Stability of sumatriptan succinate in extemporaneously prepared oral liquids.

The stability of sumatriptan succinate in extemporaneously prepared oral liquids was studied. Suspensions of sumatriptan (as the succinate salt) in Ora-Sweet, Ora-Sweet SF, and Syrpalta syrups (Paddock Laboratories and Humco Laboratory) were extemporaneously compounded to produce a sumatriptan concentration of 5 mg/mL. Each suspension was prepared in triplicate. The suspensions were stored at 4 degrees C in amber glass bottles for 60 days. Two 1-mL samples were removed from each bottle initially and on days 2, 7, 14, 21, 28, 35, and 60. Sumatriptan concentrations were determined by high-performance liquid chromatography. The samples also underwent visual inspection and microbial testing. The mean concentration of sumatriptan in all suspensions remained above 90% of the initial concentration for up to 21 days. By day 28, the sumatriptan concentration of all suspensions had decreased to less than 90% of the initial concentration. None of the suspensions had microbial growth up to day 28, and there were no visible changes in the suspensions throughout the study period. Sumatriptan 5 mg/mL (as the succinate salt) in three oral suspensions was stable for up to 21 days when stored without light at 4 degrees C.

Rapid postmortem invasion of cecal mucosa of macaques by nonpathogenic Entamoeba chattoni.

Although Entamoeba histolytica is the third leading parasitic cause of death in the world, most infections in humans are asymptomatic and restricted to the intestinal lumen. Entamoeba histolytica infections have also been reported in most species of captive nonhuman primates, with New World monkeys being particularly susceptible to fatal invasive amebiasis. In contrast, Old World monkeys appear to be resistant to the disease, although tissue invasion in asymptomatic monkeys has been reported. Our initial objectives were to determine the incidence, the predisposing factors, and the light microscopic and ultrastructural features of invasive amebiasis in Macaca mulatta (rhesus) and and M. fasicularis (cynomolgus) macaques. Our findings indicate that nonpathogenic E. chattoni in macaques can invade cecal mucosa rapidly (within 1 hr) after death. Therefore, the presence of invasive Entamoeba trophozoites in routinely collected necropsy materials should be interpreted with caution, particularly in cases where tissue fixation is delayed.

Pretreatment regimens for adverse events related to infusion of amphotericin B.

Infusion-related adverse events (IRAEs) such as nausea, vomiting, fever, chills, and thrombophlebitis that are associated with amphotericin B therapy often lead clinicians to prescribe a number of adjunctive pretreatment medications in an attempt to reduce the incidence and severity of these events. The purpose of this study was to determine the incidence of IRAEs during the first week of systemic amphotericin B therapy and to identify pretreatment regimens that are effective in preventing these IRAEs. Three hundred ninety-seven adult inpatients receiving amphotericin B therapy were prospectively monitored, and data regarding IRAEs and pretreatment regimens were collected. Of these patients, 282 (71%) developed at least one IRAE during the first 7 days of therapy. The IRAEs most commonly reported were fever (51% of patients) and chills (28%), followed by nausea (18%), headache (9%), and thrombophlebitis (5%). The most common regimens included diphenhydramine, a corticosteroid, acetaminophen, and heparin, administered alone or in combination with these or other drugs. Overall, common pretreatment regimens were similar in efficacy to no pretreatment in the prevention of IRAEs. Thus empirical premedication for IRAEs associated with amphotericin B cannot be routinely advocated; instead, patients should be treated when symptoms first arise and then premedicated for subsequent amphotericin B infusions.

Pharmacokinetics and safety of levofloxacin in patients with human immunodeficiency virus infection.

