Penetration of biofilm and targeted, sustained release from liposomes can explain the superior in vivo efficacy of inhaled liposomal amikacin versus free drug observed in a 14 day infection model. Inhaled liposomal amikacin may represent an important therapy for chronic lung infections.

We evaluated the molecular mechanism for resistance of 360 enterococci for which the gentamicin MICs were >128 g/ml. The aac(6)-Ie-aph(2؆)-Ia, aph(2؆)-Ic, and aph(2؆)-Id genes were identified by PCR in isolates from animals, food, and humans. The aph(2؆)-Ib gene was not identified in any of the isolates. Two Enterococcus faecalis isolates (MICs > 1,024 g/ml) from animals failed to generate a PCR product for any of the genes tested and likely contain a new unidentified aminoglycoside resistance gene. Pulsed-field gel electrophoresis (PFGE) analysis showed a diversity of strains. However, 1 human and 18 pork E. faecalis isolates from Michigan with the aac(6)-Ie-aph(2؆)-Ia gene had related PFGE patterns and 2 E. faecalis isolates from Oregon (1 human and 1 grocery store chicken isolate) had indistinguishable PFGE patterns. We found that when a gentamicin-resistant gene was present in resistant enterococci from animals, that gene was also present in enterococci isolated from food products of the same animal species. Although these data indicate much diversity among gentamicin-resistant enterococci, the data also suggest similarities in gentamicin resistance among enterococci isolated from humans, retail food, and farm animals from geographically diverse areas and provide evidence of the spread of gentamicin-resistant enterococci from animals to humans through the food supply.

Quinupristin-dalfopristin-resistant E. faecium contaminates a large proportion of chickens sold in U.S. supermarkets. However, the low prevalence and low level of resistance of these strains in human stool specimens suggest that the use of virginiamycin in animals has not yet had a substantial influence. Foodborne dissemination of resistance may increase, however, as the clinical use of quinupristin-dalfopristin increases.

The pharmacokinetics and pharmacodynamics of a novel liposomal amikacin for inhalation were evaluated in cystic fibrosis patients with chronic pseudomonas infection. Twenty-four patients from two studies received 500 mg of liposomal amikacin by inhalation once daily for 14 days. Serum, sputum, and 24-h urine samples were collected on days 1 and 14 of therapy; pulmonary function tests (PFT) and sputum for quantitative microbiology were assessed at baseline and serially for 14 days. Relationships between amikacin exposure in serum and sputum and absolute change in PFT endpoints and log 10 CFU of Pseudomonas aeruginosa from baseline on days 7 and 14 of therapy were assessed. On days 7 and 14, absolute change from baseline in forced expiratory volume in 1 s (FEV 1 ), percent predicted forced expiratory volume in 1 s (FEV 1 % predicted), and forced expiratory flow between 25 and 75% of forced vital capacity (FEF 25-75% ) increased by 0.24 (P ‫؍‬ 0.002) and 0.13 (P ‫؍‬ 0.10) liters, 7.49 (P < 0.001) and 4.38 (P ‫؍‬ 0.03), and 0.49 (P < 0.001) and 0.42 (P ‫؍‬ 0.02) liters/s, respectively. In addition, relative change from baseline in FEV 1 % predicted was 10.8% (P < 0.001) and 5.62% (P ‫؍‬ 0.073) on days 7 and 14, respectively. While significant relationships between absolute change in PFT endpoints and the ratio of serum or sputum area under the concentration-time curve to the MIC (AUC/MIC) were not observed, relationships between change in log 10 CFU and serum AUC/MIC ratio and change in log 10 CFU and absolute changes in all PFT endpoints were significant. Together, these findings likely represent drug effect and warrant the further development of liposomal amikacin for inhalation.

9525 Background: Pulmonary relapse is the most common site of relapse for patients with osteosarcoma (OS). Few therapeutic options are available for these patients. By encapsulating the drug within liposomes, sustained release lipid inhalation targeting (SLIT) cisplatin is a novel sustained-release formulation of cisplatin designed for administration via inhalation, thereby targeting the lungs with little systemic exposure. Methods: A two-center, open-label, phase Ib/IIa study was designed to characterize the safety and efficacy of SLIT cisplatin in patients with OS metastatic to the lung. Two dose levels were utilized: 24 mg/m2/dose, and 36 mg/m2/dose. Study drug was administered via nebulizer once every two weeks. OS patients with only pulmonary relapse were eligible. Toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Response was evaluated radiographically according to the World Health Organization criteria after every 2 cycles. When clinically indicated, metastasectomy was undertaken in patients on study after 2 cycles, and levels of SLIT cisplatin were measured in tumor samples upon metastasectomy. Results: Fourteen patients have been treated on study. SLIT cisplatin has been well tolerated in heavily pre-treated patients who have received multiple cycles of therapy, including one patient, approaching cumulative doses of 840 mg of SLIT cisplatin over one year and a second patient receiving 1,020 mg. Specifically, no patients have experienced hematologic toxicity, nephrotoxicity or peripheral neuropathy. Nausea (= grade 3) was attributed to study drug in 5 patients. Respiratory symptoms (= grade 3) were attributable to study drug in 4 patients. No adverse events required discontinuation of study drug. Two patients are pulmonary disease free one year after initiation of therapy. Conclusions: SLIT cisplatin is well tolerated in patients with pulmonary relapse of OS. Two of 14 patients are pulmonary disease free one year after initiation of therapy. SLIT cisplatin provides a novel therapeutic modality for patients with pulmonary relapse of OS, and warrants further study. No significant financial relationships to disclose.