Distribution of therapeutic response in asthma control between oral montelukast and inhaled beclomethasone.

The distribution of responses in study populations provides a novel method of comparing the benefit of two treatments. This 6-week, randomised, placebo-controlled, double-blind study compared the effectiveness of oral montelukast with inhaled beclomethasone in chronic asthma by assessing the distribution and overlap of patient responses to therapy, as measured by a clinical outcome (asthma control days). A total of 730 adult patients with asthma, age 15-65 yrs, with a forced expiratory volume in one second (FEV1) at baseline of 50-85% of predicted and > or = 15% improvement in FEV1 after inhaled beta-agonist were enrolled. After a 2-week placebo run-in period, patients were randomly allocated to receive montelukast (10 mg once daily), inhaled beclomethasone (200 microg twice daily) or placebo. The primary end-point (per cent of asthma control days) was compared between treatments as the overlap in the response distributions. The overlap of the distribution of responses between the montelukast and beclomethasone groups was 89% for per cent asthma control days and 96% for change from baseline in FEV1. The mean (+/-SD) per cent asthma control days in the montelukast and beclomethasone groups was significantly higher than that in the placebo group (placebo 40.0+/-35.8, montelukast 50.7+/-37.1, beclomethasone 57.9+/-36.1). The mean differences between montelukast and placebo, beclomethasone and placebo, and montelukast and beclomethasone were significant. The mean per cent change (+/-SD) from baseline in FEV1 was 12.1+/-18.7 and 13.9+/-20.8 in the montelukast and beclomethasone groups, respectively, and significantly greater than that in the placebo group (6.4+/-20.1); there was no significant difference between the montelukast and beclomethasone groups in mean values or response distribution. There was also no difference among treatment groups in the frequency of adverse experiences. A comparison of the response distribution is an important approach to comparing therapies; montelukast and beclomethasone provided similar response distributions for the end-point of per cent asthma control days over a 6-week treatment period.

Single-dose miconazole nitrate vaginal ovule in the treatment of vulvovaginal candidiasis: two single-blind, controlled studies versus miconazole nitrate 100 mg cream for 7 days.

To determine the efficacy and safety of a single-dose (1200 mg) soft gel insert (vaginal ovule) with miconazole nitrate (2%) topical cream compared with Monistat 7 (miconazole nitrate 2%) Vaginal Cream (Advanced Care Products, North Brunswick NJ) in treating vulvovaginal candidiasis (VVC), two randomized, single-blind, multicenter, controlled, comparative phase III studies were performed. Five hundred fifty-eight patients received either a single-dose miconazole nitrate (1200 mg) ovule or seven consecutive doses of Monistat 7. Ovule arm patients also received miconazole nitrate 2% cream for symptom relief, as needed, up to twice daily. The primary end point was a therapeutic cure. Also evaluated were time to complete symptom relief, safety, and patient preference. The ovule had overall cure rates of 71.7% (71 of 99 patients) and 61.5% (64 of 104 patients). Monistat 7 had overall cure rates of 70.1% (68 of 97 patients) and 61.1% (55 of 90 patients). A significantly greater proportion of patients experienced complete symptom relief by day 3 with the ovule (p = 0.008 and p = 0.025), and time to complete relief was significantly faster (median 4 versus 5 days and 3 versus 4 days). Overall safety results were consistent between groups in both studies. Miconazole nitrate vaginal ovule is as safe and efficacious in curing VVC as Monistat 7 while providing complete symptom relief significantly faster. Patients preferred the ovule to prior therapy.

The Costa Rican emergency medicine residency: design and implementation of a new specialty training program in Central America.

A program of physician training in the specialty of emergency medicine was developed in Costa Rica, Central America, during the years 1993 and 1994. The program involved 2 phases: a faculty preparation course, and the residency itself. The preparation of faculty members for the residency was undertaken in Costa Rica, with a US emergency faculty physician residing in the host country to assist in the development of the program. Twenty-one faculty members were prepared to teach the residency curriculum. A core group of Costa Rican physician educators with assistance from the US emergency medicine specialist developed a curriculum suitable for the needs of the region. A selection process for prospective applicants to the residency program is described. The first residents began training in February 1994, just before completion of the faculty program. The first emergency medicine specialists graduated from the 3-year training program in 1997. The residency program continues to function at the time of this publication. This description is offered as one model for the initiation of emergency medicine specialty training in a developing country.

Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/Beclomethasone Study Group.

BACKGROUND: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma. OBJECTIVE: To compare the clinical benefit of montelukast, a once-daily oral leukotriene receptor antagonist; placebo; and inhaled beclomethasone. DESIGN: Randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 12-week study. SETTING: 36 sites worldwide. PATIENTS: 895 patients 15 to 85 years of age with chronic asthma and an FEV1 50% to 85% of predicted. INTERVENTIONS: Montelukast, 10 mg once daily at bedtime; inhaled beclomethasone, 200 microg twice daily, administered with a spacer device; or placebo. MEASUREMENTS: Primary end points were daytime asthma symptom score and FEV1. Secondary end points were peak expiratory flow rates in the morning and evening, as-needed beta-agonist use, nocturnal awakenings, asthma-specific quality of life, and worsening asthma episodes. RESULTS: Over the 12-week treatment period, the average percentage change from baseline in FEV1 was 13.1% with beclomethasone, 7.4% with montelukast, and 0.7% with placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). The average change from baseline in daytime symptom score was -0.62 for beclomethasone, -0.41 for montelukast, and -0.17 for placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). Each agent improved peak expiratory flow rates and quality of life, reduced nocturnal awakenings and asthma attacks, increased the number of asthma-control days, and decreased the number of days with asthma exacerbations (P < 0.001 for each active treatment compared with placebo for each end point; P < 0.01 for beclomethasone compared with montelukast for each end point). Although beclomethasone had a greater mean clinical benefit than montelukast, montelukast had a faster onset of action and a greater initial effect. The two agents caused similar decreases in peripheral blood eosinophil counts (P < 0.05 for each agent compared with placebo). Both agents had tolerability profiles similar to that of placebo over the 12-week study. CONCLUSIONS: Although beclomethasone had a larger mean effect than montelukast, both drugs provided clinical benefit to patients with chronic asthma. This finding is consistent with the use of these agents as controller medications for chronic asthma.

Efficacy of twice-daily amoxycillin/clavulanate in lower respiratory tract infections.

In this double-blind, double-dummy study, 324 patients with clinical evidence of community-acquired pneumonia (CAP) or an acute exacerbation of chronic bronchitis were randomly assigned to receive 10 days' treatment with either amoxycillin/clavulanate 875/125 mg twice daily or amoxycillin/clavulanate 500/125 mg three times daily. At the end of therapy, clinical success rates were 92.4% for the twice daily regimen and 94.2% for the three times daily regimen. There was no statistically significant difference between treatments (p = 0.647) and the 95% confidence interval around the treatment difference indicated that the two treatments were equivalent. Treatment equivalence was also confirmed at follow-up, four weeks after the end of treatment. Both regimens were well tolerated. In conclusion, amoxycillin/clavulanate 875/125 mg twice daily is as effective as amoxycillin/clavulanate 500/125 mg three times daily for the treatment of community-acquired lower respiratory tract infections and could improve patient compliance.

Ofloxacin treatment of difficult infections of the skin and skin structure.

We report an open evaluation of ofloxacin therapy, 400 mg every twelve hours (parenterally followed by oral treatment) in hospitalized subjects with infections of the skin and skin structure that were recalcitrant. There were 105 evaluable subjects with an average age of fifty-five years, thirty-two (30 percent) of whom had diabetes mellitus, and in sixty-one (58 percent), a regimen of parenteral antibiotics (typically combinations involving aminoglycosides) had recently failed. There were 115 pathogens isolated; the most common were Enterobacteriaceae (fifty-five), Staphylococcus aureus (thirty), coagulase-negative Staphylococcus (ten), and Pseudomonas aeruginosa (ten). Overall, 103 (90 percent) pathogens were eradicated by therapy, and twelve (10 percent) persisted, including four coagulase-negative Staphylococcus which emerged as resistant during therapy. For thirty-five (33 percent) subjects, colonization or superinfection was documented; seven of these organisms (five Enterococcus, one S. aureus, and one P. aeruginosa) were resistant to treatment with ofloxacin. Clinical response was rated as cure in seventy (67 percent) subjects, improvement in twenty-one (20 percent) subjects, and failure in fourteen (13 percent). Failures were accompanied by persistence of the original pathogen (eight), persistent or resistant superinfection (six), or both (one). Adverse effects were infrequent, mild, and self-limiting. There was one death during the study, attributed to septic shock after postoperative abdominal leak, and not related to ofloxacin therapy. Intravenous/oral ofloxacin is effective and safe for the treatment of many difficult infections of the skin and skin structure, including those in diabetic subjects and in patients in whom previous parenteral therapy may have failed.

