after parenteral (i.v. or i.m.)…”

Section: Discussionmentioning

confidence: 98%

“…The anatomic site of sample collection is of importance since earlier reports mentioned that aminoglycoside concentrations in whole-lung tissue, sputum, and bronchial secretions approximate, respectively, 50%, 20 to 60%, and 20% of serum levels (22). It is also known that bronchial secretions cannot be used to predict ELF concentrations of aminoglycosides (26). The introduction of BAL as a sampling procedure resulted in more standardized measurements.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the data retrieved, Valcke et al registered the highest peak aminoglycoside concentration in ELF (14.7 mg/liter) after i.v. administration of 450 mg of netilmicin once daily in adults with pneumonia (26). Our study was performed only in neonates after an extended antibiotic interval and with the BAL procedure to collect samples.…”

Section: Discussionmentioning

confidence: 99%

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Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Tayman

El-Attug

Adams

et al. 2011

Antimicrob Agents Chemother

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Aminoglycosides like amikacin are frequently administered in the treatment of suspected or proven Gram-negative infections in neonates, often in combination with penicillins. Due to a concentration-dependent killing combined with a postantibiotic effect, the bactericidal efficacy of amikacin relates to its peak serum concentration. Consequently, therapeutic peak levels at the infection site will define the effectiveness of antibiotic therapy. Renal side effects and ototoxicity relate to the trough serum amikacin concentration, based on the saturation of renal and cochlear cell-binding sites. The pharmacokinetics (PK) of amikacin displays extensive interindividual variability, which makes it difficult to achieve an effective and safe administration in the individual neonate (1).Based on maturational differences in body composition and renal immaturity in early life, differences in both distribution volume (V d , in liters/kg) and clearance (CL t , in ml/kg/min) of this hydrophilic drug have been observed. Because of the higher water content in preterm infants, and thus a higher distribution volume for hydrophilic drugs, a relatively higher amikacin dose is necessary in this population (3,25).Since pulmonary infections can be a major cause of neonatal morbidity and mortality, antibiotic levels in bronchial secretions and bronchial and alveolar epithelial lining fluid (ELF) are of specific interest. Measuring antibiotic concentrations in the lung is not easy and is usually represented by ELF concentrations. Keeping the anatomy of the blood-bronchial barrier in mind, one can imagine that to reach ELF, the antibiotic must pass through the epithelial lining cells linked by tight junctions (14). Consequently, biochemical characteristics like the degree of protein binding and the lipophilicity and diffusibility of the antibiotic will influence antibiotic concentrations in interstitial fluid and in ELF. In adults, we are aware of studies to assess the blood-alveolar barrier after parenteral administration of amikacin. Dull et al. showed that, after intramuscular (i.m.) administration, the highest amikacin serum concentration correlated significantly with the highest bronchial secretion concentration of that individual and that elimination of amikacin from serum and bronchial secretions occurred at approximately the same rate, with a peak concentration that is blunted in the alveolar compared to the blood compartment (12). Since data in neonates are lacking, the aim of this study is to describe amikacin concentration in the bronchial ELF of newborns.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Tayman

El-Attug

Adams

et al. 2011

Antimicrob Agents Chemother

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“…However, the systemic use of this antibiotic class is limited by its toxicity and poor penetration into the lung [2-4]. Also, minimum inhibitory concentrations (MIC) of still active antibiotics on multidrug-resistant Gram-negative bacteria, mainly aminoglycosides, are higher.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia

et al. 2009

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IntroductionAminoglycosides aerosolization might achieve better diffusion into the alveolar compartment than intravenous use. The objective of this multicenter study was to evaluate aerosol-delivered amikacin penetration into the alveolar epithelial lining fluid (ELF) using a new vibrating mesh nebulizer (Pulmonary Drug Delivery System (PDDS), Nektar Therapeutics), which delivers high doses to the lungs.MethodsNebulized amikacin (400 mg bid) was delivered to the lungs of 28 mechanically ventilated patients with Gram-negative VAP for 7-14 days, adjunctive to intravenous therapy. On treatment day 3, 30 minutes after completing aerosol delivery, all the patients underwent bronchoalveolar lavage in the infection-involved area and the ELF amikacin concentration was determined. The same day, urine and serum amikacin concentrations were determined at different time points.ResultsMedian (range) ELF amikacin and maximum serum amikacin concentrations were 976.1 (135.7-16127.6) and 0.9 (0.62-1.73) μg/mL, respectively. The median total amount of amikacin excreted in urine during the first and second 12-hour collection on day 3 were 19 (12.21-28) and 21.2 (14.1-29.98) μg, respectively. During the study period, daily through amikacin measurements were below the level of nephrotoxicity. Sixty-four unexpected adverse events were reported, among which 2 were deemed possibly due to nebulized amikacin: one episode of worsening renal failure, and one episode of bronchospasm.ConclusionsPDDS delivery of aerosolized amikacin achieved very high aminoglycoside concentrations in ELF from radiography-controlled infection-involved zones, while maintaining safe serum amikacin concentrations. The ELF concentrations always exceeded the amikacin minimum inhibitory concentrations for Gram-negative microorganisms usually responsible for these pneumonias. The clinical impact of amikacin delivery with this system remains to be determined.Trial RegistrationClinicalTrials.gov Identifier: NCT01021436.

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“…The parenteral administration of aminoglycosides in humans, however, is associated with relatively low lung concentrations of these antibiotics, and high peak serum concentrations (C max ) are needed to obtain microbiologically active concentrations in the alveoli, in the pulmonary interstitium, and intracellularly within macrophages, the most common sites of M. tuberculosis infection. In the few published clinical studies specifically evaluating alveolar lining fluid concentrations of aminoglycosides after systemic administration, alveolar concentrations ranged from 32% to 50% of the peak systemic concentration (9)(10)(11). Furthermore, preclinical studies of capreomycin pharmacokinetics in mice have shown that parenteral doses penetrate poorly into the lung (12).…”

mentioning

confidence: 99%

Phase I, Single-Dose, Dose-Escalating Study of Inhaled Dry Powder Capreomycin: a New Approach to Therapy of Drug-Resistant Tuberculosis

Dharmadhikari

Kabadi²,

Gerety³

et al. 2013

Antimicrob Agents Chemother

115

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dMultidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults (n ‫؍‬ 5 per group) were recruited to self-administer a single dose of inhaled dry powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 g/ml (MIC for Mycobacterium tuberculosis) following the highest dose; the half-life (t 1/2 ) was 4.8 ؎ 1.0 h. A novel inhaled microparticle dry powder formulation of capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen. M ultidrug-resistant tuberculosis (MDR-TB) is difficult to treat and readily spread and threatens global tuberculosis control, especially where HIV coinfection is common. According to the WHO, an estimated 440,000 new cases of MDR-TB occur each year (1, 2), but only a small fraction are receiving qualityassured treatment (1). In most public health treatment programs, 18 to 24 months of therapy with four or more second-line drugs are required. Second-line drugs are less efficacious, more toxic, and associated with treatment success rates of only 40 to 80% (1, 3-6). According to current WHO MDR-TB treatment guidelines, at least one injectable antibiotic (kanamycin, amikacin, or capreomycin) is an essential part of the 6-month intensive phase of treatment. These 3-to 7-times-per-week injections are painful for patients, especially for children and those with little muscle mass. Injections require skilled health care staff and place them at risk of needle stick injuries and infections (3). Treatment with injectable drugs is associated with systemic toxicity, including nephrotoxicity, which is typically mild and reversible, and ototoxicity, which can be significant and irreversible. Dosing must also be adjusted in individuals with preexisting renal...

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Penetration of Netilmicin in the Lower Respiratory Tract after Once-Daily Dosing

Cited by 38 publications

References 24 publications

Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates

Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia

Phase I, Single-Dose, Dose-Escalating Study of Inhaled Dry Powder Capreomycin: a New Approach to Therapy of Drug-Resistant Tuberculosis

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