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Purpose: The implementation and effectiveness of targeted interventions aimed at decreasing the frequency of antiretroviral-related errors in hospitalized patients with human immunodeficiency virus (HIV) are described., Summary: A prospective investigation conducted at the University of North Carolina Hospitals revealed a high rate of antiretroviral-related errors occurring on admission to the hospital and throughout a patient's hospital stay. The high frequency of errors emphasized the need for targeted interventions aimed at preventing these errors and quickly identifying and resolving errors that do occur. Several interventions aimed at decreasing this error rate were instituted, including the addition of computer alerts for incorrect doses and drug interactions to the pharmacy order-entry system, distribution of an educational pocket-sized card among the staff, addition of commercially available combination antiretroviral products to the hospital formulary, updates of the computerized prescriber-order-entry (CPOE) system to include common dosage defaults, involvement of the infectious diseases consultation service to evaluate prescribed regimens of newly admitted patients with HIV, and daily review of newly initiated anti-retroviral regimens by a clinical pharmacist trained in HIV care. A follow-up analysis was conducted after these interventions were implemented to evaluate their effectiveness. Of the 78 patients identified during the postintervention analysis, 12 (15%) had at least one error in their initial drug regimen versus 49 patients (72%) in the preintervention study (p < 0.001)., Conclusion: Antiretroviral medication error rates decreased after the implementation of targeted interventions that included distributing an educational pocket-sized card, adding alerts to the pharmacy order- entry system, incorporating default dosages into the CPOE system, and adding combination antiretrovirals to the formulary.

Objective: To describe a case of severe sepsis, cavitary pneumonia, and pyomyositis caused by Arcanobacterium haemolyticum., Case Summary: An 18-year-old male with a medical history significant for mild asthma presented to the emergency department complaining of a 7-day history of fever, diffuse myalgias, nausea, vomiting, diarrhea, and pain in his right upper quadrant, right shoulder, and left thigh. Cultures of blood, bronchoalveolar fluid, and surface and surgical swabs from the patient's left lower extremity grew A. haemolyticum. The patient was successfully treated with intravenous penicillin G 4 million units every 4 hours and azithromycin 500 mg once daily for 14 days. Within 36 hours after initiation of focused therapy, he became afebrile, pain decreased, and pulmonary symptoms abated. Oral azithromycin 500 mg/day for an additional 3 weeks was prescribed on discharge, and the patient showed no relapse at 2-month follow-up., Discussion: A. haemolyticum is a weakly acid-fast, branching gram-positive bacillus most commonly implicated in pharyngitis in healthy adolescents and skin and soft-tissue infections in older, immunocompromised patients. Systemic infections are rarely reported in the literature. This organism remains susceptible to most classes of antimicrobials, including penicillins, cephalosporins, carbapenems, macrolides, tetracyclines, clindamycin, and vancomycin. Routine resistance has been reported only with trimethoprim/sulfamethoxazole., Conclusions: To our knowledge, there are no published case reports of severe sepsis caused by A. haemolyticum. While treatment options are numerous, we recommend the use of intravenous penicillin or a cephalosporin as first-line pharmacologic management of deep-seated infections caused by this rare organism.

Background: Retrospective studies of hospitalized HIV-infected patients have noted a high occurrence of drug-related errors, ranging from 5% to 30%., Objective: To prospectively evaluate errors in antiretroviral (ARV) prescribing in the inpatient setting of a hospital tertiary care center and the association of risk factors with the occurrence of errors., Methods: HIV-infected patients who received care and continued their ARVs for HIV infection on admission to a large academic teaching hospital between January and April 2006 were included in this study. The care and assessment of these patients was conducted on a daily basis by an infectious diseases/HIV specialized clinical pharmacist. All errors were documented and classified based on a severity scale., Results: Among the 68 patients who met the study's eligibility criteria, at least one error in the initial HIV regimen occurred in 72% of patients, and in 56% of patients, the error had the potential to cause moderate-to-severe discomfort or clinical deterioration. Patients on atazanavir-based therapy had a statistically significant increased occurrence of errors throughout their hospitalization (RR = 1.69; 95% CI 1.03 to 2.78; p = 0.02). Receiving nonformulary (combination) HIV medications increased patients' risk of having more than one error occur in their ARV regimen on admission and during hospitalization (RR = 1.95; 95% CI 1.25 to 3.04; p = 0.02). The clinical pharmacist recommendations had 100% acceptance., Conclusions: The alarmingly high frequency of potentially harmful errors uncovered in this study necessitates further investigation using larger sample sizes. Interventions to reduce and prevent these errors must be sought to eliminate the unintended harm associated with hospitalization.

