Clinical characteristics and outcomes of diabetic patients with Staphylococcus aureus bacteremia and endocarditis.

The complications from S. aureus bacteremia (SAB) and infective endocarditis (SAIE) are higher in patients with diabetes. We summarize the characteristics and outcome of diabetic patients enrolled in a multicenter trial of daptomycin vs. standard therapy for SAB and SAIE. Adult patients with SAB were randomized to daptomycin 6 mg/kg/day or standard therapy (vancomycin 1 g every 12 h or antistaphylococcal penicillin 2 g every 4 h, both with gentamicin 1 mg/kg every 8 h for 4 days). Clinical success was defined as survival, resolution of S. aureus infection, and clinical outcome of cure or improved 6 weeks after end of therapy. Diabetic patients (86/235) were older, more overweight, and were more likely to present with systemic inflammatory response syndrome (SIRS) and to have complicated SAB. Clinical success rates were similar (67.4% in diabetics and 70.5% in non-diabetics). The mortality rate was significantly higher among diabetic patients (22.1% vs. 11.4%, p = 0.038). In the diabetes subgroup, the clinical success and mortality rates were comparable between the daptomycin and the standard therapy arms. The presence of diabetes is associated with significantly higher mortality in patients with SAB and SAIE. Daptomycin is an alternative therapeutic option in diabetic patients with these serious staphylococcal infections.

Outcomes with daptomycin versus standard therapy for osteoarticular infections associated with Staphylococcus aureus bacteraemia.

OBJECTIVES: To evaluate the clinical characteristics, treatment and outcomes of patients with osteoarticular infections (OAIs) associated with Staphylococcus aureus bacteraemia (SAB). METHODS: The clinical characteristics and outcomes for patients with OAI were described using a post hoc analysis of an open label, randomized trial comparing daptomycin with standard therapy (vancomycin or anti-staphylococcal penicillin with initial gentamicin) for the treatment of SAB. RESULTS: OAI occurred in 32 of 121 patients (21 daptomycin and 11 standard therapy) with complicated SAB (18 septic arthritis, 9 vertebral osteomyelitis and 7 others). Two patients had osteomyelitis in more than one site. Success rates seen in two groups were as follows: vertebral osteomyelitis [3/5 (60%) daptomycin versus 0/2 (0%) comparator], septic arthritis [7/11 (64%) versus 3/5 (60%)], sternal osteomyelitis [3/3 (100%) versus 1/2 (50%)] and long bone osteomyelitis [0/1 (0%) versus 1/1 (100%)]. Success rates in both treatment groups improved with surgical therapy. Creatine phosphokinase elevations to >500 IU/L occurred in one patient on daptomycin who discontinued therapy, whereas renal impairment developed in three patients on standard therapy, two of whom discontinued therapy. Two patients treated with daptomycin and one patient on vancomycin had increases in S. aureus MICs to daptomycin and vancomycin, respectively. Three patients treated with daptomycin died following completion of therapy, with mortality attributed to multiple co-morbid conditions and inadequate debridement of OAIs in these patients. No deaths were reported in the standard therapy group. CONCLUSIONS: Daptomycin may be considered an alternative to standard therapy in the treatment of patients with complicated SAB and OAI.

Transcriptional and translational expression kinetics of the UL25 homologue of bovine herpesvirus 1.1.

We investigated whether the bovine herpesvirus 1.1 (BHV1) ORF, a homologue of the herpes simplex virus 1 (HSV1) UL25 gene, represented a functional gene. The BHV1 UL25 ORF, which is located at positions 60602<--62398 of the viral genome, generated a 4.5 kb transcript accumulating at low abundance as soon as 3 hours p.i. after which the levels increased up to 12h p.i. and remained constant up to 24 hours p.i. In addition, UL25 transcription initiated at 303 bases upstream from the translation initiation codon, corresponding to 26 and 354 b downstream from putative TATA and CAAT boxes, respectively, thus providing evidence that these elements function as the UL25 promoter. Western blotting of BHV1-infected cell lysates, using a BHV1-UL25 specific antiserum generated against a T7-Tag/UL25 fusion recombinant protein expressed in E. coli, detected a 63 kDa protein of the expected size (63,083 Da) whose expression profile followed that of its transcript. The synthesis of the 63 kDa protein was abrogated by a DNA synthesis inhibitor, unambiguously demonstrating that the viral specific protein expressed from the BHV1 UL25 ORF belongs to the gamma2 class.

Chloramphenicol treatment for vancomycin-resistant Enterococcus faecium bacteremia.

