In vitro evaluation of Augmentin by broth microdilution and disk diffusion susceptibility testing: regression analysis, tentative interpretive criteria, and quality control limits.

Augmentin (Beecham Laboratories, Bristol, Tenn.), a combination drug consisting of two parts amoxicillin to one part clavulanic acid and a potent beta-lactamase inhibitor, was evaluated in vitro in comparison with ampicillin or amoxicillin or both for its inhibitory and bactericidal activities against selected clinical isolates. Regression analysis was performed and tentative disk diffusion susceptibility breakpoints were determined. A multicenter performance study of the disk diffusion test was conducted with three quality control organisms to determine tentative quality control limits. All methicillin-susceptible staphylococci and Haemophilus influenzae isolates were susceptible to Augmentin, although the minimal inhibitory concentrations for beta-lactamase-producing strains of both groups were, on the average, fourfold higher than those for enzyme-negative strains. Among the Enterobacteriaceae, Augmentin exhibited significantly greater activity than did ampicillin against Klebsiella pneumoniae, Citrobacter diversus, Proteus vulgaris, and about one-third of the Escherichia coli strains tested. Bactericidal activity usually occurred at the minimal inhibitory concentration. There was a slight inoculum concentration effect on the Augmentin minimal inhibitory concentrations. On the basis of regression and error rate-bounded analyses, the suggested interpretive disk diffusion susceptibility breakpoints for Augmentin are: susceptible, greater than or equal to 18 mm; resistant, less than or equal to 13 mm (gram-negative bacilli); and susceptible, greater than or equal to 20 mm (staphylococci and H. influenzae). The use of a beta-lactamase-producing organism, such as E. coli Beecham 1532, is recommended for quality assurance of Augmentin susceptibility testing.     

Pain, depression, and fatigue as a symptom cluster in advanced cancer

Context

Pain, depression, and fatigue are common symptoms in cancer populations. They often coexist and have been suggested as a specific symptom cluster. Systemic inflammation (SI) may be a possible common mechanism.

Objective

This study examined whether pain, depression, and fatigue exist as a symptom cluster in advanced cancer patients with cachexia and might be related to the presence of SI.

Methods

Secondary data analysis was undertaken of two clinical trials in patients with cancer cachexia (n = 654). Pain, depression, and fatigue were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. Plasma C-reactive protein (CRP) was measured as a marker of SI in a subgroup (n = 436). Multivariate analysis and a series of regression analyses were undertaken relating pain, depression, fatigue, and CRP.

Results

Pain, depression, and fatigue clustered, with between two and four times as many patients having all three symptoms as would be expected if the symptoms only coexist by chance (P < 0.001). CRP was not related to the symptom cluster. There was a strong relationship between the pattern of symptoms and physical functioning (P < 0.001).

Conclusion

Pain, depression, and fatigue is an identifiable symptom cluster in a cohort of cachexic cancer patients and is associated with reduced physical functioning.     

Quantitation of basal dyssynchrony and acute resynchronization from left or biventricular pacing by novel echo-contrast variability imaging

OBJECTIVES: This study sought to test a novel echocardiographic method based on contrast variability imaging (CVI), to quantify cardiac dyssynchrony and magnitude of resynchronization achieved by left ventricular (LV) and biventricular (BiV) pacing therapy. BACKGROUND: Left ventricular or BiV pacing is a promising new therapy for patients with heart failure and intraventricular conduction delay. However, precise quantitation of the extent of resynchronization achieved remains scant. METHODS: Ten patients treated with BiV or LV pacing therapy were studied. Echo-contrast was infused slowly, and gated images were acquired before and during contrast appearance. The temporally normalized variance derived from 30 to 50 sequential beats was determined at each pixel to yield the CVI image-displaying improved wall delineation. Systolic regional fractional area of radial sectors was calculated with active and temporarily suspended (AAI) pacing. All analyses were performed blinded to both patient and treatment. RESULTS: Pacing increased septal inward motion from -20.4 +/- 9.6% to -30.5 +/- 14.0%, whereas lateral wall motion occurred earlier with no net magnitude change. Both spatial and temporal dyssynchrony in the LV declined nearly 40% with LV or BiV pacing (p < or = 0.001), and this correlated with increasing ejection fraction (31% to 39%; p < 0.02; p < 0.004 for correlation with dyssynchrony). CONCLUSIONS: The new imaging and regional dyssynchrony analysis methods provide quantitative assessment of resynchronization analogous to that previously obtained only by tagged magnetic resonance imaging. This could provide a useful noninvasive method for both identifying candidates and following long-term therapy.     

Effect of Lactobacillus rhamnosus GG Administration on Vancomycin-Resistant Enterococcus Colonization in Adults with Comorbidities

Vancomycin-resistant enterococci (VRE) are endemic in health care settings. These organisms colonize the gastrointestinal tract and can lead to infection which is associated with increased mortality. There is no treatment for VRE colonization. We conducted a randomized, double-blind, placebo-controlled clinical trial to examine the safety and efficacy of administration of the probiotic Lactobacillus rhamnosus GG (LGG) for the reduction or elimination of intestinal colonization by VRE. Colonized adults were randomized to receive LGG or placebo for 14 days. Quantitative stool cultures for LGG and VRE were collected at baseline and days 7, 14, 21, 28, and 56. Day 14 stool samples from some subjects were analyzed by quantitative PCR (qPCR) for LGG. Patients were closely monitored for adverse events. Eleven subjects, of whom 5 received LGG and 6 received placebo, were analyzed. No differences in VRE colony counts were seen at any time points between groups. No decline in colony counts was seen over time in subjects who received LGG. LGG was detected by PCR in all samples tested from subjects who received LGG but was only isolated in culture from 2 of 5 subjects in the LGG group. No treatment-related adverse events were seen. We demonstrated that LGG could be administered safely to patients with comorbidities and is recoverable in some patients'' stool cultures. Concomitant administration of antibiotics may have resulted in an inability to recover viable organisms from stool samples, but LGG DNA could still be detected by qPCR. LGG administration did not affect VRE colonization in this study. (This study was registered at Clinicaltrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00756262","term_id":"NCT00756262"}}NCT00756262.)     

The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis

Mycobacterium tuberculosis has two discrete beta-ketoacyl synthases encoded by kasA and kasB that are located in tandem within a five-gene operon that has been implicated in isoniazid-sensitivity and mycolic acid synthesis. We have developed an in vitro meromycolic acid synthase assay to elucidate the anabolic role of these enzymes. Overproduction of KasA and KasB individually and together in M. smegmatis enabled cell-free incorporation of [(14)C]malonyl-CoA into lipids whose chain length was dependent upon the M. tuberculosis elongating enzyme used. KasA specifically elongated palmitoyl-CoA to monounsaturated fatty acids that averaged 40 carbons in length. KasB hyperproduction in the presence of KasA produced longer chain multiunsaturated hydrocarbons averaging 54 carbons in length. These products comigrated with a synthetic standard of meromycolic acid and their production was sensitive to isoniazid, thiolactomycin, and triclosan. KasA mutations associated with isoniazid resistance produced an enzyme that had a diminished overall catalytic activity but conferred enhanced resistance to isoniazid. In vivo analysis confirmed that overexpression of each of the four mutant KasAs enhanced isoniazid resistance when compared to overexpression of wild-type KasA. These results suggest discrete anabolic roles for both KasA and KasB in mycolic acid synthesis and substantiate the involvement of KasA mutations in isoniazid resistance.