Cost-effectiveness of implementing routine hearing screening using a tablet audiometer for pediatric cystic fibrosis patients receiving high-dose IV aminoglycosides.

BACKGROUND: Cystic fibrosis (CF) patients who receive high-dose aminoglycosides can acquire inner ear damage and subsequent hearing loss. There is no current standard protocol for assessing ototoxicity in CF centers in the United States. OBJECTIVE: To evaluate the cost-effectiveness of a pharmacist-implemented routine hearing screening for ototoxicity among pediatric patients using a clinically validated tablet audiometer to allow for earlier detection of hearing loss in an exploratory analysis. METHODS: A Markov decision-analytic model was developed to assess the cost-effectiveness of implementing routine screening with monthly cycles over a 3-year time horizon. The model measured the difference in promptly detected hearing loss, delayed detected hearing loss, and undetected hearing loss, compared with current screening practices. Model inputs were obtained through a comprehensive literature review. Primary model outcomes included total health care costs and quality-adjusted life-years (QALYs) gained with a 3% yearly discount. One-way, two-way, and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. RESULTS: In a hypothetical cohort of 100 patients, routine screening using a tablet audiometer increased promptly detected hearing loss by 8 patients. There was an incremental gain of 3.2 QALYs at an increased cost of $333,826 compared with current screening practices. This resulted in an incremental cost-effectiveness ratio (ICER) of $103,771 per QALY. In the 1-way sensitivity analysis, the ICER ranged between $64,345 and $258,830 per QALY. CONCLUSIONS: Using a tablet audiometer for routine hearing screening appears to be a cost-effective option at a $150,000 per QALY willingness-to-pay threshold when only considering the immediate benefits gained. This analysis did not examine the long-term effects of early detection in language development for pediatric patients. DISCLOSURES: Huang reports funding from the University of North Carolina and GlaxoSmithKline Health Outcomes Fellowship. GlaxoSmithKline had no involvement in the study creation, analysis, or manuscript composition. The other authors have nothing to disclose.

Application of physiologically based pharmacokinetic modeling to predict the pharmacokinetics of telavancin in obesity with renal impairment.

PURPOSE: U.S. Food and Drug Administration (FDA) recommended telavancin dosing is based on total body weight (TBW) but lacks adjusted regimens for obese subjects with varying renal function. Our aim was to develop a physiologically based pharmacokinetic (PBPK) model of telavancin to design optimized dosing regimens for obese patients with hospital-acquired pneumonia (HAP) and varying renal function. METHODS: The PBPK model was verified using clinical pharmacokinetic (PK) data of telavancin in healthy populations with varying renal function and obese populations with normal renal function. Then, the PBPK model was applied to predict the PK in obese HAP patients with renal impairment (RI). RESULTS: The fold error values of PK parameters (AUC, Cmax, Tmax) were all within 1.5. The telavancin AUC0-inf was predicted to increase 1.07-fold in mild RI, 1.23-fold in moderate RI, 1.41-fold in severe RI, and 1.57-fold in end-stage renal disease (ESRD), compared with that in obese HAP with normal renal function. The PBPK model combined with Monte Carlo simulations (MCS) suggested that dose adjustment based on a 750-mg-fixed dose could achieve effectiveness with reduced risk of toxicity, compared with current TBW-based dosing recommendations. CONCLUSION: The PBPK simulation proposed that using TBW-based regimen in obesity with RI should be avoided. Dose recommendations in obesity from the PBPK model are 750 mg daily for normal renal function and mild RI, 610 mg daily for moderate RI, 530 mg daily for severe RI, and 480 mg daily for ESRD.

Is computer-assisted aminoglycoside dosing managed by a pharmacist a safety tool of pharmacotherapy?