Purpose: The effects of omeprazole on indinavir when administered alone or in combination with ritonavir were evaluated., Methods: Fourteen men and women age 18-55 years not infected with human immunodeficiency virus who met study qualifications were randomized to receive placebo, 20 mg of omeprazole, or 40 mg of omeprazole daily. After seven days, the single-dose pharmacokinetic profile of an 800-mg dose of indinavir alone or in combination with 200 mg of ritonavir was evaluated. Study participants received each of four study regimens in one of four randomly assigned orders. Blood samples were collected, and plasma indinavir and ritonavir concentrations were analyzed using high-performance liquid chromatography., Results: The coadministration of 20 or 40 mg of omeprazole with indinavir significantly reduced the mean indinavir area under the concentration-versus-time curve (AUC) from 30.0 mg x hr/L (95% confidence interval [CI], 21.9-41.1 mg x hr/L) to 19.7 mg x hr/L (95% CI, 14.6-26.8 mg x hr/L) or 16.0 mg x hr/L (95% CI, 11.8-21.7 mg x hr/L), respectively (p < 0.002). The addition of 200 mg of ritonavir to 800 mg of indinavir in combination with 40 mg of omeprazole significantly increased the mean indinavir AUC from 30.0 mg x hr/L (95% CI, 21.9-41.1 mg x hr/L) to 46.6 mg x hr/L (95% CI, 34.0-63.8 mg x hr/L), but it did not significantly affect mean omeprazole concentrations (p < or = 0.02)., Conclusion: The AUC of indinavir was substantially decreased in healthy volunteers who received omeprazole 20 or 40 mg daily for seven days before the administration of a single 800-mg dose of indinavir. Concomitant administration of ritonavir 200 mg with indinavir in participants receiving omeprazole led to a significant increase in the AUC of indinavir.

Anidulafungin (Vicuron Pharmaceuticals) is a new echinocandin antifungal with potent activity against Aspergillus and Candida spp. Anidulafungin is a noncompetitive inhibitor of (1,3)-beta-D-glucan synthase within fungal cells. The drug is rapidly distributed and steady-state concentrations are achieved after the first dose, when a loading dose of twice the daily maintenance dose is given on day 1. Drug biotransformation occurs via chemical degradation, with no hepatic metabolism or renal elimination. A favorable pharmacokinetic profile and lack of significant drug interactions suggest that patients can receive anidulafungin without dosage adjustments. These characteristics, in addition to comparable efficacy to fluconazole (Diflucan, Pfizer Ltd) in the treatment of esophageal candidiasis, support further investigation of its use in the treatment of systemic fungal infections caused by Candida and Aspergillus spp.

Objective: To evaluate the available clinical data regarding single versus combination antimicrobial therapy for treatment of gram-negative infections, focusing on the more recent data in predominantly nonneutropenic hosts. In vitro and in vivo data regarding various antimicrobial combinations are also discussed., Data Sources: Clinical trials, review articles, and meta-analyses were identified from a MEDLINE search (1960-July 2003). Special attention was given to clinical outcome trials performed since 1989. Search terms included gram-negative infections, drug synergism, Pseudomonas aeruginosa, monotherapy, combination therapy, carbapenems, beta-lactams, cefepime, aminoglycosides, and fluoroquinolones., Data Synthesis: Although most of the studies were not randomized, double-blind, or controlled, the most recent literature indicates that monotherapy with agents that are active against isolated organisms, including P. aeruginosa, may be appropriate for most patients. Efficacy outcomes, including mortality, did not significantly differ in most studies comparing single and combination therapies. Some trials suggest that combination therapy may be preferred in neutropenic patients and those with pseudomonal infections., Conclusions: Hospitalized patients with gram-negative infections are often treated with combination antimicrobial agents; however, some of the recently available data, although limited, suggest that administration of monotherapy is a feasible alternative in certain patient populations.

