The pharmacodynamic effects of combined administration of flibanserin and alcohol.

WHAT IS KNOWN AND OBJECTIVE: Flibanserin is a serotonin 5-HT1A agonist and 5-HT2A antagonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Because of the increased risk of hypotension- and syncope-related adverse events (AEs) observed with coadministration of flibanserin and alcohol, alcohol use is contraindicated. To provide a more comprehensive understanding of the interaction between flibanserin and alcohol, the results of a dedicated phase 1 alcohol-interaction study and a pooled analysis of phase 3 studies of premenopausal women with HSDD are presented. METHODS: In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4 ). Pooled data from five phase 3 studies of patients receiving flibanserin 100 mg once daily (n=1543), or placebo (n=1905), were analysed. RESULTS: In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use. WHAT IS NEW AND CONCLUSION: Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear.

First Report of Charcoal Rot Caused by Macrophomina phaseolina on Sunflower in Illinois.

In September 2009, sunflower (Helianthus annuus L.) plants (cv. Mycogen 8C451) from a University of Illinois field research trial in Fayette County, Illinois exhibited silvery gray girdling lesions on the lower stems and premature death. When lower stems and roots were split open, the pith tissue was compressed into layers. Black microsclerotia (90 to 180 µm) were present on the outside of the lower stem tissue and in the stem vascular tissue. Five pieces (approximately 1 cm long) of symptomatic stem tissue from five different affected plants (25 pieces total) were soaked in a 0.5% solution of NaOCl for 30 s, rinsed with sterile distilled water, and placed on potato dextrose agar (PDA; Becton, Dickinson, and Company, Franklin Lakes, NJ). Gray hyphae grew from all of the stem pieces, which subsequently turned black and formed black microsclerotia (75 to 175 µm). On the basis of plant symptoms and size and color of the microsclerotia, the disease was diagnosed as charcoal rot caused by Macrophomina phaseolina (Tassi) Goid (2). To confirm that the isolated fungus was M. phaseolina, DNA was extracted from the pure culture, and PCR amplification of a subunit rDNA and internal transcribed spacer (ITS) region with primers EF3RCNL and ITS4 was performed (3). The Keck Biotechnology Center at the University of Illinois, Urbana sequenced the PCR product. The resulting nucleotide sequence shared the highest homology (99%) with sequences of M. phaseolina when compared with the subunit rDNA and ITS sequences in the nucleotide database ( http://www.ncbi.nlm.nih.gov ). A greenhouse experiment was conducted to confirm pathogenicity; the greenhouse temperature was approximately 27°C and sunflower plants (cv. Cargill 270) were grown in pots and watered daily to maintain adequate soil moisture for growth. Sterile toothpicks were infested with M. phaseolina and placed through the stems (10 cm above the soil surface) of five 40-day-old sunflower plants that were approximately at growth stage R4 (1,4). Five sterile, noninfested toothpicks were similarly placed through sunflower plants to act as controls. Parafilm was used to hold the toothpick in the stem and seal the stem injury. Thirty-five days after inoculation, the mean lesion length on stems inoculated with M. phaseolina was 595 mm and no lesions developed on the control plants. M. phaseolina-inoculated plants also began to wilt and die. Cultures identical to the original M. phaseolina isolate were reisolated from stem lesions of the M. phaseolina-inoculated plants. This is the first report of charcoal rot on sunflower in Illinois to our knowledge. Sunflower is currently not a major crop grown in Illinois, but on-going research is focused on evaluating sunflower as a potential late-planted crop to follow winter wheat. If sunflower production increases in Illinois, growers may need to take precautions to manage charcoal rot. References: (1) L. K. Edmunds. Phytopathology 54:514, 1964. (2) T. Gulya et al. Page 263 in: Sunflower Technology and Production. American Society of Agronomy, Madison, WI, 1997. (3) N. S. Lord et al. FEMS Microbiol. Ecol. 42:327, 2002. (4) A. A. Schneiter and J. F. Miller. Crop Sci. 21:901, 1981.

Phase II, randomized, double-blind, multicenter study comparing the safety and pharmacokinetics of tefibazumab to placebo for treatment of Staphylococcus aureus bacteremia.

Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 microg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.

Detection of HCV in bile duct epithelium by laser capture microdissection (LCM).