This pilot prospective study verified the hypothesis that use of computer-assisted therapeutic drug monitoring of aminoglycosides by pharmacists leads to better safety therapeutic outcomes and cost avoidance than only concentration measurement and dose adjustments based on a physician's experience. Two groups of patients were enrolled according to the technique of monitoring. Patients (Group 1, n=52) underwent monitoring by a pharmacist using pharmacokinetic software. In a control group (Group 2, n=11), plasma levels were measured but not interpreted by the pharmacist, only by physicians. No statistically significant differences were found between the groups in factors influenced by therapy. However, the results are not statistically significant but a comparison of the groups showed a clear trend towards safety and cost avoidance, thus supporting therapeutic drug monitoring. Safety limits were achieved in 76 % and 63 % of cases in Groups 1 and 2, respectively. More patients achieved both concentrations (peak and trough) with falling eGFR in Group 1. In present pilot study, the pharmacist improved the care of patients on aminoglycoside therapy. A larger study is needed to demonstrate statistically significantly improved safety and cost avoidance of aminoglycoside therapy monitoring by the pharmacist using pharmacokinetic software.

Success rates, characteristics, and costs of articulating antibiotic spacers for total knee periprosthetic joint infection.

BACKGROUND: The optimal type, characteristics, and success rates of articulating antibiotic spacers used during total knee arthroplasty (TKA) periprosthetic joint infection (PJI) have not been well defined in a single series. We sought to (1) determine the success rate for three unique spacer constructs and (2) evaluate any microbiological, surgical, or patient characteristics that would influence the success rate. METHODS: We retrospectively reviewed patients who underwent a two-stage exchange for a TKA PJI with a prefabricated spacer (PREFAB), home-made mold (MOLD), or autoclaved femoral component (AUTOCL). Patient demographics, microbiology data, amount of antibiotic in each spacer construct, postoperative course, and infection cure outcomes were evaluated. RESULTS: The success rate for being infection free at final follow-up without the need for further reoperation for infection was 82.7% in the PREFAB group, 88.4% in the MOLD group, and 79.4% in the AUTOCL group (p=0.54). There was no clear statistical link between raw quantities of vancomycin and aminoglycoside in the spacer and a successful outcome. The surgeon's own intraoperatively created mold group had the lowest construct cost at a mean $1341.00±889.10 (p<0.0001) per construct, while the commercial cement molds had the highest mean cost at $5439.00±657.80 (p<0.0001). CONCLUSIONS: There was no statistically significant difference in the success rates between the antibiotic spacer types. The surgeon's own intraoperative mold had the least overall associated cost.

Appropriateness of aminoglycoside prescriptions in a French university hospital.

INTRODUCTION: Aminoglycosides are a major class of antibiotics. Their use is particularly interesting in the treatment of severe infections but their toxicity is well known. They are mostly prescribed combined with other agents and as first-line treatments. We aimed to assess the appropriateness of aminoglycoside prescriptions in a French university hospital on the basis of the latest French recommendations published in 2011. METHOD: We conducted a prospective study between January 17th and February 4th, 2014 to assess prescription modalities of aminoglycosides on the basis of the following criteria: indication, duration of treatment, dosing schedule, administration modalities, and drug level monitoring. Prescriptions were then compared to the 2011 national guidelines. RESULTS: A total of 68 consecutive prescriptions were analyzed and only 47.8% complied with guidelines. Most physicians complied with recommendations, particularly with the indication for severe infections (95.6%), the administration of a single daily dose (92.6%), and the slow intravenous infusion (30minutes) administration (84%). However, physicians tended to prescribe lower doses than recommended (40.3%), especially to patients presenting with renal insufficiency, and drug level monitoring was not optimal. CONCLUSION: Although new and accurate national recommendations were recently published, aminoglycoside prescription is still not optimal, in particular for dosing and plasma concentration monitoring.

Assessment of aminoglycoside dosing and estimated glomerular filtration rate in determining gentamicin and tobramycin area under the curve and clearance.