OBJECTIVE: To evaluate the results of treating vancomycin-resistant Enterococcus faecium (VREF) bacteremia with chloramphenicol. METHODS: We retrospectively reviewed the charts of all adult patients with VREF bacteremia treated with chloramphenicol during the calendar year 1998 at a 522-bed tertiary referral center in New York City. Patients were identified by reviewing microbiology laboratory records. Patients with clinically significant VREF bacteremia who received chloramphenicol for at least 48 h were included in the study. Clinical and microbiological outcomes were determined. Microbiological and molecular tests were performed on a small representative sample of isolates to identify the presence of resistance mechanisms and to look for similarity among the isolates. RESULTS: Seven episodes of significant VREF bacteremia occurred in six patients. Mean age was 54 years. All patients had cancer and three had severe neutropenia. Five of seven episodes were associated with chronic indwelling devices, but in only one of these cases was the device removed. All isolates were susceptible to chloramphenicol in vitro. All six microbiologically evaluable episodes had a favorable response to chloramphenicol treatment, and four of seven (57%) clinically evaluable episodes had favorable outcomes. Only one death may have been due to VREF bacteremia, so the maximal attributable mortality was 14%. The three representative samples that were tested further were indistinguishable from one another and they displayed no evidence of resistance mechanisms. CONCLUSIONS: In a cohort of severely ill cancer patients, chloramphenicol was effective in treating VREF bacteremia. The use of chloramphenicol should be considered in treating infections with this highly resistant organism, where therapeutic options are limited.

Cyclic loading of rotator cuff repairs: A comparison of bioabsorbable tacks with metal suture anchors and transosseous sutures.

PURPOSE: The purposes of the study were (1) to compare rotator cuff repair strengths after cyclic loading of 2 bioabsorbable nonsuture-based tack-type anchors, transosseous sutures, and a metal suture-based anchor, and (2) to correlate bone mineral density with mode of failure and cycles to failure. We hypothesized that specimens with a lower bone density would fail through bone at a lower number of cycles independent of the method of cuff fixation. TYPE OF STUDY: Ex vivo biomechanical study. METHODS: Standardized full-thickness rotator cuff defects were created in 30 fresh-frozen cadaveric shoulders that were randomized to 1 of 4 repair groups: transosseous sutures; Mitek Super suture anchors (Mitek Surgical Products, Westwood, MA); smooth bioabsorbable 8-mm Suretacs (Acufex, Smith & Nephew Endoscopy, Mansfield, MA); or spiked bioabsorbable 8-mm Suretacs (Acufex). All repairs were cyclically loaded from 10 to 180 N; the numbers of cycles to 50% (gap, 5 mm) and 100% (gap, 10 mm) failure were recorded. RESULTS: In comparing the repair groups, we found only 1 significant difference: the number of cycles to 100% failure was significantly higher (P <.05) for the smooth bioabsorbable tack than for the transosseous suture group. There were no statistically significant (P

In vivo activity of evernimicin (SCH 27899) against methicillin-resistant Staphylococcus aureus in experimental infective endocarditis.

Currently, there exist few satisfactory alternatives to vancomycin for therapy of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. We employed a rat model of aortic valve endocarditis to assess the potential efficacy of evernimicin (SCH 27899) compared with vancomycin against infection with a strain susceptible to both agents (MICs of 0.25 and 0.50 microg/ml, respectively). Infected animals were assigned to one of three groups: controls (no treatment), evernimicin at 60 mg/kg of body weight by intravenous (i.v.) infusion once daily, or vancomycin at 150 mg/kg of body weight per day by continuous i.v. infusion. Therapy was administered for 5.5 days. At the start of therapy, colony counts in vegetations were 6.63 +/- 0.44 log(10) CFU/g. In both treatment groups, bacterial density within vegetations was significantly reduced in comparison with control animals that had not been treated. Final colony counts were as follows (mean +/- standard deviation): controls, 10.12 +/- 1.51 log(10) CFU/g of vegetation; evernimicin, 7.22 +/- 2.91 log(10) CFU/g of vegetation; vancomycin, 5.65 +/- 1.76 log(10) CFU/g of vegetation. The difference between the evernimicin and vancomycin groups was not significant. These results confirmed the bacteriostatic activity of evernimicin in vivo in an experimental model of severe MRSA infection.

In vitro activities of the glycylcycline GAR-936 against gram-positive bacteria.

The in vitro activities of GAR-936, the 9-t-butylglycylamido derivative of minocycline, were compared with those of doxycycline, minocycline, and tetracycline against 527 gram-positive clinical isolates. GAR-936 inhibited all strains, including those resistant to other tetracyclines, at concentrations of

Clinical implications of stenotrophomonas maltophilia resistant to trimethoprim-sulfamethoxazole: a study of 69 patients at 2 university hospitals.