Chronic hepatitis C affects 0.3 to 1.5% of the general population worldwide. The estimated total number of newly acquired hepatitis C virus (HCV) infections is 28,000 in the USA, with 10,000 deaths each year resulting from HCV-associated chronic liver disease. Histological examination of liver tissue from chronic HCV infection shows lymphoid aggregates or follicles in the portal triads, focal fatty change and lobular inflammation. Hepatitis-associated bile duct lesion (HBL) is seen in 5 - 91% of the cases. While the morphological spectrum of HBL has been well described, its pathogenesis in hepatitis C is not known. To this date, evidence supports both the direct injury and immune-mediated mechanisms, but to what extent these mechanisms are involved in the pathogenesis of HBL in chronic hepatitis C remains unclear. Our study showed the presence of HCV in the bile duct epithelium of patients with chronic hepatitis C infection, using the laser capture microdissection technique. These results will enhance our diagnostic capabilities and treatment of chronic hepatitis C infection.

Process improvement plan for the reduction of sternal surgical site infections among patients undergoing coronary artery bypass graft surgery.

In an attempt to reduce sternal infections caused by Staphylococcus aureus, a protocol was introduced that included the administration of intranasal mupirocin calcium 2% before surgery to patients undergoing cardiothoracic surgery. Surveillance data indicated a 55% reduction in the rate of deep sternal wound infections caused by S aureus and superficial sternal wound infections have declined from 25 to 6 since the adoption of the protocol. At the study institution, this protocol is now an ongoing process to reduce the incidence of sternal infections caused by S aureus among cardiothoracic patients.

Nasal Carriage of Staphylococcus aureus As a Risk Factor for Skin and Soft Tissue Infections.

Nasal carriage of Staphylococcus aureus is a major risk factor for the development of S. aureus infection, including skin and soft tissue infections and foreign body infections, such as catheter-associated bacteremia and peritonitis. In this article, we review the recent literature on S. aureus nasal carriage, including the emergence of methicillin- resistant S. aureus in the community, the pathophysiology of nasal carriage, and the epidemiology and prevention of S. aureus infections associated with nasal carriage.

The many faces of Staphylococcus aureus infection. Recognizing and managing its life-threatening manifestations.

Serious infections caused by S aureus, particularly those associated with bloodstream infection, are rapidly increasing in frequency, likely as a result of the proliferation of invasive procedures, the increasing severity of illness of hospitalized patients, suboptimal adherence to infection control practices, selection of resistant strains by antibiotic use, high rates of injecting drug use, and diabetes mellitus. In many cases, being aware of the clinical manifestations and treatment of S aureus can help to decrease the incidence of these infections and promote better care for patients who have been--or could be--exposed to the pathogen.

A viral gastroenteritis outbreak associated with person-to-person spread among hospital staff.

OBJECTIVE: To identify the etiologic agent and risk factors associated with a hospital ward outbreak of gastroenteritis. SETTING: A regional referral hospital in upstate South Carolina. METHODS: We reviewed patient charts, surveyed staff, and tested stool from acutely ill persons. A case was defined as diarrhea and vomiting in a staff member or patient from January 5 to 13, 1996. RESULTS: The initial case occurred on January 5 in a staff nurse who subsequently was hospitalized on the ward and visited by many staff colleagues. The staff were at a significantly greater risk for gastroenteritis than were patients (28/89 [31%] vs 10/91 [11%]; relative risk [RR], 2.9; 95% confidence interval [CI95], 1.5-5.5). All 10 case-patients had been exposed to case-nurses (assigned nurses who were primary caretakers), and eight had documented exposure to case-nurses 1 to 2 days before their illness. Patients exposed to case-nurses had a significantly increased risk of illness (8/57 [14%] vs 0/32; RR, >4.5; CI95, undefined). Neither staff nor patients had significantly increased risk from food, water, ice, or exposure to case-patients. Electron microscopy identified small round-structured viruses (SRSVs) in nine of nine stool samples. CONCLUSION: This nosocomial outbreak of gastroenteritis was likely caused by SRSVs introduced by a staff member and spread via person-to-person transmission from and among staff. The potential for spread of SRSV-associated gastroenteritis from and among staff should be considered in developing strategies to prevent similar outbreaks in hospital settings.

Molecular typing and fluconazole susceptibility of urinary Candida glabrata isolates from hospitalized patients.