Objective: To review the data regarding the pharmacotherapy of Lyme disease, Rocky Mountain spotted fever (RMSF), and the human ehrlichioses., Data Sources: English-language literature was identified via MEDLINE (1966-January 2002) using the keywords Lyme disease, Rocky Mountain spotted fever, and ehrlichiosis. Textbooks and other pertinent resources were also reviewed., Study Selection and Data Extraction: All articles identified through the data sources above were evaluated and reviewed if pertinent to the objective., Data Synthesis: Tick-borne diseases are the most common vector-transmitted diseases in North America. Each disease causes significant morbidity and, in the case of RMSF, mortality if patients go untreated. If the disease syndromes are recognized early and treatment is initiated, complications are greatly reduced. Doxycycline is active against each of the causative organisms, simplifying empiric treatment., Conclusions: Effective pharmacotherapy exists to treat each of these diseases, assuming diagnosis is made quickly. The beta-lactam and tetracycline antibiotics appear to be the most effective therapy for Lyme disease. The tetracyclines, but not the beta-lactams, are effective for RMSF and the human ehrlichioses. Since Borrelia burgdorferi and the human granulocytic ehrlichiosis agent are becoming more common coinfecting pathogens, tetracycline or doxycycline should be considered the drugs of choice for patients from endemic areas where exposure to both pathogens may have occurred. Doxycycline is the preferred agent because of decreased frequency of administration and adverse effects.

Objective: Susceptibility and minimum inhibitory concentration (MIC) studies of ampicillin-resistant enterococci (ARE) were performed with vancomycin, ciprofloxacin, and trovafloxacin. Ampicillin MICs were determined to make comparisons with achievable urinary concentrations of ampicillin., Design: From July 1998 to April 1999, all enterococci isolated from urinary specimens were tested for susceptibility to ampicillin by disk diffusion. For all ARE, vancomycin, ciprofloxacin, and trovafloxacin susceptibilities were determined by use of either disk diffusion or the E-test. Ampicillin MICs were determined for these isolates by liquid agar microdilution testing. ARE were identified to the species level on the basis of biochemical reactions., Setting: The study was performed at a university-affiliated tertiary care hospital., Outcome Measures: In vitro susceptibility studies and MIC determinations were performed in accordance with the National Committee for Clinical Laboratory Standards., Results: A total of 310 urine samples were culture positive for enterococcus. Thirty (9.7%) unduplicated isolates were resistant to ampicillin. Of these, nine ARE isolates (30%) were also vancomycin resistant, whereas only 2 ampicillin-susceptible isolates were vancomycin resistant (p < 0.05). All ARE were resistant to ciprofloxacin, and 29 (96.7%) were resistant to trovafloxacin. Nine (30%), 18 (60%), and 3 (10%) isolates had an ampicillin MIC of 128, 256, and 512 micrograms/mL, respectively. Ampicillin MICs did not differ significantly between vancomycin-susceptible and -resistant isolates (p = 0.963). Twenty-seven isolates (90%) were identified as Enterococcus faecium; the other 3 were either Enterococcus avium or Enterococcus raffinosus., Conclusions: Ampicillin resistance is associated with resistance to vancomycin. Most ARE are resistant to fluoroquinolone antibiotics such as ciprofloxacin and trovafloxacin. Ampicillin MICs for ARE found in these urinary specimens were all within 1 dilution of 256 micrograms/mL, a concentration achievable in the urine with higher doses of oral amoxicillin or intravenous ampicillin. Additional studies are needed to assess the clinical implications of these data.

Purpose: To describe a patient who developed oxacillin-resistant Staphylococcus aureus endophthalmitis after insertion of a ganciclovir intraocular implant., Method: Case report., Results: A 42-year-old man with acquired immunodeficiency syndrome (AIDS) and a history of cytomegalovirus retinitis was admitted with right-sided eye pain and decreased visual acuity 10 days after receiving a second ganciclovir intraocular implant in the right eye. A therapeutic vitrectomy, right eye, was performed on the day of admission. A vitreal tap produced frank pus and white, fluffy debris. Cultures of the vitreal fluid grew oxacillin-resistant S aureus, sensitive only to vancomycin, rifampin, and trimethoprim/sulfamethoxazole. The patient was successfully treated with removal of both ganciclovir implants in the right eye and a 4-week course of vancomycin and rifampin. However, the infection left the patient blind in the infected eye., Conclusion: Bacterial endophthalmitis is an infrequent but serious complication of the ganciclovir intraocular implant.