We conducted a retrospective case study at 2 tertiary care centers to determine the clinical implications of trimethoprim-sulfamethoxazole resistant Stenotrophomonas maltophilia (TSRSM). Of 69 reviewed cases (mean age, 57 y; male gender, 70%), 40 (58%) were classified as infections associated with TSRSM (respiratory tract, 14; soft tissue, 11; bloodstream, 8; other sites, 7). Severe underlying comorbidities (86%) and previous antibiotic exposure (99%) were common. Cefotetan (susceptibility, 55%), chloramphenicol (49%) and ticarcillin-clavulanate (45%) showed the highest in vitro activity against TSRSM, but were seldom used for therapy (7%). Among the 40 infected cases, 8 developed sepsis disorders and 8 died. Only 1 death could be directly attributed to autopsy-proven TSRSM infection (pneumonia). McCabe score (p = 0.03) and organ dysfunction (p = 0.006) were associated with an increased risk of death in infected patients; exposure to appropriate therapy tended to be protective against death (p = 0.08). 22 infected patients were treated medically; an additional procedure was necessary to clear the infection in 18 cases (surgery, 13; catheter removal, 5). Isolation precautions were rarely exercised, even in the presence of panresistant isolates. In summary, TSRSM-related infections occurred in severely ill patients with extensive exposure to the health-care system, and often required invasive procedures for cure. Infections were directly associated with severe morbidity, and tended to have an indirect rather than a direct impact on mortality.

A randomized phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma: an Eastern Cooperative Oncology Group Study (E1587).

BACKGROUND: Patients with metastatic nonsmall cell lung carcinoma (NSCLC) usually have a poor prognosis. A chemotherapy regimen containing cisplatin is commonly used for symptom palliation. Echinomycin is a potent bifunctional intercalator of double-strand DNA; trimetrexate is a new derivative of methotrexate and is active against methotrexate-resistant tumor cells in vitro. METHODS: The Eastern Cooperative Oncology Group conducted a randomized Phase II study. Eligible patients were assigned to receive echinomycin 1200 microg/m2 by intravenous (i.v.) infusion over 30-60 minutes once a week for 4 weeks, repeated every 6 weeks; trimetrexate 12 mg/m2 i.v. bolus on Days 1-5 every 3 weeks, or 8 mg/m2 i.v. bolus on Days 1-5 for patients who had prior radiation to greater than 30% of their bone marrow; or cisplatin 60 mg/m2 i.v. on Day 1 and etoposide 120 mg/m2 i.v. on Days 1-3 every 4 weeks. Patients were evaluated before each cycle for tumor response, toxicity, and quality-of-life measurements. RESULTS: One hundred thirty-six patients were entered on the study, and 118 were evaluable for toxicity and response. The response rates were 16%, 5%, and 5% in patients treated with cisplatin and etoposide, echinomycin, and trimetrexate, respectively. There were no complete responses. The median survival was 37.9, 24.3, and 28.0 weeks for patients who received cisplatin and etoposide, echinomycin, and trimetrexate, respectively. Although cisplatin and etoposide appeared to give better therapeutic results, the response rate or survival did not reach statistical significance. This may have been due to inadequate sample size. Neither did quality-of-life measurement show any significant differences among treatments. CONCLUSIONS: Echinomycin and trimetrexate had minimal antitumor activity in patients with metastatic NSCLC: Response rate and survival remained poor in all three treatment arms. Patients should be encouraged to participate in clinical trials so that more effective therapy can be identified.

A novel group I intron in Candida dubliniensis is homologous to a Candida albicans intron.

In the present study, we determined the sequence of group I self-splicing introns found in the large ribosomal RNA subunit of Candida albicans, Candida stellatoidea and the recently-described species Candida dubliniensis. It was found that both the intron and ribosomal RNA nucleotide sequences are almost perfectly identical between different C. albicans strains as well as between C. albicans and C. stellatoidea strains. Comparisons of ribosomal RNA sequences suggest that local isolates of atypical C. albicans from individuals infected with human immunodeficiency virus can be assigned to the C. dubliniensis species. C. dubliniensis strains also harbor a group I intron in their ribosomal RNA, as observed in about 40% of C. albicans strains and all C. stellatoidea strains. This novel C. dubliniensis group I intron is identical to the C. albicans and C. stellatoidea intron, except for two widely divergent stem-loop regions. Despite these differences, the C. dubliniensis intron possesses self-splicing ability in an in vitro assay. Taken together, these data support the idea that C. albicans and C. stellatoidea should be joined together as variants of the same species while C. dubliniensis is a distinct but closely related microorganism. To our knowledge, the C. albicans and C. dubliniensis introns are the first example of a pair of homologous group I introns differing only by the presence of apparently facultative sequences in some stem-loops suspected to be involved in stabilization of tertiary structure.

Design and analysis of group sequential logrank tests in maximum duration versus information trials.