Multicenter open-label study of parenteral ofloxacin in treatment of pyelonephritis in adults.

The efficacy and safety of parenteral ofloxacin were evaluated in an open, multicenter study of hospitalized patients with pyelonephritis. The patients received ofloxacin 400 mg IV as an initial dose followed by ofloxacin 200 mg IV b.i.d. for a minimum of three days. The patients could then continue ofloxacin orally 200 mg b.i.d. for a total of seven to fourteen days. The most common pathogens isolated were Escherichia coli, Enterobacter cloacae, and Klebsiella pneumoniae. Microbiologic eradication was achieved in 65 of 66 evaluable patients (98%), and clinical cure or clinical improvement was noted in all patients. Of 82 patients evaluable for safety, 12 (15%) reported drug-related adverse events, the most frequent of which was pruritus or rash. None of the patients experienced drug-related central nervous system symptoms. Ofloxacin is well tolerated and highly effective in the treatment of pyelonephritis.

Oral ofloxacin therapy for lower respiratory tract infection.

We made an open, noncomparative evaluation of ofloxacin, 400 mg orally bid for 10 days, in 98 subjects with community-acquired pneumonia or pathogen-confirmed bronchitis. Thirty-nine (40%) of the subjects were treated in the hospital and 59 (60%) were treated as outpatients. The mean age of those treated was 56.2 years; 73 (74%) of the subjects either were more than 60 years old or had a history of chronic obstructive pulmonary disease, or both. There were 95 organisms initially isolated in sputum, aspirate, or lavage fluid; all were susceptible to ofloxacin, and none acquired resistance during therapy. Haemophilus influenzae was the most common pathogen (19 isolates), followed by Streptococcus pneumoniae (18) and Staphylococcus aureus (10). Clinical responses included cure in 70 patients (71%), improvement in 26 (27%), and failure in two (2%). After 10 days of therapy, pathogens persisted in two cases; in one case, Streptococcus salivarius was isolated, though it remained susceptible to ofloxacin, and in the other, Klebsiella pneumoniae was accompanied by superinfection due to a resistant strain of Serratia marcescens. We included in this study three confirmed cases of atypical pneumonia successfully treated with ofloxacin, two of them due to Mycoplasma pneumonia and one to Legionella pneumophila. Ofloxacin was well tolerated. Our data indicate that ofloxacin is effective and safe as specific and empiric treatment for many lower respiratory tract infections.

Parenteral followed by oral ofloxacin for nosocomial pneumonia and community-acquired pneumonia requiring hospitalization.

We report a multicentric, open trial of intravenous followed by oral ofloxacin, 400 mg every 12 h, as therapy for 100 cases of nosocomial pneumonia and community-acquired pneumonia requiring hospitalization. The typical subject was 57 yr old, and underlying diseases, such as chronic obstructive pulmonary diseases (COPD), diabetes mellitus, and congestive heart failure, were common. For 10 subjects previous therapy had failed. There were 118 pathogens isolated in blood or sputum; S. pneumoniae was the most common (42), followed by H. influenzae (13), Klebsiella spp. (11), and S. aureus (10). Ofloxacin was administered for an average of 5.7 days intravenously followed by 6.9 days orally. Response to therapy was judged to be cure in 71 subjects, improvement in 24, and failure in 5. Among the more seriously ill subjects, ofloxacin therapy was successful for four of five immunocompromised subjects, for 12 of 12 subjects with nosocomial pneumonia, three of whom were on the ventilator, and for nine of 10 subjects with community-acquired pneumonia and bacteremia, including seven of eight cases due to S. pneumoniae. Univariate risk factor analysis revealed underlying COPD and/or tachypnea upon admission to be associated with failure of ofloxacin therapy, with bacteremia suggestive of failure. Conversely, ofloxacin was equally effective in cases in whom previous therapy failed and in cases of nosocomial pneumonia, multilobar pneumonia, and/or pneumonia due to S. pneumoniae. Results for P. aeruginosa were inconclusive. Intravenous followed by oral ofloxacin was highly effective in many difficult cases of pneumonia.