This retrospective cohort study used North Carolina Medicaid paid-claims data to assess clinical and economic outcomes of treatments for urinary tract infection (UTI). The study population comprised female Medicaid recipients, between 15 and 64 years of age, with a paid claim filed for a primary diagnosis of UTI or acute UTI from January 1 to June 30, 1994, who were treated with ciprofloxacin, nitrofurantoin, or trimethoprim/sulfamethoxazole (TMP/SMZ). Patients had follow-up for 6 months after the primary diagnosis. Patients who did not receive further treatment for UTI with 1 of the 3 drugs within 30 days after initial treatment were assumed to be cured. Costs were measured as the sum of reimbursements for UTI-related medical services and drug treatments. Outcomes for 409 patients were assessed. Cure rates of initial treatment with ciprofloxacin, nitrofurantoin, and TMP/SMZ were 81%, 88%, and 93%, respectively. Cost-effectiveness ratios of initial treatment with the 3 drugs were $150.80, $81.20, and $69.00, respectively. When efficacy rates generated from published randomized clinical studies were applied, cost-effectiveness ratios for the 3 drugs were $130.96, $86.17, and $72.00, respectively. A decision model of treatment pattern and associated costs is presented. Several patient variables indicate that the ciprofloxacin group included more severe cases of UTI than did the other groups. Study limitations, confounders, and future research suggestions are discussed. Our results show that treatment for >7 days results in a better cure rate regardless of the drug used than does treatment for < or =7 days and that TMP/SMZ is the most cost-effective of the 3 drugs for UTI or acute UTI.

Objective: A retrospective study was performed to determine whether twice-daily ritonavir 400 mg plus twice-daily saquinavir 400 mg (ritonavir 400/saquinavir 400) was better tolerated than ritonavir 600 mg twice daily (ritonavir 600). A secondary objective was to determine whether the rate of discontinuation due to therapeutic failure differed between the two ritonavir regimens., Design: The study was a retrospective chart review. Data collected included ritonavir dose; length of ritonavir therapy; reason for discontinuation; HIV-1 RNA prior to and at discontinuation of ritonavir therapy; CD4+ count; and antiretroviral therapy prior to, concomitant with, and initiated after ritonavir therapy., Setting: Patient charts were reviewed in a university teaching hospital clinic., Patients: Patients were identified through a search of the pharmacy database from December 18, 1995, to December 18, 1997. Patients were > 18 years old, but not restricted by gender or race., Main Outcome Measures: The main outcome measures were frequency of discontinuation of ritonavir due to intolerance or due to lack of therapeutic efficacy., Results: The search identified 116 patients, including 57 patients taking ritonavir 400/saquinavir 400 and 54 patients taking ritonavir 600. Five patients on other ritonavir regimens were excluded. Significantly fewer patients receiving ritonavir 400/saquinavir 400 (14%) discontinued ritonavir due to intolerance compared with ritonavir 600 (37%; p = 0.002). Discontinuations due to therapeutic failure were not significantly different: 8.8% for ritonavir 400/saquinavir 400 and 7.4% for ritonavir 600, despite the fact that ritonavir/saquinavir therapy followed another protease inhibitor in 41 patients (73.2%) compared with 12 patients (24.5%) for ritonavir 600 (p = 0.001)., Conclusions: Ritonavir 400/saquinavir 400 is better tolerated than ritonavir 600.

Objective: To review the pathophysiology, epidemiology, treatment, and prophylaxis of disseminated Mycobacterium avium complex (MAC) infection in HIV-infected individuals., Data Sources: A MEDLINE (January 1966-July 1997) and AIDSLINE (January 1980-July 1997) search of basic science articles pertinent to the MAC infection in HIV-infected patients., Study Selection and Data Extraction: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion., Data Synthesis: The organism, epidemiology, and pathophysiology of disseminated MAC are discussed for background. A review of clinical trials for the treatment and prophylaxis of disseminated MAC are presented, along with unresolved issues concerning these topics., Conclusions: The incidence of disseminated MAC has increased dramatically with the AIDS epidemic. The infection can lead to increased morbidity and mortality in HIV-infected patients. Treatment regimens for patients with a positive culture for MAC from a sterile site should include two or more drugs, including clarithromycin. Prophylaxis against disseminated MAC should be considered for patients with a CD4 cell count of less than 50/mm3.

