Penetration of Anti-Infective Agents into PulmonaryEpithelial Lining Fluid

Abstract

Epithelial lining fluid (ELF) is often considered to be the site of extracellular pulmonary infections. During the past 25 years, a limited number of studies have evaluated the intrapulmonary penetration of antifungal, antitubercular, antiparasitic and antiviral agents. For antifungal agents, differences in drug concentrations in ELF or bronchoalveolar lavage (BAL) fluid were observed among various formulations or routes of administration, and between agents within the same class. Aerosolized doses of deoxycholate amphotericin B, liposomal amphotericin B and amphotericin B lipid complex resulted in higher concentrations in ELF or BAL fluid than after intravenous administration. The mean concentrations in ELF following intravenous administration of both anidulafungin and micafungin ranged between 0.04 and 1.38 μg/mL, and the ELF to plasma concentration ratios (based on the area under the concentration-time curve for total drug concentrations) were between 0.18 and 0.22 during the first 3 days of therapy. Among the azole agents, intravenous administration of voriconazole resulted in the highest mean ELF concentrations (range 10.1-48.3 μg/mL) and ratio of penetration (7.1). The range of mean ELF concentrations of itraconazole and posaconazole following oral administration was 0.2-1.9 μg/mL, and the ELF to plasma concentration ratios were <1. A series of studies have evaluated the intrapulmonary penetration of first- and second-line oral antitubercular agents in healthy adult subjects and patients with AIDS. The ELF to plasma concentration ratio was >1 for isoniazid, ethambutol, pyrazinamide and ethionamide. For rifampicin (rifampin) and rifapentine, the ELF to plasma concentration ratio ranged between 0.2 and 0.32, but in alveolar macrophages the concentration of rifampicin was much higher (145-738 μg/mL compared with 3.3-7.5 μg/mL in ELF). No intrapulmonary studies have been conducted for rifabutin. Sex, AIDS status or smoking history had no significant effects on the magnitude of ELF concentrations of antitubercular agents. Subjects who were slow acetylators had higher plasma and ELF concentrations of isoniazid than those who were fast acetylators. Penetration of dapsone into ELF was very good, with the range of mean ELF to plasma concentration ratios being 0.65-2.91 at individual sampling times over 48 hours. Once-daily dosing of aerosolized pentamidine resulted in higher concentrations in BAL fluid than after intravenous administration. The mean BAL concentrations at 15-32 days after once- or twice-monthly administration of aerosolized pentamidine 300 and 600 mg ranged from 6.5 to 28.4 ng/mL. No differences in pentamidine BAL concentrations were observed in symptomatic patients who developed Pneumocystis jirovecii pneumonia compared with patients who did not. Zanamivir concentrations in ELF were similar in magnitude (range 141-326 ng/mL) following administration by continuous intravenous infusion (3 mg/hour), oral inhalation (10 mg every 12 hours) and intravenous bolus (200 mg every 12 hours). Data from case rep...

Amikacin in Critically Ill Patients: A Review of Population Pharmacokinetic Studies

“…With regard to the pulmonary system, pneumonia is the most common infection in critically ill patients and is an important cause of morbidity and mortality in ICU patients [32]. The antibiotic concentration in epithelial lining fluid may determine therapeutic success [33]. For hydrophilic antibiotics, such as amikacin, some authors suggest that higher doses should be used in patients with severe nosocomial pneumonia to optimize epithelial lining fluid concentrations [34,35].…”

Tissue Penetration of Antifungal Agents

“…(ii) physiological factors, such as inflammation, which may increase tissue permeability, i.e., by disruption of normal physiological barriers such as the blood-brain barrier (29,40); the underlying disease (41), which may result in a range of effects, including modification of plasma protein composition and hence drug binding (42,43,44); the recruitment of drug-containing phagocytic cells, i.e., the "dump truck phenomenon," which may increase drug concentrations at the site of infection (12,13,32,45,46); drug export via pumps, e.g., for itraconazole and P-glycopro- Fluid multiples are from g/ml concentrations. *, autopsy data; in these cases, the multiples are based on plasma C max values at the same dose in volunteers (188).…”

“…The inhalation of aerosolized amphotericin B formulations is a potential option for prophylaxis (133,134,135). Antifungal drug concentrations within ELF after aerosol inhalation or systemic administration were recently reviewed (12). However, for treatment of established invasive infections, drug concentrations in the lung parenchyma may be more relevant (Fig.…”

“…Penetration into the site of infection to achieve microbe-eliminating concentrations is a key requirement for efficacy of all antimicrobial agents (11,12,13,14,15). The importance of tissue concentrations for the various classes of antibacterial agents has been reviewed extensively, but relatively less attention has been paid to the currently available antifungal agents (12,16,17,18,19).…”

“…The importance of tissue concentrations for the various classes of antibacterial agents has been reviewed extensively, but relatively less attention has been paid to the currently available antifungal agents (12,16,17,18,19). This review examines the tissue penetration of 11 commonly used systemic antifungal agents (amphotericin B deoxycholate [AmBd], amphotericin B lipid complex [ABLC], liposomal amphotericin B [L-AMB], fluconazole, itraconazole, posaconazole, voriconazole, 5-fluorocytosine [5FC], anidulafungin, caspofungin, and micafungin) into the clinically relevant compartments for human infection and disease.…”