Randomized comparison of cefepime and ceftazidime for treatment of skin, surgical wound, and complicated urinary tract infections in hospitalized subjects.

We undertook a prospective, randomized open comparison of the broad-spectrum cephalosporins cefepime and ceftazidime in treatment of hospitalized subjects with skin or wound infections and complicated nosocomial urinary tract infections. Cefepime treatment (dosage, 2.0 g intravenously twice daily for 4 to 28 days) was successful in 36 (90%) of 40 infections of the skin and skin structure or wounds and in 16 (84%) of 19 nosocomial urinary tract infections. Ceftazidime treatment, 2.0 g every 8 h, was successful in 34 (96%) of 36 infections of the skin and skin structure and in 15 (88%) of 17 urinary tract infections. Microbiological eradication rates of each agent overall and for Pseudomonas aeruginosa were greater than 90%. In the cefepime group, one death occurred, contributed to by an enterococcal superinfection acquired during study drug therapy, and there were two mild and transient adverse experiences observed. Cefepime was comparable to ceftazidime in treatment of infections of the skin and skin structure requiring hospitalization and of complicated nosocomial urinary tract infections.

Ofloxacin versus parenteral therapy for chronic osteomyelitis.

We conducted a randomized comparison of oral ofloxacin (400 mg twice a day) and parenteral agents (cefazolin, 1.0 g intravenously every 8 h, or ceftazidime, 2.0 g intravenously every 12 h) in biopsy-confirmed, nonprosthesis osteomyelitis. A total of 19 subjects received ofloxacin for an average of 8 weeks, and 14 received parenteral antibiotics for an average of 4 weeks; both therapies were well tolerated. Infections were due to Staphylococcus aureus (40%), Enterococcus spp. (3%), Pseudomonas aeruginosa (15%), and other gram-negative organisms (42%). At the completion of therapy, one P. aeruginosa infection in the ofloxacin group persisted and the organism acquired resistance, accompanied by a resistant Acinetobacter superinfection. In the parenteral group, one S. aureus infection persisted, and there was a resolved superinfection due to S. aureus as well. Eighteen-month follow-up data have been obtained. Among those treated with ofloxacin, four subjects whose initial response to therapy was successful suffered relapses of infection, three due to S. aureus and one due to P. aeruginosa, while in the parenteral group, one subject with a P. aeruginosa infection relapsed. Long-term response to therapy was successful for 14 of 19 (74%) subjects who received ofloxacin and 12 of 14 (86%) who received parenteral antibiotics; the difference was not significant. Oral ofloxacin appears comparable to parenteral antibiotics in chronic osteomyelitis due to susceptible organisms, and oral ofloxacin offers advantages in economics and convenience.

A comparative evaluation of oral ofloxacin versus intravenous cefotaxime therapy for serious skin and skin structure infections.

In a single-blind, placebo-controlled randomized trial, 100 successive patients were enrolled with serious skin and soft-tissue infections, whose illnesses had precipitated an initial hospital admission or an extension of inpatient care. There were 93 evaluable patients who received either ofloxacin, 400 mg orally every 12 hours plus an intravenously administered placebo every eight hours, or cefotaxime, 2.0 g intravenously every eight hours plus an orally administered placebo every 12 hours. The average length of therapy was 12 days. Both patient groups had similar demographics and underlying conditions. Wound infection was the most common diagnosis, followed by abscess, cellulitis, and trophic ulcer. Multiple pathogens were commonly isolated from infected sites (1.4 pathogens/patient). The most common pathogen was Staphylococcus aureus, followed by Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, Serratia marcescens, Proteus/Providencia spp., and Enterobacter spp. Persistence of the initial pathogen at the end of therapy was observed in 22.5 percent of the cefotaxime-treated group, but in only 10 percent of the ofloxacin-treated group. There was one clinical failure in the cefotaxime group, caused by a susceptible strain of Enterobacter cloacae, and there was one clinical failure in the ofloxacin group, in which the patient had an Acinetobacter calcoaceticus var. anitratus wound infection and subsequently developed a P. aeruginosa superinfection. Adverse experiences, including rash, insomnia, and nausea, occurred in 16 percent of the patients in each group. It was concluded that oral ofloxacin is as safe and efficacious as parenteral cefotaxime in the treatment of serious skin and skin structure infections.