Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model.

An in vitro pharmacodynamic investigation was conducted to explore whether the area under the concentration time curve from 0 to 24 h (AUC(0-24))/MIC ratio could predict fluoroquinolone performance against Bacteroides fragilis. An in vitro model was used to generate kill curves for trovafloxacin (TVA) and levofloxacin (LVX) at AUC(0-24)/MIC ratios of 1 to 406 against three strains of B. fragilis (ATCC 25285, ATCC 23745, and clinical isolate M97-117). TVA and LVX were bolused prior to the start of experiments to achieve the corresponding AUC(0-24)/MIC ratio. Experiments were performed in duplicate over 24 h and in an anaerobic environment. Analyses of antimicrobial performance were conducted by comparing the rates of bacterial kill (K) using nonlinear regression analysis with 95% confidence intervals. Statistical significance was defined as a lack of overlap in the 95% confidence limits generated from the slope of each kill curve. For both TVA and LVX, K was maximized once an AUC(0-24)/MIC ratio of > or =40 was achieved and was not further increased despite a 10-fold increase in AUC(0-24)/MIC from approximately 40 to 400 against all three strains of B. fragilis. No significant differences were found in K between AUC(0-24)/MIC ratios of approximately 40 to 200. In experiments where AUC(0-24)/MIC ratios that were > or = 5 and < or = 44 were conducted, 64% demonstrated regrowth at 24 h. Resistant strains were selected in 50% of those experiments, demonstrating regrowth, which resulted in increased MICs of two- to 16-fold for both TVA and LVX. Regrowth did not occur, nor were resistant strains selected in any studies with an AUC/MIC that was > 44. Our findings suggest that fluoroquinolones provide antibacterial effects against B. fragilis in a concentration-independent manner associated with an AUC(0-24)/MIC ratio of > or =40. Also, the potential for the selection of resistant strains of B. fragilis may increase with an AUC(0-24)/MIC ratio of < or =44.

Application of fluoroquinolone pharmacodynamics.

Pharmacodynamics provides a rational basis for optimizing dosing regimens by describing the relationship between drug, host and antimicrobial effect. The successful identification of meaningful pharmacodynamic outcome parameters can, therefore, greatly assist clinicians in making objective prescribing decisions rather than relying on static in vitro MIC data. While pharmacodynamic outcome parameters have been proposed for select antimicrobial agents, their clinical application remains to be defined fully. Quinolone antibiotics are generally considered to have concentration-dependent bactericidal activity and peak/MIC and AUC/MIC ratios have been identified as possible pharmacodynamic predictors of clinical and microbiological outcome as well as the development of bacterial resistance. Investigators have suggested that AUC/MIC ratios of 100-125 or peak/MIC ratios of >10 are required to predict clinical and microbiological success and to limit the development of bacterial resistance. These conclusions are derived primarily from studies of Gram-negative bacteria, and recent data suggest that these ratios may not be applicable for Streptococcus pneumoniae, where an AUC/MIC ratio of <40 appears to be a more accurate predictor. There is considerable variation in pharmacodynamic calculations and outcome parameters appear to be quinolone- and pathogen-specific. Additional prospective clinical research is needed to characterize quinolone pharmacodynamic parameters and answer unresolved questions regarding optimal pharmacodynamic outcome predictors for Gram-positive bacteria, anaerobes and atypical respiratory pathogens.

Gram-positive infections: pharmacy issues and strategy for quinupristin/dalfopristin.

The development of the first streptogramin antibiotic, quinupristin/dalfopristin represents an attempt to bring new antimicrobial strategies on line to combat the menacing problem of Gram-positive-resistant bacteria. With introduction to the medical center formulary, the pharmacy will need to be aware of several practical issues surrounding the use of quinupristin/dalfopristin. Cost and unit size will be important issues. Initially, this drug will only be available in 500-mg vials which may not always accommodate the suggested dose of 7.5 mg/kg of actual body weight. In addition, the drug can only be reconstituted with D5W or sterile water, and it can not be mixed with normal saline, heparin, or other drugs. Institutions adding this drug to their formularies must address the expected logistical concerns with their medical, nursing, and pharmacy staffs prior to patient usage.

Cyclospora: review of an emerging parasite.

Cyclospora is a parasite traditionally associated with diarrhea in travelers to endemic countries. Recently, several cases of cyclosporiasis were reported in nontravelers in the United States and Canada, implicating various fruits and vegetables as vehicles of infection. The life cycle of cyclospora is not fully known, but is believed to involve both asexual and sexual stages of proliferation. Food- and water-borne transmission of infection have been implicated. Patients infected with Cyclospora cayetanensis have protracted watery diarrhea. Various generalized symptoms are also present, making cyclosporiasis indistinguishable from infectious diarrhea caused by other microorganisms. Diagnosis depends on identifying the organism by microbiologic examination of stool samples. Treatment consists of supportive care, maintenance of fluid and electrolyte status, symptomatic relief, and antibiotic therapy. Trimethoprim-sulfamethoxazole is the only antibiotic available that is effective in eradicating the organism.