At our community teaching hospital between August 1994 and August 1995, Candida glabrata accounted for 14% of all Candida isolates and for 31% of urinary Candida isolates. The culture site was urine for 68% of C. glabrata isolates compared to 30% of all Candida isolates (p < 0.001, chi 2). To study the association between C. glabrata and isolation from the urine, we analyzed all available C. glabrata urinary isolates over a 3-month period (23 isolates from 20 patients) using electrophoretic karyotyping, random amplified polymorphic DNA analysis, and fluconazole susceptibility testing. Random amplified polymorphic DNA generated eight types, although electrophoretic karyotyping generated 17 types. Combining the two methods resulted in 19 types indicating that urinary C. glabrata strains at our hospital are genetically diverse and the association between C. glabrata and urinary tract isolation does not appear to be due to horizontal transmission of a single or small number of strains. In vitro susceptibility tests showed that C. glabrata isolates from patients receiving fluconazole had significantly higher minimum inhibitory concentrations to fluconazole than those not receiving fluconazole (p < 0.05). Despite a limited number of patients and isolates, our data suggest that selection of less susceptible organisms by the presence of antifungal agents may be an important contributor to increased urinary isolation of C. glabrata from patients in our hospital.

The results of a phase II randomized trial comparing 5-fluorouracil and 5-fluorouracil plus alpha-interferon: observations on the design of clinical trials for androgen-independent prostate cancer.

The therapeutic benefit of chemotherapy in androgen independent prostate cancer is limited. 5-Fluorouracil has been reported to have modest antitumor activity in androgen independent prostate cancer. Although alpha-interferon is inactive as a single agent in prostate cancer, preclinical data indicate that it increases the in vitro cytotoxicity of 5-fluorouracil against a variety of malignant cells. We evaluated the relative antitumor activity and tolerance of 5-fluorouracil versus 5-fluorouracil plus alpha-interferon in 50 patients with histologically confirmed metastatic adenocarcinoma of the prostate. These patients had progressive disease in the presence of castrate levels of testosterone. A prospective randomized phase II open labeled trial was performed because of the difficulty in measuring responses in patients with metastatic prostate cancer. Of 23 patients treated with 5-fluorouracil alone and 28 treated with 5-fluorouracil plus alpha-interferon 17 and 23, respectively, were evaluable for response and toxicity, and 5 and 5, respectively, were evaluable for toxicity only. Only 2 of 17 (11.7%) and 4 of 23 (17%) patients, respectively, showed a greater than 50% decrease in serum prostate specific antigen (no significant difference). There was no difference in duration of response or duration of survival between the 2 groups (mean duration of response 8.64 and 6.17 weeks, respectively, and mean duration of survival 33.70 and 38.65 weeks, respectively). Both regimens caused significant morbidity (mucositis and neurotoxicity) and 3 treatment related deaths at the high 5-fluorouracil doses. 5-Fluorouracil alone and with alpha-interferon at the doses used have minimal antitumor activity against androgen independent prostate cancer and, therefore, should not be tested further in these patients. Androgen independent prostate cancer selected using our criteria is a rapidly progressive disease, and these patients are an ideal target population for phase II studies.

Nosocomial outbreak of Pseudomonas cepacia associated with contamination of reusable electronic ventilator temperature probes.

OBJECTIVE: The investigation and control of an outbreak of nosocomial Pseudomonas cepacia respiratory tract colonization and infection. DESIGN: Epidemiologic investigation based on infection control surveillance data, including definition and characterization of case patients, environmental cultures based on epidemiologic information, and institution of control measures based on study results. SETTING: A 1,171-bed, university-affiliated tertiary care hospital. RESULTS: Between January 1, 1988, and June 30, 1989, 127 patients were culture-positive for P cepacia, 117 (92%) of whom were culture-positive from sputum and were treated in the intensive care unit. Review of respiratory care procedures revealed that when mechanical ventilators were serviced between patients, the electronic temperature probes used with servo-controlled humidifiers were wiped with the same odor-counteractant cleaning solution used on ventilator cabinets. P cepacia was isolated from nine of 12 in-use temperature probe tips, three of which were from patients with negative sputum cultures for P cepacia, one of whom subsequently developed culture positivity for P cepacia. P cepacia also was isolated from the diluted odor-counteractant solution. Following the institution of a disinfection procedure for temperature probe tips, the incidence of P cepacia sputum culture positivity in ICU patients fell significantly compared to the outbreak period (138 of 5,225 discharges versus 52 of 3,678 discharges, P < 0.01). CONCLUSIONS: This investigation identified contamination of reusable electronic temperature probes as a source of nosocomial respiratory infection due to P cepacia and emphasizes the need to carefully evaluate disinfection practices for reusable patient care equipment.

Candida parapsilosis: epidemiology, pathogenicity, clinical manifestations, and antimicrobial susceptibility.