Levofloxacin, the bacteriologically active isomer of ofloxacin, has microbiologic activity against many pathogens common in human immunodeficiency virus (HIV)-infected patients, including Mycoplasma species which may be cofactors in the progression of HIV disease. The purpose of this phase I, double-blind, randomized (1:1), placebo-controlled trial was to evaluate the pharmacokinetics and safety of levofloxacin hemihydrate in 10 asymptomatic HIV-infected males. Plasma concentrations by chiral high-performance liquid chromatography (HPLC) were evaluated for 48 h after a single 350-mg oral dose, at morning predose during the multiple-dosing phase, and for 72 h at steady state after a week of 350 mg every 8 h orally. Mean +/- standard deviation levofloxacin pharmacokinetic parameters (by noncompartmental moment method) after multiple dosing were as follows: area under the concentration-time curve, 31.24 +/- 5.60 mg.h/liter; apparent total body clearance, 11.18 +/- 1.76 liters/h; renal clearance, 8.63 +/- 2.82 liters/h; steady-state volume of distribution, 104.10 +/- 12.48 liters; and effective half-life, 6.50 +/- 0.51 h. Single-dose parameters were not significantly different from the multiple-dose parameters, with the exception of peak concentrations in plasma, which were 4.79 +/- 1.00 and 6.92 +/- 1.56 mg/liter for single- and multiple-dose data, respectively. Essentially identical parameter values were obtained from curve-fitting analysis when the entire 13-day plasma concentration profiles of the subjects were analyzed simultaneously by a two-compartmental distribution model. Levofloxacin pharmacokinetics in HIV-infected patients remained linear upon multiple dosing. The dosing regimen studied provides levels in plasma and urine well above those found to be effective in vitro against pathogens common in HIV-infected patients. Levofloxacin was well- tolerated in this group of asymptomatic HIV-infected males: there were no statistically significant differences in adverse effects in the two groups (P = 0.22). Use of placebo control helped to differentiate disease-related adverse effects from those related to the study drug.

Use of antifungal therapy in hospitalized patients. I. Results prior to the marketing of fluconazole.

OBJECTIVE: To evaluate the use of antifungal agents in hospitalized patients prior to marketing of fluconazole and to assess characteristics associated with their use. DESIGN: A cohort of hospitalized patients receiving topical or systemic antifungal therapy was monitored concurrently. SETTING: Sixty-nine hospitals ranging in size from 100 to more than 500 beds, 70.1 percent affiliated with medical schools. PATIENTS: Participating clinical pharmacists each identified 15 consecutive patients receiving systemic antifungal therapy and 5 consecutive patients receiving topical antifungal therapy at their institutions. Data collection began October 1989 and ended March 1990. INTERVENTION: All data collected were observational in nature, and no patient intervention was required. MEASURES: Characteristics of patients receiving antifungal therapy were compared using t-tests and chi-square tests. Utilization and patterns of use of antifungal therapy were reported. RESULTS: The most common risk factors necessitating antifungal therapy, in descending order, were: administration of broad-spectrum antibiotics and/or presence of invasive catheters, carcinoma, AIDS, leukemia or lymphoma, diabetes mellitus, solid organ or bone marrow transplantation, and chronic obstructive pulmonary disease. Five hundred seventeen patients received systemic therapy and 464 (89.7 percent) received a single systemic agent. Of these, 242 (52.2 percent) received amphotericin B, 215 (46.3 percent) received ketoconazole, 6 (1.3 percent) received flucytosine, and 1 (0.2 percent) received intravenous miconazole. Fifty-three patients received two systemic agents either concurrently or consecutively. Ketoconazole was most often used for presumed or documented oral, urogenital, or esophageal infections and amphotericin B was the preferred agent for disseminated infections and fungemia (p < 0.001). Almost half of the patients receiving amphotericin B or ketoconazole (48.3 percent) received these drugs as empiric therapy. Documented infections were more likely to be treated with amphotericin B (54.8 percent) than with ketoconazole (27.4 percent) (p < 0.001). The predominant fungal isolates were Candida albicans, Candida spp., and unspecified yeasts. Amphotericin B toxicity led to discontinuation of drug therapy in only 5.1 percent of cases. Two hundred sixty-nine patients (34.2 percent) received topical antifungal therapy only. Nystatin oral suspension was prescribed to 65.3 percent of the patients, clotrimazole troches to 23.0 percent, amphotericin B irrigation to 10.9 percent, and nystatin tablets to 0.8 percent. CONCLUSIONS: The utilization patterns of antifungal agents in this survey follow established therapeutic guidelines. Prior to the introduction of fluconazole, amphotericin B was the agent of choice for documented systemic fungal infections. Ketoconazole was more often used for prophylaxis of fungal infections and treatment of oral and esophageal infections.

Use of antifungal therapy in hospitalized patients. II. Results after the marketing of fluconazole.