Hepatitis associated with terbinafine therapy: three case reports and a review of the literature.

Terbinafine is an allylamine antifungal agent first launched in the USA in May 1996 with an estimated 7.5 million individuals worldwide having used the drug. Given orally it is effective for the treatment of dermatophyte infections and is prescribed predominantly for the superficial mycoses. Adverse effects have been reported in 46.7% of patients receiving the oral drug (compared with 29.2% receiving placebo, the attributable risk to terbinafine being 17.5%). Thus, oral terbinafine is associated with the rare development of symptomatic idiosyncratic hepatobiliary dysfunction (1:45,000-1:54,000) and we now describe three patients who developed this disorder whilst taking the medication. The hepatitis produced has the features of both hepatocellular necrosis (with elevations of hepatic enzyme concentrations) and cholestatic injury (with elevations of alkaline phosphatase and cholesterol levels), the latency period between the start of medication and the development of liver injury being approximately 4-6 weeks. The US terbinafine product monograph recommends that serum hepatic enzymes should be assessed in individuals receiving terbinafine for more than 6 weeks, as a result of which some physicians monitor these values at baseline and at 4-6 weeks.

Violence against women during the Liberian civil conflict.

CONTEXT: Civilians were often the casualties of fighting during the recent Liberian civil conflict. Liberian health care workers played a crucial role in documenting violence against women by soldiers and fighters during the war. OBJECTIVE: To document women's experiences of violence, including rape and sexual coercion, from a soldier or fighter during 5 years of the Liberian civil war from 1989 through 1994. DESIGN: Interview and survey. SETTING: High schools, markets, displaced persons camps, and urban communities in Monrovia, Liberia, in 1994. PARTICIPANTS: A random sample of 205 women and girls between the ages of 15 and 70 years (88% participation rate). RESULTS: One hundred (49%) of 205 participants reported experiencing at least 1 act of physical or sexual violence by a soldier or fighter. Survey participants reported being beaten, tied up, or detained in a room under armed guard (17%); strip-searched 1 or more times (32%); and raped, subjected to attempted rape, or sexually coerced (15%). Women who were accused of belonging to a particular ethnic group or fighting faction or who were forced to cook for a soldier or fighter were at increased risk for physical and sexual violence. Of the 106 women and girls accused of belonging to an ethnic group or faction, 65 (61%) reported that they were beaten, locked up, strip-searched, or subjected to attempted rape, compared with 27 (27%) of the 99 women who were not accused (P< or =.02, .07, .001, and .06, respectively). Women and girls who were forced to cook for a soldier or fighter were more likely to report experiencing rape, attempted rape, or sexual coercion than those who were not forced to cook (55% vs 10%; P< or =.001, .06, and .001, respectively). Young women (those younger than 25 years) were more likely than women 25 years or older to report experiencing attempted rape and sexual coercion (18% vs 4%, P=.02 and .04, respectively). CONCLUSIONS: This collaborative research allowed Liberian women to document wartime violence against women in their own communities and to develop a unique program to address violence against women in Liberia.

Implementing a successful home i.v. program.

Anyone who has worked on planning a program that spans both hospital and community knows the differences in focus, philosophy and general organization. Kelowna General Hospital and the community of South Okanagan, B.C. worked beyond these differences, using the strengths and expertise of both spectrums of care, to implement a successful home infusion program. But first, the pros and cons of program ownership.

Manipulation of the fatty acid composition of milk by feeding protected canola seeds.

The feeding to dairy cows of canola seed protected from ruminal metabolism by emulsification and encapsulation in a matrix of aldehyde-treated protein resulted in a 10% increase in milk fat and no change in milk yield or protein content. Feeding the protected canola supplement significantly reduced the proportions of saturated fatty acids C16:0, C14:0, and C12:0 in milk fat; there were corresponding increases in proportions of C18:0, C18:1, C18:2, and C18:3. Yield of C18 monounsaturated and polyunsaturated fatty acids increased by 54%, which is equivalent to 143 g/d. Canola seed, enriched in C18:1, can be included in the diet and can result in significant changes in the proportions of saturated and unsaturated fatty acids in milk fat.

HELLP syndrome: an often unrecognized complication of preeclampsia.

We describe a case of preeclampsia with the HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets) syndrome and highlight the delayed diagnosis due to its nonspecific presentation. This syndrome is associated with significant maternal and perinatal mortality and morbidity and we discuss the importance of early recognition of the condition, aggressive management and a multidisciplinary approach.