BACKGROUND: Aminoglycoside clearance depends on kidney function, but the Australian Therapeutic Guidelines for antibiotics (version 14, 2010) recommend initial dosing based on weight without consideration of kidney function. Other guidelines that modify dosing based on kidney function estimates often use the Cockroft-Gault equation, but the role of the estimated glomerular filtration rate equations for this purpose is unclear. AIM: To determine the performance of current guideline dosing in achieving target area-under-the-curve and examine the relative precision of the estimated glomerular filtration rate equations compared with traditional Cockroft-Gault creatinine clearance in predicting aminoglycoside clearance. METHODS: We analysed 496 aminoglycoside treatment episodes involving 1377 infusions in adult patients. Conformity with antibiotic guideline dosing was achieved if the discrepancy between prescribed and recommended dose was less than 15%. Aminoglycoside clearance was determined from linear regression using a one compartment model with the Aminoglycoside Levels and Daily Dose Indicator programme. We assessed the precision of the Cockroft-Gault, Modification of Diet in renal Disease Study and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations in predicting aminoglycoside clearance by correlation and linear regression. RESULTS: Conformity with guideline dosing was not associated with achieving target area-under-the-curve. The CKD-EPI estimated glomerular filtration rate adjusted for body surface area showed the highest correlation (gentamicin, r = 0.66; tobramycin, r = 0.82) and best predictive model for aminoglycoside clearance. CONCLUSION: Current guideline dosing may be suboptimal for achieving target area-under-the-curve. The CKD-EPI equation adjusted for patient body surface area best predicts aminoglycoside clearance, and could be evaluated as a covariate in determining initial aminoglycoside dosing.

Incidence and management of extended-spectrum beta-lactamase and quinolone-resistant Escherichia coli infections after prostate biopsy.

OBJECTIVE: To provide an overview of the incidence, bacteriologic characteristics, and antimicrobial resistance in acute prostatitis after transrectal ultrasonography (TRUS)-guided prostate biopsy. MATERIALS AND METHODS: We reviewed the medical records of 9568 patients who underwent TRUS-guided biopsy between March 1995 and May 2013. These patients received oral quinolone and/or cephalosporin and intramuscular aminoglycoside as antibiotic prophylaxis. In patients with acute prostatitis, blood and urine cultures were obtained on hospital admission. The incidences of acute prostatitis and antimicrobial resistance were examined according to time period. RESULTS: A total of 11,345 cases of TRUS-guided biopsy were performed for 9568 patients. Acute prostatitis developed in 103 patients (0.91%). In 63 patients, the causative organism was isolated from blood and/or urine culture. The most frequent etiologic organism was Escherichia coli, which was present in 47 of 49 patients (95.9%) in blood and from 39 of 41 patients (95.1%) in urine. Extended-spectrum beta-lactamase (ESBL)-producing E coli were detected continuously since 2008 and found in 10 patients (21.3%) in blood and 8 patients (20.5%) in urine. Forty-four patients (93.6%) in blood and 36 patients (92.3%) in urine of the positive cultures and all cases with ESBL-producing E coli infection showed resistance to quinolone. ESBL-producing E coli were susceptible to imipenem, amikacin, and cefoxitin. CONCLUSION: In the treatment of acute prostatitis after TRUS-guided biopsy, quinolone is not an effective antimicrobial of choice. We should take into account antimicrobial-resistant patterns because of the high prevalence of quinolone resistance and emergence of an ESBL-producing strain.

Prescribing practices for intravenous aminoglycosides in UK cystic fibrosis clinics: a questionnaire survey.

BACKGROUND: Intravenous aminoglycoside antibiotics are widely used to treat pulmonary infection with Pseudomonas aeruginosa in individuals with cystic fibrosis (CF). Over the last decade evidence has accumulated showing that the choice of aminoglycoside and the dosing regimen may help reduce adverse effects such as nephrotoxicity. METHODS: We undertook an online survey to determine current practice in UK CF Centres. RESULTS: We received a response from 35/48 (73%) centres. A once daily regimen was used in 30/35 (86%) centres. Around one third had stopped using gentamicin in the last 10 years. In most cases respondents reported changing practice in response to new evidence or evidence based guidelines. Obstacles to introducing evidence based practice were identified both at the level of the CF Centre and the hospital trust. CONCLUSIONS: A once daily aminoglycoside regimen is now used in the majority of UK CF Centres. Tobramycin is first line and many centres have stopped using gentamicin. Obstacles to evidence based practice remain in a minority of centres.

Fidaxomicin: a minimally absorbed macrocyclic antibiotic for the treatment of Clostridium difficile infections.

Fidaxomicin was approved for the treatment of Clostridium difficile infections in 2011. It has a novel mechanism of action and narrow spectrum of activity that makes it unique among the currently used therapies for this disease. Phase III clinical studies demonstrated a benefit of fidaxomicin over vancomycin for the outcomes of recurrence and global cure or sustained clinical response. This observation was confirmed within specific populations, including those of older age, immunocompromised due to active cancers, and patients taking concomitant antibiotics. Additionally, fidaxomicin significantly reduced recurrence rates compared to vancomycin among patients receiving treatment for recurrent C. difficile episodes. Fidaxomicin represents an advance in therapy for the treatment of C. difficile infections.