When monitoring a clinical trial with failure time data using the logrank test and the type I error spending function approach, the information time has to be estimated as a fraction of the maximum number of failures. In maximum duration trials, the denominator of this fraction is a random quantity and has to be estimated; besides, there are two candidates for the denominator, one under the null hypothesis of no treatment difference and the other under the specified alternative hypothesis. Either way, some adjustments are necessary in determining group sequential boundaries in order to maintain type I error at a desired significance level. As a consequence, the type I error spending function will be altered from the one chosen for the design, thus affecting the operating characteristics of the subsequent group sequential logrank tests. In maximum information trials, however, the maximum amount of information is fixed, and thus the estimate of the information time is always unbiased. The net effect is that computation of group sequential boundaries becomes straightforward, with a potential saving in study durations as compared to maximum duration trials. We will illustrate how adjustments are made in maximum duration trials to maintain type I error when the information times are estimated with the information horizons under the null and alternative hypotheses and present numerical explorations to compare robustness of two different estimates of the information times. We then propose a design procedure for maximum information trials and investigate the properties of maximum information trials for different group sequential boundaries. We also compare maximum information trials and maximum duration trials based on an example.

Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women.

Sixty-three healthy post-menopausal women participated in the study aimed at determining the efficiency of percutaneous administration of estradiol (E2) giving physiological plasma levels of the estrogen to provide an efficient relief of climacteric and urogenital symptoms. Among these women, 31 had previous hysterectomy and were randomly allocated to one of the two estrogen replacement therapies while, similarly, the 32 women having an uterus were randomly divided between two groups who received in addition to estrogens, micronized oral progesterone. As estrogen, women received either E2 by percutaneous administration (Oestrogel) or oral conjugated estrogens (Premarin). With Oestrogel, serum E2 and estrone levels were within those seen during premenopause and showed a ratio close to 1.0. Climacteric symptoms were reduced or eliminated similarly in all groups. No changes was noticed on the concentration of serum angiotensinogen with Oestrogel therapy while a 2.5-fold increase was found in women receiving Premarin. As indicated by the 24-week endometrial biopsy, the progestational response induced by oral progesterone at the dose used was sufficient in twenty out of thirty-two women to cause endometrial atrophy, thus suggesting the need for higher amounts of micronized progesterone in a proportion of women. The present data also indicate that Oestrogel provides efficient relief of climacteric and urogenital symptoms without exerting any detectable effect on hepatic function while maintaining the ratio of serum E2/E1 at the physiological value of 1.0.

Important prognostic value of standardized objective criteria of response in stage D2 prostatic carcinoma.

One hundred and eighty-six previously untreated patients with clinical stage D2 prostate cancer have been followed according to the criteria of objective response of the National Prostatic Cancer Project (NPCP). All patients received combination therapy with the antiandrogen Flutamide and the LHRH agonist (D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (or surgical castration, 10 patients) as first treatment. Forty-nine patients (26.3%) achieved a complete response as best response while 56 (30.1%) and 69 (37.1%) patients had partial and stable responses, respectively, and only 12 patients (6.5%) did not respond to treatment. The median times required to achieve stable, partial and complete responses were 155, 183 and 401 days, respectively. The best response achieved has a major influence on the probability of continuing response and survival. While the 50% probability of continuing response is more than 3 years for the complete responders, it is reduced to 630 and 517 days for partial and stable responders, respectively. While the non-responders have a median life expectancy of 10.0 months, this value is increased to 30.3 and 37.8 months for the stable and partial responders, respectively. The best probability of survival is for the complete responders with a 95.9% probability of survival at 3 years. There is no significant correlation between the time required to achieve a best response (phase 1) and the duration of the response before progression occurs (phase 2) or the time between progression and death (phase 3) for any of the categories of responses. A longer period of time required to achieve a complete response is associated with a longer survival. When analysis is made, in an attempt to predict response, of the baseline characteristics of the patients before treatment, a low number of bone metastases and better performance status are associated with a greater chance of achieving a complete response while partial, stable and progression responses cannot be predicted from the baseline characteristics. The present data show the importance of standardization of the objective criteria of response to treatment in advanced prostate cancer. Thus, the patients who achieve a complete response have a much more favorable prognosis while partial and stable categories of response have a closely similar prognosis which is inferior to the complete responders. Moreover, the present data indicate that the stable category of response has an important prognostic value which is almost superimposable and not statistically different from the partial response in terms of duration of response and survival.(ABSTRACT TRUNCATED AT 400 WORDS)

Dexfenfluramine and body weight regulation: experimental study with hoarding behavior.

At very low doses dexfenfluramine, a serotonin agonist, is a potent inhibitor of hoarding behavior. The dose able to suppress 40% of this food motivated response (ED 40) is approximately 0.3 mg/kg. The action of dexfenfluramine is mediated through serotoninergic receptors because it is suppressed by a pretreatment with metergoline, a selective serotonin-receptor blocker, but is not modified by haloperidol, a dopamine antagonist.