Effect of mouse epidermal growth factor on plasma concentrations of LH, FSH and testosterone in rams.

Two experiments were conducted to examine the effects of mouse epidermal growth factor (EGF) on the concentrations of testosterone, LH and FSH in jugular blood plasma and on the pituitary responsiveness to LHRH. In 20 rams treated with subcutaneous doses of EGF at rates of 85, 98 or 113 micrograms/kg fleece-free body weight, mean plasma LH and testosterone concentrations were significantly reduced (P less than 0.05) at 6 h after treatment but not at 24 h. EGF treatment at 130 micrograms/kg fleece-free body weight suppressed the plasma content of these hormones for up to 48 h. Mean plasma FSH concentrations decreased significantly (P less than 0.05) for up to 48 h after EGF treatment, the effect being most pronounced in rams with mean pretreatment FSH values greater than or equal to 0.5 ng/ml. Intravenous injections of 1.0 micrograms LHRH given to each of 5 rams before and at 6 h, 24 h and 72 h after EGF treatment produced LH and testosterone release patterns which paralleled those obtained in 5 control rams similarly treated with LHRH. These results suggest that, in rams, depilatory doses of mouse EGF temporarily impair gonadotrophin and androgen secretion by inhibiting LHRH release from the hypothalamus. Such treatment appears to have no effect on the responsiveness of the pituitary to LHRH.

A note on comparing growth rates of animals between groups.

A statistical analysis of growth rates for groups of animals is considered. An overall analysis of variance is given that is conditional upon the acceptance of a preliminary homogeneity test for parameters that describe the growth of individuals within groups.

Cellularity of organs in mature rams of different breeds.

The relative importance of cell number and cell size in determining the mass of 16 organs and tissues in mature rams of six different breeds was studied through estimation of organ deoxyribonucleic acid (DNA) content. The mean fleece-free empty body weight (FFEBW) ranged from 54.6 +/- 0.3 kg for Camden Park Merinos to 76.7 +/- 1.6 kg for Strong Wool Merinos. For all organs, mass increased with FFEBW, but the relationship was significant across all sheep for only eight organs (blood, kidney, liver, abomasum, vastus lateralis muscle, skin, perirenal fat and triceps muscle). There were significant differences between breeds in the mass of 11 organs. With four (heart, rumen reticulum, small intestine and testicular fat) this difference was independent of breed differences in FFEBW, whereas with another four (kidney, abomasum, vastus lateralis muscle and skin), it was closely related to FFEBW. Breed differences in the mass of the remaining three organs (blood, liver and perirenal fat) were partly related to FFEBW and partly breed specific. Blood mass increased with FFEBW across all animals, but, within a breed, it declined as FFEBW increased. The increase in the mass of perirenal fat with FFEBW was significantly greater within a breed than between breeds. Cell number increased significantly with the mass of all organs except blood and brain. There were between-breed differences in the number of cells in seven organs (liver, heart, rumen reticulum, abomasum, small intestine, vastus lateralis muscle and skin), which, except for heart, were attributable to between-breed differences in organ mass. With heart, the increase in cell number with organ mass within a breed was greater than across all breeds. Cell size was significantly related to organ mass only with vastus lateralis muscle, spleen, perirenal fat and liver. The relationship for vastus lateralis muscle and spleen was negative, indicating that cells were smaller in larger organs. There were differences between breeds in cell size for heart, vastus lateralis and triceps muscles. These differences for heart and triceps muscle were breed specific, whereas for vastus lateralis muscle it was attributed to breed differences in organ weight. There was a 30-fold range in mean cell size across organs, with adipose tissue having the largest cells, muscle tissue intermediate and visceral tissues the smallest. In general, organ mass is positively related to FFEBW. Cell number, not cell size, is largely responsible for differences in organ mass between mature sheep of different breeds.

Evaluation of a medication refill reminder system for a community pharmacy.

The problem of maintaining compliance in patients taking chronic medications is well established. One recommended approach to reducing this problem is to develop a system which identifies non-compliers in order that interventions can be devised to improve that behavior. A medication refill reminder system is an example of this approach. The refill behavior was observed for 102 cardiovascular patients who were patrons of one community pharmacy in order to assess the effects of a postcard/telephone reminder system. Patients who failed to refill their prescriptions on time were sent a postcard reminding them to have them refilled. A telephone call would follow if the patient failed to visit the pharmacy after the postcard. The study results showed that the average day s late for patients who failed to refill their prescription as expected decreased from 19.15 to 6.6 days after the reminder system was used (P less than 0.005). In addition, the percent of late refills of these patients was 13% less than controls. These findings provide strong evidence that a refill reminder system can be used successfully in a community pharmacy as part of a program to identify non-compliant patients and improve their compliance with chronic medication therapy.