Cost-effectiveness analysis evaluating fidaxomicin versus oral vancomycin for the treatment of Clostridium difficile infection in the United States.

OBJECTIVES: Fidaxomicin is a novel treatment for Clostridium difficile infections (CDIs). This new treatment, however, is associated with a higher acquisition cost compared with alternatives. The objective of this study was to evaluate the cost-effectiveness of fidaxomicin or oral vancomycin for the treatment of CDIs. METHODS: We performed a cost-utility analysis comparing fidaxomicin with oral vancomycin for the treatment of CDIs in the United States by creating a decision analytic model from the third-party payer perspective. RESULTS: The incremental cost-effectiveness ratio with fidaxomicin compared with oral vancomycin was $67,576/quality-adjusted life-year. A probabilistic Monte Carlo sensitivity analysis showed that fidaxomicin had an 80.2% chance of being cost-effective at a willingness-to-pay threshold of $100,000/quality-adjusted life-year. Fidaxomicin remained cost-effective under all fluctuations of both fidaxomicin and oral vancomycin costs. The decision analytic model was sensitive to variations in clinical cure and recurrence rates. Secondary analyses revealed that fidaxomicin was cost-effective in patients receiving concominant antimicrobials, in patients with mild to moderate CDIs, and when compared with oral metronidazole in patients with mild to moderate disease. Fidaxomicin was dominated by oral vancomycin if CDI was caused by the NAP1/Bl/027 Clostridium difficile strain and was dominant in institutions that did not compound oral vancomycin. CONCLUSION: Results of our model showed that fidaxomicin may be a more cost-effective option for the treatment of CDIs when compared with oral vancomycin under most scenarios tested.

Impurity profiling of micronomicin sulfate injection by liquid chromatography-ion trap mass spectrometry.

The characterization of impurities present in micronomicin sulfate injection by liquid chromatography (LC) coupled with mass spectrometry (MS) is described. A reversed phase (RP)-LC method using a C18 column resistant to an alkaline (pH 11) aqueous mobile phase was developed and coupled to MS with an electrospray ionization (ESI) source in the positive ion mode which provides MS(n) capability. A total of thirty six impurities were detected in commercial samples: five impurities were identified by comparison of their fragmentation patterns with those of available related substances, eleven of them were identified in accordance with relevant literature, while the other twenty impurities were newly identified using the MS/MS spectra of the available related reference substances as interpretative templates combined with knowledge of the nature of functional group fragmentation behaviors. This work was applied to evaluate the quality of micronomicin sulfate injection from different manufacturers.

Fidaxomicin: the newest addition to the armamentarium against Clostridium difficile infections.

BACKGROUND: Fidaxomicin, a macrolide antibiotic, was the first medication for the management of Clostridium difficile infections (CDI) to be approved by the US Food and Drug Administration in more than 20 years. OBJECTIVE: This article reviews published literature on fidaxomicin for management of CDI, including its chemistry, spectrum of activity, pharmacokinetic properties, pharmacodynamics, therapeutic efficacy, adverse events, dosing, administration, and pharmacoeconomic considerations. METHODS: Pertinent English-language literature was reviewed through searches of MEDLINE, EMBASE, and BIOSIS from 1975 through September 2011. Reference lists of identified publications and published abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy meetings were also reviewed. Search terms included, but were not limited to, fidaxomicin, difimicin, lipiarmycin, tiacumicin B, OPT-80, Clostridium spp, and diarrhea. RESULTS: A total of 79 publications were identified and 10 were excluded; 6 review articles and 4 abstracts that were later published as articles. Fidaxomicin's in vitro profile is favorable compared with oral metronidazole and vancomycin, with minimum inhibitory concentrations against C difficile that are 2 dilutions lower. From the 2 published Phase III trials, fidaxomicin was deemed to be noninferior in the treatment of mild to moderate CDI compared with oral vancomycin. Recurrence rates for all strains of CDI were lower with fidaxomicin than vancomycin. Adverse events associated with fidaxomicin were similar to placebo, with nausea and vomiting being the most common. Although no pharmacoeconomic studies have compared fidaxomicin with metronidazole or vancomycin, the current price exceeds $2500 (US) per treatment course. CONCLUSIONS: Reports suggest that fidaxomicin is noninferior to oral vancomycin in the treatment of mild or moderate CDI, although no published comparisons with metronidazole exist to date. Additionally, fidaxomicin improved outcomes compared with oral vancomycin in terms of rates of relapse and recurrent CDI, and in patients who might require concomitant antibiotics. Prospective, randomized studies comparing fidaxomicin with metronidazole in the treatment of mild or moderate CDI, as well as against vancomycin for severe CDI, should be undertaken to clarify the exact role of fidaxomicin in clinical practice.