Objective: To evaluate the pharmacokinetics of didanosine in patients with normal kidney function or chronic kidney failure., Methods: Three groups of patients with human immunodeficiency virus (HIV) infection were studied: group I, six men with normal kidney function (creatinine clearance > 90 ml/min/1.73 m2); group II, six men with chronic renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD); and group III, four men and two women with chronic renal failure receiving hemodialysis three times a week. A 300 mg dose of didanosine was administered orally and intravenously according to a two-period randomized crossover design. Patients in group III were studied between hemodialysis sessions during the crossover periods. In addition, patients in group III were studied in a third period after administration of a 300 mg oral dose of didanosine 4 hours before hemodialysis., Results: After intravenous administration in group I, the mean (+/-SD) total clearance (CLT) was 13.0 +/- 1.6 ml/min/kg and the elimination half-life (t 1/2) was 1.56 +/- 0.43 hour. In groups II and III, the CLT decreased significantly to 3.4 +/- 1.2 and 3.2 +/- 1.2 ml/min/kg, respectively, whereas the t1/2 increased to 3.60 +/- 0.82 hours and 3.11 +/- 0.88 hours, respectively. The absolute bioavailability of didanosine in groups I, II, and III was 42% +/- 12%, 52% +/- 6%, and 38% +/- 11%, respectively, and did not differ significantly. CAPD had little effect on the removal of didanosine, whereas approximately 30% of the drug present in the body at the start of dialysis was eliminated by an average 3-hour dialysis session., Conclusion: The clearance of didanosine is impaired in patients with chronic renal failure. To compensate, the dose and schedule of administration should be adjusted. It is recommended that one-fourth of the total daily dose of didanosine be administered once a day in this patient population.

Pyrimethamine pharmacokinetics were studied in 11 human immunodeficiency virus (HIV)-positive patients who were seropositive for exposure to Toxoplasma gondii and were taking zidovudine (AIDS Clinical Trials Group Protocol 102). Pyrimethamine was administered at 50 mg daily for 3 weeks to achieve steady state, and pharmacokinetic profiles were determined after administration of the last dose. Noncompartmental and compartmental analyses were performed. Population pharmacokinetic analysis assuming a one-compartment model yielded the following estimates: area under the 24-h concentration-time curve, 42.7 +/- 12.3 micrograms.h/ml; halflife, 139 +/- 34 h; clearance, 1.28 +/- 0.41 liters/h; volume of distribution, 246 +/- 641; and absorption rate constant, 1.5 +/- 1.3 liters/h. These values are similar to those seen in subjects without HIV infection. Pyrimethamine pharmacokinetics did not differ significantly in those subjects who were intravenous drug users. Adverse effects were noted in 73% of those initially enrolled in this study, leading to discontinuation for 38%. No association was noted between pyrimethamine levels and the incidence of adverse events. No significant differences were seen in zidovudine pharmacokinetic parameters obtained from studies performed before and during treatment with pyrimethamine. In summary, pyrimethamine exhibited pharmacokinetics in HIV-infected patients that were similar to those in non-HIV-infected subjects and it did not alter the pharmacokinetics of zidovudine in these patients.

1. Fasting causes atrophy of small bowel mucosa which rapidly resolves with luminal feeding. This effect of enteral nutrient may be mediated by stimulation of growth factor secretion. We therefore evaluated whether luminal administration of epidermal growth factor, a peptide hormone found in gastro-intestinal contents and trophic for small bowel mucosa, would prevent the mucosal atrophy associated with starvation. 2. Adult rats were: (i) fasted for 3 days, (ii) fasted and then refed for 1 day or (iii) fasted and then refed for 2 days. During the 2 days before study, animals in each group received infusions of epidermal growth factor (2.5 micrograms/day) or diluent alone into distal jejunum. 3. Epidermal growth factor treatment of fasted animals resulted in a tripling of mucosal ornithine decarboxylase activity (P < 0.001) and a doubling of mucosal DNA content (P < 0.001) in the jejunum, values similar to those of refed animals. Epidermal growth factor infusion in refed rats resulted in a further doubling of mucosal ornithine decarboxylase activity (P < 0.001), but no additional increase in DNA content. Effects of epidermal growth factor infusion were generally greater in jejunum than ileum. 4. In conclusion, luminal exposure to epidermal growth factor prevents starvation-induced mucosal atrophy in the small bowel, but does not enhance the mucosal growth associated with refeeding. Effects are greatest at the site of administration. Luminal epidermal growth factor is a potential mediator of the indirect effects of nutrient on mucosal growth in the small bowel. Enteral administration of epidermal growth factor holds promise for preventing atrophy and maintaining mucosal integrity in starved and post-operative patients.