OBJECTIVE: To evaluate the prescribing patterns of antifungal agents in the hospital setting after the introduction of fluconazole, a new broad-spectrum bis-triazole antifungal agent. Also compared are the prescribing patterns of antifungal agents prior to (phase I) and following (phase II) fluconazole marketing. DESIGN: A prospective cohort of hospitalized patients prescribed topical or systemic antifungal agents. Data were collected from December 1990 to April 1991. SETTING: Fifty-seven hospitals ranging in size from 100 to more than 500 beds. Sixty-three percent are affiliated with medical schools. PATIENTS: Participating pharmacists consecutively identified 15 patients receiving systemic antifungal therapy and 5 patients receiving topical antifungal therapy. INTERVENTIONS: Observational data on patient antifungal therapy, risk factors for fungal infections, comorbidities, concurrent medications, and culture data were collected. MEASURES: Differences in prescribing patterns before and after the marketing of fluconazole were assessed using t-tests and chi-square tests. RESULTS: Of 818 patients studied, 615 (75.2 percent) received systemic antifungal therapy. Five hundred forty-six patients received a single antifungal agent; 348 (63.7 percent) received fluconazole, 105 (19.2 percent) received ketoconazole, 92 (16.8 percent) received amphotericin B, and 1 (0.2 percent) received flucytosine. Sixty-nine patients received two or more systemic agents either concurrently or consecutively. The use of parenteral amphotericin B, alone or in combination with flucytosine and/or an azole, declined from 56.8 percent in the phase I study to 24.2 percent in the current study. The use of parenteral therapy also declined from 56.8 to 40.2 percent. Ketoconazole was used in more than 90 percent of the oral and esophageal infections in the phase I study, but its use declined to only 33 percent in this study. Fluconazole was used most frequently across all sites of presumed or documented infections, with the exception of fungemia. Of the presumed or proven systemic or blood infections, amphotericin B was used alone or in combination in 48.4 percent of the patients and fluconazole was used exclusively in 39.0 percent of the patients. Fluconazole was used more often than amphotericin B (22 vs. 3 patients, respectively) for prophylaxis of systemic infections. The overall use of antifungal prophylaxis also increased from the phase I (9.5 percent) to phase II (13.7 percent). CONCLUSIONS: The introduction of fluconazole had a major impact on the prescribing patterns of antifungal therapy. Although amphotericin B remained the preferred agent for treatment of suspected or proven systemic, central nervous system, or blood infections, use of fluconazole for these indications approached nearly 40 percent. Further studies are needed to address the role of fluconazole in the prophylaxis and treatment of systemic mycoses.

Pneumocystis carinii pneumonia in human immunodeficiency virus-infected infants and children.

Pneumocystis carinii pneumonia (PCP) is the most common opportunistic infection in adults and children infected with the human immunodeficiency virus (HIV). Without prophylaxis, half of all these children will develop PCP at sometime during their illness. The disease is associated with high mortality and a poor prognosis for long-term survival in this patient population. In infants and young children, PCP may be a primary infection, compared with reactivation of a latent infection that is usually the case in older children and adults. Clinical features, radiographic findings and diagnostic strategies are similar in children and adults. Although alternative agents are being investigated, trimethoprimsulfamethoxazole (TMP-SMX) and pentamidine remain the standard therapeutic agents. Insufficient data are available to recommend routine adjunctive corticosteroids in children with acquired immunodeficiency syndrome (AIDS), PCP, and significant respiratory disease. Prophylaxis against PCP occurrence or recurrence is indicated for HIV-infected children and infants under 1 year of age, children with less than 20% T4 helper lymphocytes, those meeting age-related Centers for Disease Control (CDC) guidelines for prophylaxis, and those with a history of suspected or documented PCP. The CDC recommends intermittent TMP-SMX for PCP prophylaxis in children with AIDS.

Antifungal prophylaxis in immunocompromised hosts.