An information campaign on aminoglycosides use during septic shock failed to improve the quality of care.

BACKGROUND: Septic shock remains a major cause of death in intensive care units (ICU) and an inappropriate antibiotic regimen worsens the prognosis. The aim of the study was to assess the impact of an information campaign on modalities of prescription of aminoglycosides in septic shock. STUDY DESIGN: A prospective observational study. METHODS: Consecutive septic shock patients admitted to the surgical ICU over a 2-year period were included. An information campaign allowed to differentiate between a pre- (P1) and a post- (P2) interventional period. The campaign clarified the rules and requirements for pharmacological monitoring of aminoglycosides. The main objective was to increase the rate of prescription of peak serum aminoglycoside following the first intravenous injection. RESULTS: One hundred and forty-eight patients (P1=76 and P2=72) were finally included into the study. Similar clinical characteristics were observed during both periods. The rate of prescription of peak serum aminoglycoside following the first injection was performed in 49% (P1) versus 65% (P2), P=0.09. The length of stay in ICU was 16 days [extremes: 1-74] (P1) versus 17 days [extremes: 1-133] (P2) (P=0.84). Inhospital mortality was 28% (P1) versus 26% (P2), P=0.86. CONCLUSIONS: An information campaign describing the modalities of prescription of aminoglycosides in septic shock failed to improve medical practices and patient outcomes. A mobile team of antibiotics could be useful in daily practice.

Applicability of a "Pick a Winner" trial design to acute myeloid leukemia.

Randomized clinical trials remain the gold standard to establish efficacy and safety of new treatments. In acute myeloid leukemia, large trials have been associated with gradual improvement in outcome over 2 decades in younger patients without major differences emerging between treatments. By contrast, in older patients, improvement has been minimal, which justifies a new approach to identifying effective treatments. Given the urgent unmet need, and with the emergence of several novel agents or combinations that are likely to be expensive, large benefits are probably required to change clinical practice. To address this issue, we have evolved a "Pick a Winner" randomized progressive design with a rolling incorporation of novel treatments (drug X), which has been tested in older patients with acute myeloid leukemia. The rationale, operational characteristics, and initial experience of such an approach in the context of the United Kingdom National Cancer Research Institute AML16 trial are presented.

[Level of evidence for therapeutic drug monitoring of aminoglycosides]. / Niveau de preuve du suivi thérapeutique pharmacologique des aminosides.

Aminoglycosides are major antibiotics indicated for the treatment of infection with gram-negative bacilli. They are characterized by high clinical effectiveness but their main drawback is the occurrence of toxicity in a significant number of patients. Pharmacokinetic parameters of aminoglycosides exhibit wide inter-individual variability and the relationships between concentration and effect have been clearly demonstrated. Consistent studies have demonstrated that therapeutic drug monitoring (TDM) of aminoglycosides administered in multiple daily doses was cost-effective in maximising antibiotic efficacy and/or reducing incidence of toxicity. Therefore TDM of aminoglycosides should be considered "essential". Level of evidence for TDM of aminoglycosides administered once daily is not so clearly demonstrated however it should be highly recommended.

[Quality of antibiotic (fluoroquinolons, aminosids and amoxicillin-clavulanic acid) prescription in a French teaching hospital]. / Qualité des prescriptions antibiotiques (fluoroquinolones, aminosides et amoxicilline-acide clavulanique); évaluation dans les secteurs de médecine d'un centre hospitalier universitaire.