Objective: To determine the effect of multiple dosing of combined sulfamethoxazole and trimethoprim on the single-dose pharmacokinetics of lamivudine., Methods: Fourteen subjects with human immunodeficiency virus who had CD4+ cells > or = 200/mm3 received two single doses of 300 mg lamivudine, separated by 7 to 14 days, in a randomized two-day crossover study. Treatment consisted of lamivudine alone versus trimethoprim-sulfamethoxazole (160/180 mg) daily on days 1 through 4 followed by lamivudine plus trimethoprim-sulfamethoxazole on day 5. Blood and urine were collected over 24 to 32 hours to determine lamivudine, trimethoprim, sulfamethoxazole, and N-4-acetylsulfamethoxazole concentrations., Results: Coadministration of a single dose of lamivudine and trimethoprim-sulfamethoxazole after daily dosing for 5 days altered the pharmacokinetics of lamivudine. A 43% increase in area under the concentration-time curve (AUC infinity) and a 35% decrease in renal clearance (CLR) were observed when lamivudine was coadministered with trimethoprim-sulfamethoxazole compared with lamivudine alone. The geometric least-squares trimethoprim-sulfamethoxazole were as follows: AUC infinity, 10,124 (9,432-10,866) and 14,448 (13,461-15,508) ng . hr/ml, respectively; CLR, 16.6 (14.1-19.4) and 10.8 (9.5-12.6) L/hr, respectively. Coadministration did not significantly alter the pharmacokinetics of trimethoprim or sulfamethoxazole., Conclusions: Coadministration of lamivudine with trimethoprim-sulfamethoxazole resulted in an increased AUC infinity and a decreased CLR of lamivudine. However, given the favorable safety profile of lamivudine, it is unlikely that this interaction will result in a significant increase in concentration-related toxicity at the doses studied.

The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over a 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 +/- 192 ng.h/ml), maximum concentration of drug in serum (1,751 +/- 180 ng/ml), and half-life (2.04 +/- 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 +/- 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 +/- 1,222 ng.h/ml) and maximum concentration of drug in serum (5,220 +/- 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2.79 +/- 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 +/- 0.15 in HIV-infected patients with hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy-proven cirrhosis, our results suggest that ZDV, could accumulate in HIV-infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.

Objective: To review the pharmacology, pharmacokinetics, clinical efficacy, and toxicity of ticlopidine. Comparisons with other antiplatelet agents are presented, with an emphasis on efficacy, and a recommendation is provided regarding ticlopidine's place in therapy., Data Sources: A MEDLINE literature retrieval of English-language journal articles from 1987 to January 1993 and references identified from bibliographies of review articles and clinical trials., Study Selection: Randomized, blind, controlled studies of ticlopidine and other antiplatelet agents were preferentially selected., Data Extraction: Clinical trials were reviewed in terms of study design, efficacy results, and toxicity., Data Synthesis: Ticlopidine is a new antiplatelet agent with a distinct mechanism of action. In the largest trial of the drug for the prevention of stroke, it was found to be more effective than aspirin in reducing the risk of stroke or death. Clinical trials have also shown ticlopidine to decrease the rate of vascular death and myocardial infarction in patients with unstable angina, and to maintain venous graft patency after coronary artery bypass grafting. The use of ticlopidine in diabetic microangiopathy and peripheral vascular disease appears promising, but further studies are needed. Adverse reactions most commonly reported with ticlopidine are gastrointestinal complaints; the most severe reaction is transient neutropenia, which is seen in approximately 2.3 percent of patients and is severe in nearly 1 percent., Conclusions: Ticlopidine is a reasonable alternative for use in preventing stroke among patients unable to take aspirin or those who do not benefit from aspirin therapy. Its use as first-line therapy is limited by its high cost and the occurrence of hematologic adverse effects.

The rate-limiting step in cholesterol biosynthesis is controlled by the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Inhibitors of this enzyme lower serum cholesterol very efficiently by increasing cellular uptake of cholesterol-rich, low-density lipoproteins. Pravastatin, a derivative of mevastatin and in the same class as lovastatin, lowers total cholesterol concentrations by 20-30 percent in patients with hypercholesterolemia. In patients who also have hypertriglyceridemia, serum triglyceride levels are decreased. Detailed pharmacokinetic data and long-term adverse-effect experience with pravastatin are extremely limited. The issue of tissue-selectivity for pravastatin has given rise to the marketing terminology "second-generation" HMG-CoA reductase inhibitor, but any clinical advantage of pravastatin over other HMG-CoA reductase inhibitors remains to be demonstrated.

