SUMMARYGram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects,in vitroand microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena.

The steady-state concentrations of meropenem and the ␤-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ؎ the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows: C max ‫؍‬ 58.2 ؎ 10.8 and 59.0 ؎ 8.4 g/ml, V ss ‫؍‬ 16.3 ؎ 2.6 and 17.6 ؎ 2.6 liters; CL ‫؍‬ 11.1 ؎ 2.1 and 10.1 ؎ 1.9 liters/h, and t 1/2 ‫؍‬ 1.03 ؎ 0.15 and 1.27 ؎ 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC 0 -8 ) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 g/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.

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Lysinibacillus and Paenibacillus are pervasive bacteria rarely associated with human disease. Less sophisticated microbiology techniques may frequently incorrectly identify these genera as Bacillus spp., often regarded as environmental contamination. This report describes a case of severe sepsis due to persistent Lysinibacillus and Paenibacillus bacteremia, identified by matrix-assisted laser desorption and ionization time-of-flight mass spectroscopy and 16S rRNA gene sequencing.

The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1-h i.v. infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 h after dosing. The mean pharmacokinetic parameters Ϯ standard deviations of fosfomycin in plasma after 1 g and 8 g i.v., respectively, were the following: maximum clearance of drug in serum (C max ), 44.3 Ϯ 7.6 and 370 Ϯ 61.9 g/ml; time to maximum concentration of drug in serum (T max ), 1.1 Ϯ 0.05 and 1.08 Ϯ 0.01 h; volume of distribution (V), 29.7 Ϯ 5.7 and 31.5 Ϯ 10.4 liters; clearance (CL), 8.7 Ϯ 1.7 and 7.8 Ϯ 1.4 liters/h; renal clearance (CL R ), 6.6 Ϯ 1.9 and 6.3 Ϯ 1.6 liters/h; area under the concentrationtime curve from 0 to infinity (AUC 0 -∞ ), 120 Ϯ 28.5 and 1,060 Ϯ 192 g·h/ml; and half-life (t 1/2 ), 2.4 Ϯ 0.4 and 2.8 Ϯ 0.6 h. After oral administration, the parameters were the following: C max , 26.8 Ϯ 6.4 g/ml; T max , 2.25 Ϯ 0.4 h; V/F, 204 Ϯ 70.7 liters; CL/F, 17 Ϯ 4.7 liters/h; CL R , 6.5 Ϯ 1.8 liters/h; AUC 0 -∞ , 191 Ϯ 57.6 g · h/ml; and t 1/2 , 9.04 Ϯ 4.5 h. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1-g i.v. dose. Approximately 74% and 80% of the 1-g and 8-g i.v. doses were excreted unchanged in the urine by 48 h compared to 37% after oral administration, with the majority of this excretion occurring by 12 h regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of i.v. fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.