OBJECTIVES: To assess the quality of prescription of fluoroquinolons, aminosids and amoxicillin-clavulanic acids in medicine departments. METHODS: Data on target antibiotic prescription were collected on a given day and confronted to local recommendations and literature guidelines. Evaluation of antibiotic therapy was done by assessing molecule choice, administration conditions (dosages, route and administration schedule, treatment duration), reassessment of treatments 48-72 h later, dose adaptation of aminosids depending on serum monitoring. RESULTS: Sixty-three patients were included and 67 "target" antibiotics were prescribed. Prevalence of antibiotic-treated patients was 24.4%, and 14.6% for "target" antibiotic-treated patients. Antibiotic choice was appropriate in 67% of prescriptions. Dosages were adequates in 94% of case and administration schedule in 97% of cases. The oral route administration as soon as possible was applied to half of patients. Treatment duration were respected for 94% of prescriptions. Reassessment of antibiotic therapy 48-72 h later was realized in 66% of cases. Dose adaptation of aminosids, when necessary, was realized on one third of cases. For all the quality criteria assessed, the overall frequency of prescription conformity was 44%. CONCLUSION: Large diffusion of protocols, systematic reassessment of treatments at 48-72 h, promotion of training sessions for new prescribers in the institution, reinforcing the function of medical correspondents in antibiotic therapy and infectiologists, periodic evaluation of antibiotic therapy, should improve the quality of antibiotic therapy.

Impact of aminoglycoside cycling in six tertiary intensive care units: prospective longitudinal interventional study.

AIM: To determine the effect of aminoglycoside cycling in six tertiary intensive care units (ICU) on the rates of sepsis, aminoglycoside resistance patterns, antibiotic consumption, and costs. METHODS: This was a prospective longitudinal interventional study that measured the effect of change from first-line gentamicin usage (February 2002-February 2003) to amikacin usage (February 2003-February 2004) on the aminoglycoside resistance patterns, number of patients with gram-negative bacteremia, consumption of antibiotics, and the cost of antimicrobial drugs in 6 tertiary care ICUs in Zagreb, Croatia. RESULTS: The change from first-line gentamicin to amikacin usage led to a decrease in the overall gentamicin resistance of gram-negative bacteria (GNB) from 42% to 26% (P<0.001; z-test of proportions) and netilmicin resistance from 33% to 20% (P<0.001), but amikacin resistance did not change significantly (P=0.462), except for Acinetobacter baumanni (P=0.014). Sepsis rate in ICUs was reduced from 3.6% to 2.2% (P<0.001; chi(2) test), with a decline in the number of nosocomial bloodstream infections from 55/100 patient-days to 26/100 patient-days (P=0.001, chi(2) test). Furthermore, amikacin use led to a 16% decrease in the overall antibiotic consumption and 0.1 euro/patient/d cost reduction. CONCLUSION: Exclusive use of amikacin significantly reduced the resistance of GNB isolates to gentamicin and netilmicin, the number of GNB nosocomial bacteremias, and the cost of total antibiotic usage in ICUs.

Telavancin penetration into human epithelial lining fluid determined by population pharmacokinetic modeling and Monte Carlo simulation.

Telavancin is an investigational bactericidal lipoglycopeptide with a multifunctional mechanism of action, as demonstrated against methicillin-resistant Staphylococcus aureus. While the plasma pharmacokinetics have been described, the extent of the penetration of the drug into the lung, measured by the epithelial lining fluid (ELF), remains unknown. Population modeling and Monte Carlo simulation were employed to estimate the penetration of telavancin into ELF. Plasma and ELF pharmacokinetic data were obtained from 20 healthy volunteers, and the pharmacokinetic samples were assayed by a validated liquid chromatography-tandem mass spectrometry technique. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified in a population pharmacokinetic analysis (BigNPAG). Monte Carlo simulation of 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) for the drug in ELF (AUC(ELF)) and for the free drug in plasma (free AUC(plasma)) from zero to infinity after a single dose. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations in plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. The median AUC(ELF)/free AUC(plasma) penetration ratio was 0.73, and the 25th and 75th percentile value ratios were 0.43 and 1.24, respectively. In uninfected lung tissue, the median AUC(ELF) is approximately 75% of the free AUC(plasma).