OBJECTIVE: To review the literature on the efficacy and safety of antifungal agents for prophylaxis of fungal infections in populations of immunocompromised hosts (key words: hematology-oncology, surgical, solid organ transplant, HIV infection), and to develop guidelines and recommendations regarding safe and effective drug regimens for antifungal prophylaxis in this patient population. DATA EXTRACTION: Comprehensive review of clinical trials of antifungal prophylaxis published in the English literature, with an emphasis on controlled trials, and discussion of key clinical trials illustrating efficacy and safety of agents for antifungal prophylaxis in immunocompromised patients. RESULTS: Much of the clinical data evaluating the efficacy and safety of antifungal prophylaxis has been generated in cancer patients. The choice of antifungal agent for prophylaxis in this population remains controversial. However, azole compounds such as clotrimazole, ketoconazole and fluconazole appear to be more effective and better tolerated than nystatin suspension. Although ketoconazole has been shown to reduce fungal colonization in surgical patients, current data do not support the routine use of antifungal prophylaxis in this population. In renal transplant recipients, clotrimazole troches have been shown to be more effective than placebo or nystatin suspension. Selective bowel decontamination with nonabsorbable antibiotics and nystatin may be useful in reducing Candida colonization in liver transplant patients but no definitive recommendations may be made at this time regarding optimal antifungal prophylaxis in these patients. In patients with advanced HIV disease or history of prior fungal disease prophylaxis for oropharyngeal candidiasis is indicated, although the agent of choice remains controversial. Fluconazole is the drug of choice for prevention of relapse of cryptococcal meningitis in patients with AIDS. Finally, only limited data exist assessing the relationship between local colonization and systemic fungal infection. Adverse effects associated with antifungal prophylaxis, generally limited to nausea and vomiting and transient elevations in hepatic transaminases, occur with similar frequency among available oral or topical agents. However, the incidence of nausea and vomiting with resultant poor patient tolerance and compliance is usually higher with nystatin. CONCLUSIONS: Based on available data from controlled clinical trials, azole agents are currently the most effective and best-tolerated drugs for antifungal prophylaxis in immunocompromised hosts. Choice of one agent in this group over another may be dictated by cost. As new antifungal treatments are released onto the market, these drugs should be compared with existing agents in controlled clinical trials. Future studies should be designed to evaluate the relationship between local colonization and disseminated infection.

Nonsteroidal anti-inflammatory drug-associated pulmonary infiltrates with eosinophilia. Review of the literature and Food and Drug Administration Adverse Drug Reaction reports.

OBJECTIVE: The purpose of this study was to detail the clinical and pathologic presentation of pulmonary infiltrates with eosinophilia (PIE) associated with nonsteroidal anti-inflammatory drug use. METHODS: We reviewed case reports and Food and Drug Administration Adverse Drug Reaction Spontaneous Reporting Program reports. RESULTS: A case of pulmonary infiltrates with eosinophilia related to naproxen use was studied. Six similar cases from the medical literature and 22 reports from the Food and Drug Administration were reviewed. Four cases of PIE associated with ibuprofen, obtained from the Food and Drug Administration, and single literature reports of PIE associated with fenoprofen and sulindac detailed similar clinical presentations. The clinical presentation of PIE syndrome associated with nonsteroidal anti-inflammatory drugs included fever, cough, dyspnea, infiltrates on chest roentgenogram, and an absolute peripheral eosinophilia. Pathologic examination revealed poorly defined granulomas with infiltrating eosinophils. CONCLUSIONS: Naproxen and other nonsteroidal anti-inflammatory drugs can elicit the PIE syndrome. The prevalence of this side effect is likely underestimated, given the extensive use of these drugs and the relatively benign course of PIE syndrome.

A nationwide survey of clinical laboratory methodologies for fungal infections.

Many hospitalized patients are at risk for fungal infections. In order to characterize present clinical laboratory experience and facilities for diagnosis and management of fungal infections, a nationwide survey of laboratory diagnostic methodologies was conducted. Data from calendar year 1988 were collected from 71 institutions (52 university teaching hospitals and 19 community hospitals) enrolled in the Drug Surveillance Network. Surveyed hospitals received 75,828 specimens for fungal culture in 1988, representing 18,705 positive cultures from 7373 patients. About 1.3% of patients admitted to teaching or community hospitals had positive fungal cultures, the most common isolates being Candida species. Yeast identification was most commonly performed by the germ tube test and carbohydrate assimilation testing. Dimorphic fungi were identified to the species level at 67% of hospitals. Cryptococcal antigen testing was available at all hospitals, and Candida serology testing was done at 55 institutions. A small number of hospitals performed antifungal drug concentration determinations for amphotericin B (n = 9), ketoconazole (n = 7) and flucytosine (n = 12). Fungal susceptibility testing was available at 77% of hospitals, either within the institution or at an external laboratory. Laboratory testing for diagnosis and management of fungal infections represents a major laboratory investment. Proficiency in this area, along with expert clinical advice, will be needed to advance therapy of patients complicated with fungal infections during the next decade.

