We compared drugs (imipenem and doripenem), doses (500 mg and 1 g), and infusion times (0.5 and 1.0 [imipenem], 1.0 and 4.0 h [doripenem]) in our hollow-fiber model, examining cell kill and resistance suppression for three isogenic strains of Pseudomonas aeruginosa PAO1. The experiments ran for 10 days. Serial samples were taken for total organism and resistant subpopulation counts. Drug concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry (LC/MS/MS). Free time above the MIC (time > MIC) was calculated using ADAPT II. Time to resistance emergence was examined with Cox modeling. Cell kill and resistance emergence differences were explained, in the main, by differences in potency (MIC) between doripenem and imipenem. Prolonged infusion increased free drug time > MIC and improved cell kill. For resistance suppression, the 1-g, 4-h infusion was able to completely suppress resistance for the full period of observation for the wild-type isolate. For the mutants, control was ultimately lost, but in all cases, this was the best regimen. Doripenem gave longer free time > MIC than imipenem and, therefore, better cell kill and resistance suppression. For the wild-type organism, the 1-g, 4-h infusion regimen is preferred. For organisms with resistance mutations, larger doses or addition of a second drug should be studied.Pseudomonas aeruginosa continues to be a major problem in the nosocomial setting. Increasing rates of resistance make the development of effective therapeutic regimens problematic.Doripenem is a new carbapenem antibiotic with potent activity against Pseudomonas aeruginosa. Preclinical studies have indicated that it is highly stable to the AmpC enzyme seen in this pathogen and that it interacts differently with the pathogen regarding oprD downregulation, resulting in lower MIC shifts, in at least 50% of instances (6). Clinically, the use of the prolonged infusion has been shown to have a salutary impact on Pseudomonas resistance emergence during therapy, relative to the impact of imipenem (1). We chose to study imipenem because the doripenem clinical trial program employed imipenem as a comparator, as meropenem does not have the breadth of FDA indications present for imipenem (e.g., nosocomial pneumonia).Previous work from our group has shown that the use of prolonged infusion optimizes time above the MIC (time Ͼ MIC) target attainment and may have an impact on resistance emergence (3, 10). This leads to four major factors requiring exploration: (i) drug (potency), (ii) dose, (iii) infusion schedule, and (iv) differences in mechanism of resistance between drugs.In order to ascertain the contribution of each, we decided to study three different isogenic isolates: a wild-type isolate (PAO1), an isolate with a stably derepressed chromosomal AmpC enzyme (AmpC ␤-lactamase production is markedly increased when a mutation in the repressor system occurs, and the increase is stable and not dependent upon the presence or absence of drug), and an isolate with a defined downregu...

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The upper lateral cartilage articulates laterally with the frontal process of the maxilla by means of the pyriform ligament, with a variable amount of overlap between the upper lateral cartilage and maxilla. Relationships among the upper lateral cartilage, maxilla, and pyriform ligament affect the configuration of the lateral internal nasal valve area, and should be considered when planning internal nasal valve reconstruction.

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A growing evidence base has implicated immune dysfunction in the etiology of some cases of autism spectrum disorder. The precise relationship between immune disorders and autism spectrum disorder remains unclear. Herein we report a 14-year-old-male with agammaglobulinemia, who was diagnosed with autism spectrum disorder, and who has received exogenous immunoglobulins regularly for most of his life. This case study supports current theories implicating antibody deficiencies in some individuals with an autism spectrum disorder. Our case will add to the growing literature of understanding the connection between immune deficiencies in the pathogenesis of autism.