Fungal infection is a rare cause of peritonitis among patients receiving continuous ambulatory peritoneal dialysis. Most cases of fungal peritonitis are secondary to candida infection. Two uncommon agents of fungal peritonitis are Curvularia species and Trichosporon beigelii. We report on two patients receiving peritoneal dialysis who presented for medical evaluation within a 1-week period. Fungal culture of the dialysis catheter was positive for Curvularia species in one case and for T. beigelii in the other. Both patients probably had acquired their infections through environmental contamination. Successful treatment of these infections includes removal of the peritoneal dialysis catheter and administration of intravenous amphotericin B.

This study was undertaken to determine if the proportions of intravenous carbohydrate and fat calories influence the relative growth of a Walker 256 carcinosarcoma and its host. Rats injected intraperitoneally with Walker 256 carcinosarcoma cells were randomized into three total parenteral nutrition (TPN) groups, G/AA in which glucose provided all nonprotein calories, G/F/AA in which the nonprotein calories were 20% fat and 80% glucose, and F/AA in which all nonprotein calories were from fat. Except for the caloric source, TPN for each group was identical. A fourth group was sham operated, fed rat food, and was not given TPN. On the 6th day after inoculation, the tumor in each rat showed a dispersed ascites form as well as a solitary mass form involving the omentum. The total number of tumor cells in the ascitic fluid and the dry weight of the mass were determined. The three TPN groups did not differ in tumor cell count, solid tumor weight, ratio of tumor cell count to final host weight, or ratio of solid tumor to final host weight. The mean ratio of ascites tumor cell count to host weight was not different between the rat food-fed group and any of the TPN groups. The mean ratio of solid tumor to host weight was less for the TPN groups than for rat food-fed animals. We conclude that TPN had no adverse effect on the growth of tumor vs. host and that the source of intravenous calories (fat or carbohydrate) did not influence the relative growth of tumor and host in this TPN-tumor model.

Geriatric patients often require precise dose titration of certain drugs for effective, non-toxic treatment of chronic disease. When short-term antibiotic therapy is required, an oral antibiotic that would minimally disrupt a finely-tuned chronic drug regimen would be most appropriate. Chronic medication-antibiotic interactions are potentially more common with the use of erythromycin, tetracyclines, and sulfonamides. Clinicians should use care, and monitor for drug interactions when these agents are combined with chronically used drugs such as theophylline, warfarin, or carbamazepine.

To determine whether intraluminal administration of epidermal growth factor (EGF) has a trophic effect on small bowel mucosa, catheters were surgically placed in the ileum of adult rats and infused with EGF. Comparing animals receiving EGF (5 micrograms/48 h) with controls, in the ileum mean mucosal ornithine decarboxylase specific activity increased by greater than 200% (p less than 0.001), mean deoxyribonucleic acid specific activity and crypt labeling index increased by greater than or equal to 100% (p less than 0.001), and mean deoxyribonucleic acid content of the mucosa increased by 25% (p less than 0.05). During these studies, the jejunum was not exposed to ileal infusate, as shown with the use of a phenol red marker. Nevertheless, all measurements except deoxyribonucleic acid content increased in the jejunum as well, although to a lesser extent. A greater rise in mucosal ornithine decarboxylase and deoxyribonucleic acid specific activity could be demonstrated in the jejunum when EGF was infused directly into this segment. Mucosal ornithine decarboxylase activity was found to be dose-dependent and to increase in the ileum only after a latent period of 12-24 h. We conclude that intraluminal administration of EGF stimulates a mucosal proliferative response in the small intestine. Intraluminal EGF appears likely to be one of a number of endogenous trophic factors in the small bowel.

Patients with calcinosis universalis secondary to dermatomyositis or systemic sclerosis have increased levels of the calcium-binding amino acid, gamma-carboxyglutamic acid. The enzyme that effects gamma carboxylation of glutamic acid is warfarin-sensitive. Four patients with calcinosis universalis were treated with 1 mg per day of warfarin for 18 months in a non-blind initial study. Two patients had both decreased gamma-carboxyglutamic acid urinary concentration and decreased extra-skeletal uptake on technetium 99m-diphosphonate whole-body nuclear scanning. In a subsequent double-blind placebo study, two thirds of the patients receiving 1 mg per day of warfarin had decreases in extra-skeletal nuclear tracer uptake after 18 months, compared with none of the four patients receiving placebo. No patient had a change in clinical assessment, bleeding complication, or baseline normal prothrombin time. This low-dose warfarin regimen appears to have no demonstrable adverse effects, and these results suggest a beneficial effect on the progression of calcinosis in these rheumatic diseases.