Early reports associated Candida parapsilosis with endocarditis in intravenous narcotic addicts. More recently, this species has emerged as an important nosocomial pathogen, with clinical manifestations including fungemia, endocarditis, endophthalmitis, septic arthritis, and peritonitis, all of which usually occur in association with invasive procedures or prosthetic devices. Outbreaks of C. parapsilosis infections have been caused by contamination of hyperalimentation solutions, intravascular pressure monitoring devices, and ophthalmic irrigating solution. Experimental studies have generally shown that C. parapsilosis is less virulent than Candida albicans or Candida tropicalis. However, characteristics of C. parapsilosis that may relate to its increasing occurrence in nosocomial settings include frequent colonization of the skin, particularly the subungual space, and an ability to proliferate in glucose-containing solutions, with a resultant increase in adherence to synthetic materials. Recently developed molecular techniques may facilitate the continued exploration of the epidemiology and pathogenesis of C. parapsilosis infections.

Use of low-dose trimethoprim-sulfamethoxazole thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients.

We conducted an open prospective clinical trial to evaluate the efficacy and toxicity of trimethoprim-sulfamethoxazole given as one double-strength tablet thrice weekly for primary and secondary prophylaxis of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus-infected (HIV+) patients. A total of 104 HIV+ patients were evaluated, with 74 being in the primary prophylaxis group and 30 being in the secondary prophylaxis group. All except six patients received concomitant zidovudine; five patients on primary prophylaxis and one patient on secondary prophylaxis refused zidovudine. There were 70 patients evaluated for the efficacy of primary prophylaxis. The mean CD4 count was 124.4 +/- 110.1 cells per microliter. The mean follow-up time was 11.8 +/- 5.8 months (median, 12 months; range, 1 to 32 months). Two noncompliant patients developed PCP after 1 and 3 months of chemoprophylaxis. The failure rate (under the intention to treat principle) was 2 of 70 patients (2.9%; 95% confidence interval, 0.35 to 10%), or 1 per 413 patient-months of observation. There were 27 patients evaluated for the efficacy of secondary prophylaxis. The mean follow-up time was 12.4 +/- 7.2 months (median, 11 months; range, 1 to 29 months). Two patients, one of whom was noncompliant, were treatment failures, developing PCP after 14 and 15 months of chemoprophylaxis; this gave a failure rate of 2 of 27 patients (7.4%; 95% confidence interval, 0.9 to 24.3%), or 1 per 167 patient-months of observation. Adverse reactions sufficient to permanently terminate therapy occurred in 9 of 104 patients (8.7%; 95% confidence interval, 4 to 15.7%) overall. The serum trimethoprim, sulfamethoxazole, and N4-acetyl-sulfamethoxazole concentrations measured by high-pressure liquid chromatography were uniformly low. One double-strength tablet of trimethoprim-sulfamethoxazole taken weekly on Monday, Wednesday, and Friday appeared to be well tolerated and efficacious for the prophylaxis of PCP in HIV+ patients at high risk and deserves further investigation.

Cavitary Pneumocystis carinii pneumonia in patients receiving aerosol pentamidine prophylaxis.

We have described two patients with AIDS who had cavitary Pneumocystis carinii pneumonia while receiving aerosolized pentamidine prophylaxis. This is the first report of this complication. Neither patient showed a clinical response to subsequent use of pentamidine either intravenously or by aerosol followed by intravenous use. Clinicians should be aware of the possibility that cavitary pneumonia in patients receiving aerosolized pentamidine may be due to P carinii.

Molecular epidemiology of nosocomial, multiply aminoglycoside resistant Enterococcus faecalis.

The prevalence of high-level aminoglycoside resistance among Enterococcus faecalis at the Memphis VA Medical Center was 23.6% (59 of 250 isolates) from October to December 1986. Hybridization to a probe cloned from Ent. faecalis pIP1800 for 6' acetyltransferase-2" phosphotransferase (AAC6'-APH2") was observed in 55 (93.2%) of the resistant isolates and was associated with gentamicin resistance. Hybridization to a probe cloned from Ent. faecalis pJH1 for 3', 5" phosphotransferase type III (APH3', 5" III) was observed in 28 (47.4%) and was associated with streptomycin resistance. Twenty-five of the 32 isolates which were resistant to both gentamicin and streptomycin hybridized to both probes. Cell mating in conjunction with hybridization indicated that the AAC6'-APH2" gene is transferred separately from that for APH3', 5" (III), and the streptomycin resistant gene is cotransferred with the latter. The gentamicin-streptomycin resistant isolates therefore contain genes from two Ent. faecalis plasmids, and resistance to these two antibiotics appears to transfer separately. The genetic homogeneity of these isolates suggests nosocomial transmission of enterococci.