Compatibility of ciprofloxacin injection with selected drugs and solutions.

The compatibility of ciprofloxacin injection with selected antimicrobials and aminophylline was studied. Ciprofloxacin, amikacin sulfate, aminophylline, clindamycin phosphate, gentamicin sulfate, and tobramycin sulfate were mixed separately in minibags containing 0.9% sodium chloride injection or 5% dextrose injection; admixtures were stored for up to 48 hours at either 4 degrees C or 25 degrees C. Ciprofloxacin was also combined separately with each of the other drugs and solutions and stored under the same conditions. In addition, ciprofloxacin was combined with metronidazole in ready-to-use mini-bags of the latter drug and stored at 25 degrees C. Drug concentrations were measured by fluorescence polarization immunoassay or high-performance liquid chromatography. All admixtures were also examined visually. Stability was defined as retention of at least 90% of the original drug concentration with no visual evidence of incompatibility. With one exception, drugs in all single-drug admixtures were stable for 48 hours. The drug concentration eight hours after amikacin was mixed in 0.9% sodium chloride and refrigerated was 89% of the original concentration. When ciprofloxacin was combined with gentamicin, metronidazole, or tobramycin, all of the involved drugs were stable for 48 hours. Compatibility of ciprofloxacin-amikacin admixtures depended on the fluid and storage temperature; all such admixtures were stable for at least eight hours. A precipitate formed immediately whenever ciprofloxacin was mixed with clindamycin and within four hours after ciprofloxacin was mixed with aminophylline. Ciprofloxacin injection was compatible with gentamicin, metronidazole, and tobramycin and incompatible with aminophylline and clindamycin. The compatibility of ciprofloxacin-amikacin admixtures depended on the i.v. solution and storage temperature.

Management of Lyme disease.

The microbiology, transmission, epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Lyme disease are reviewed. Lyme disease, a tick-borne syndrome, was first described in 1975. The etiologic agent of Lyme disease is Borrelia burgdorferi, a slow-growing spirochete. Lyme disease is the most prevalent tick-borne disease in this country; endemic areas in the United States include the northeastern, north central, and western regions. Both infectious and immunologic mechanisms are important factors in the pathogenesis of Lyme disease. The primary mechanism, however, is thought to be infectious. Three stages of Lyme disease have been described; stage I, characterized by erythema chronicum migrans and flu-like symptoms; stage II, characterized by dermatologic, ophthalmologic, neurologic, and cardiac disorders; and stage III, characterized by arthritis, a multiple sclerosis-like syndrome, psychiatric disorders, and a chronic fatigue syndrome. Therapy with penicillin or tetracycline hastens the resolution of stage I symptoms. Treatment duration normally ranges between 10 days and three weeks. Tetracycline or doxycycline appears to be more effective than penicillin in preventing the development of late Lyme disease. Although intravenous penicillin G and ceftriaxone are both effective for the treatment of late Lyme disease, many clinicians consider ceftriaxone to be the agent of choice. Whether exposed patients from endemic areas should receive antimicrobial prophylaxis is controversial. Further clinical studies are needed to determine optimal therapy for the various stages of Lyme disease, particularly Lyme arthritis.

Prospective surveillance of intravenous amphotericin B use patterns.

Information on amphotericin B use patterns and infusion-related adverse events were prospectively collected from 397 hospitalized adults. The methods of initiating amphotericin B varied greatly, with the majority of patients being gradually titrated to a full maintenance dose over 1-5 days. Overall, 71% of patients experienced at least one episode of an infusion-related adverse event (IRAE) during the first week of therapy. Fever and chills were most commonly observed, with peak frequency on days 1-3, followed by a subsequent decline. A wide variety of pretreatment medications were used to minimize IRAE; the most common regimens included some combination of diphenhydramine, acetaminophen, and corticosteroids, with or without heparin. The majority of patients (84.7%) received a test dose, and although none experienced a severe allergic reaction, one patient subsequently had an anaphylactic episode on the third day of amphotericin B therapy. The use of a test dose and the titration process are attempts to avoid the IRAE frequency associated with large initial doses of amphotericin B, but we observed that they provided little or no benefit. In addition, our study suggests that pretreatment regimens are frequently used in conjunction with the test dose. If the intent of the test dose is to identify patients sensitive to amphotericin B, pretreatment drugs may minimize these adverse events and prevent a complete evaluation of response to the test dose.