Hypersensitivity reactions due to chloramphenicol are rarely reported in the literature. We present a case report of a patient with typhoid fever who experienced a hypersensitivity reaction subsequent to the infusion of chloramphenicol sodium succinate. The patient had previously reacted similarly to ampicillin infusion. A brief review of reported cases of chloramphenicol hypersensitivity in the English-language literature, as well as possible alternative explanations in this case, are provided.

During a 6-week period, all adult patients in a university hospital receiving ready-to-feed nasoenteric tube feeding formula were prospectively studied. The study objective was to determine each patient's caloric intake from tube feeding relative to their energy needs and to identify factors causing decreased feeding intake. Each of 35 patients was visited at least once daily to determine their volumetric intake of tube feeding formula. Daily review of patient care records and nursing interviews were used to identify interruptions in therapy. Patient's basal energy expenditures (BEE) were calculated using the Harris-Benedict equation. Calorie goals were set by members of the Nutrition Support Service or clinical dietitians. Intakes averaged 1095 +/- 41 Kcal (SEM) per day or 61% of their mean calorie goal of 1791 +/- 41 Kcal. Mean daily calorie intake was statistically different (p less than 0.05) from mean energy goal on patient study days 1 through 5, 7, and 8. Only 16 of the 35 patients achieved an intake of 100% of their energy goal on any day of therapy. Calorie goals averaged 1.4 times BEE. Mean daily calorie intake did not exceed BEE until study day 10. Eighteen % of potential feeding time was lost due to temporary feeding interruptions; primarily inadvertent extubation (4.6%), gastrointestinal intolerance (4.7%), medical procedures requiring discontinuation of feeding (2.8%), and feeding tube positioning difficulties (1.5%). In addition, physicians ordered only 75% of calculated energy goals. These data indicate that tube feeding therapy, when provided under usual hospital conditions, does not meet patient's energy requirements.

The known relationship of hyperlipidemia and pancreatitis raises the question whether intravenous fat emulsion is detrimental in acute pancreatitis. Pancreatitis was induced in 52 male Sprague-Dawley rats followed by placement of a jugular catheter which was anchored to the back with a Teflon button. The animals were placed NPO in metabolic cages and continuously infused, initially with normal saline. The 37 animals surviving 24 hr were randomly assigned to group I (mean iv intake: glucose 222 kcal/kg/day; amino acids 13.1 g/kg/day) or group II (glucose 191 kcal/kg/day; intravenous fat emulsion 10% 47 kcal/kg/day; amino acids 12.9 g/kg/day). Nine animals were eliminated from the study because of mechanical problems leaving 14 in each group for analysis. Per cent survival on days 3, 5, and 7 was 64, 50 and 36 in group I, and 50, 36 and 36 in group II. Mean urinary amylase excretion was 244 +/- 185 units/day in group I and 262 +/- 127 units/day in group II. There was no significant difference in survival or urine amylase excretion nor in pancreatic histology or gross appearance of the animals between the two groups. In this model of acute pancreatitis, intravenous fat emulsion was not detrimental as measured by survival, urinary amylase excretion, and pancreatic histology.

A case of apparent association of dextran 70 therapy with reduced factor VIII activity in a 24-year-old white woman with thrombotic thrombocytopenic purpura (TTP) is reported. Diagnosis of TTP was based on clinical and laboratory data consistent with transient neurological deficits, thrombocytopenia and hemolytic anemia. Intravenous dextran 70 (250 ml every 12 hours) and oral prednisone (80 mg daily) were given for TTP. Additional oral medications included codeine, Maalox and Tabron. When assay showed a factor VIII activity of 14% on the third day of dextran 70 administration, the drug was discontinued and oral administration of dipyridamole (100 mg four times daily) was begun. Factor VIII activity increased to 82% on day six. Dextran 70 (125 ml every 12 hours) was resumed on day seven following a splenectomy on the previous day. When factor VIII activity subsequently decreased from 75% to 29% within two days, dextran 70 was again discontinued and dipyridamole reinstituted at its earlier dosage. The patient's discharge medications included dipyridamole and 60 mg of prednisone daily (to be tapered). Reports of dextran 70-induced hemostatic defects involving platelets and factor VIII are reviewed. Dextran will form, with factors I and VIII, cryoprecipitates that may reduce the activity of factor VIII. It is suggested that patients receiving dextrans be monitored with partial thromboplastin times and, if available, with assays of factor VIII activity.