Phase I study of repeated cycles of high-dose cyclophosphamide, etoposide, and cisplatin administered without bone marrow transplantation.

Forty-two patients with advanced malignancy judged unlikely to respond to standard treatment received high-dose combination chemotherapy with cyclophosphamide, etoposide, and cisplatin in a phase I trial. Twenty-two of these patients who had at least a partial response (PR) to the first cycle of therapy received a second cycle, and eight patients received three or more cycles of therapy. Bone marrow replacement was not used. The maximum-tolerated doses (MTDs) were cyclophosphamide 2.5 g/m2 on days 1 and 2; etoposide 500 mg/m2 on days 1, 2, and 3; and cisplatin 50 mg/m2 on days 1, 2, and 3. Hematologic toxicity was not dose-limiting by study design. Recovery to an absolute granulocyte count above 100/microL occurred at a median of 9 days from onset (range, 3 to 23 days) at the MTD. Recovery was delayed after the third cycle. Only one patient on his third cycle failed to recover peripheral blood counts and died of sepsis an day 43. Hematologic toxicity was not dose-dependent. Nonhematologic toxicities included emesis, fatigue, alopecia, diarrhea, and anorexia and were generally well tolerated. The dose-limiting toxicities were fatal pulmonary or cardiac toxicities in five of nine patients treated at the highest dose level. Patients likely to do well can be selected by tumor type, response to prior therapy, and performance status. Nine of 36 assessable patients had a complete response (CR) and 13 a PR for a response rate of 61%. Five patients (12%) remain alive and free of disease at 15 to 32 months. Repeated cycles of dose-intensive combination therapy can produce long-term disease-free remissions in patients with refractory tumor types. The toxicity of the regimen is acceptable if patients are carefully selected.

Prospective randomized study comparing the efficacy and safety of ciprofloxacin with cefaclor in the treatment of patients with purulent bronchitis.

We compared safety and efficacy of ciprofloxacin and cefaclor in the treatment of patients with purulent bronchitis. Fifty-five patients were randomized prospectively to receive ciprofloxacin with a dose of 500 mg orally twice daily or cefaclor 250 mg over 8 hr for 5 days or longer. Patient groups did not differ with respect to age, duration of illness, severity of infection, or number of other concomitant disease states. A significantly larger number of patients in the ciprofloxacin group had poor health status (39.3% vs 7.4% for the ciprofloxacin and cefaclor groups, respectively, p = 0.02). The response to therapy did not differ between groups. Infection was completely resolved in 71.4% vs 66.7% and markedly improved in 7.1% and 11.1% for the ciprofloxacin and cefaclor groups, respectively. The response to therapy and adverse reaction rate did not differ between groups. Seven patients treated with ciprofloxacin and five patients treated with cefaclor developed adverse reactions. We conclude that ciprofloxacin is a useful agent for the treatment of purulent bronchitis.

Osteomyelitis: sensitivity of 0.064 T MRI, three-phase bone scanning and indium scanning with biopsy proof.

We compared the ability of magnetic resonance imaging (MRI) using a 0.064 T permanent magnet, three-phase bone scanning, and indium-labeled white blood cell (111In-WBC) scanning, to diagnose osteomyelitis. Twenty-three patients underwent biopsy. All patients were examined at presentation with all three modalities. Sensitivities for each modality were calculated using biopsy as a gold standard. The results were 72% for MRI, 68% for bone scan, and 45% for 111In-WBC. Specificities were not calculated because of lack of negative biopsies. MRI was as sensitive as bone scanning in the diagnosis of osteomyelitis. All modalities had lower than previously reported sensitivities for imaging osteomyelitis.

Pharmacoeconomic analysis of selected antibiotics in lower respiratory tract infection.

An interactive pharmacoeconomic model was designed to evaluate the effects of clinical response and adverse drug events on the comparative cost and cost-effectiveness of a relatively new antibiotic, clarithromycin, compared with those of six other antibiotics used to treat community-acquired lower respiratory tract infection. The cost and cost-effectiveness analyses were based don 12 randomized, double-blind, controlled clinical trials conducted between 1987 and 1992 in regionally distributed outpatient clinics in the United States. The trials enrolled a total of 2377 patients. Of the 2377, 1102 patients were treated for acute exacerbation of chronic bronchitis, 591 for pneumonia, and 201 for either of the two conditions. Safety data for one of the antibiotics was obtained from a trial of patients with sinusitis (N = 483). The antibiotics included in the analysis were amoxicillin/clavulanate, ampicillin, cefaclor, cefixime, cefuroxime, clarithromycin, and erythromycin. The main outcome measures were the costs of resources to achieve a clinical response, costs related to managing adverse drug events, and costs of antibiotic treatment from the perspective of managed care. The mean total cost per episode ranged from approximately $137 to $267. The drug acquisition cost typically contributed a small amount to the overall cost. For the cost-effectiveness analysis, in which complication-free cure was used as a proxy for patient satisfaction, the range of mean cost per complication-free cure varied from approximately $307 for clarithromycin to $612 for cefaclor. When ranked from most to least cost-effective, the order was as follows: clarithromycin, cefixime, amoxicillin/clavulanate, erythromycin, cefuroxime, ampicillin, and cefaclor. The costs associated with clinical management (including treatment failure) and managing adverse drug events significantly contribute to the total cost and cost-effectiveness of antibiotics in the outpatient setting. Cost-effectiveness analyses are valuable in analyzing the various costs associated with the treatment of lower respiratory tract infection (acute exacerbation of chronic bronchitis or pneumonia) and may be useful tools for physicians managing patients, members of pharmacy and therapeutics committees developing formularies, and medical staff implementing practice guidelines.

A comparative study of 48 host valve and 24 prosthetic valve endocarditis cases.

Forty-eight cases of host valve endocarditis and 24 cases of prosthetic valve endocarditis occurring during a concurrent period of time were analyzed to assess differences between the two groups. The over-all incidence of prosthetic valve endocarditis during this 40 month period was 4.4%. The symptoms and signs in both groups were similar, except that PVE patients had more frequent occurrences of changing heart murmurs and splenic and cerebral emboli. Spleen scans may be helpful in the diagnosis of selected cases of culture-negative prosthetic valve endocarditis. There was no significant difference between the two groups for the various infecting microorganisms. However, the culture-negative prosthetic valve group had a mortality rate of 77.7% compared to 46.2% for the host valve group. In the HVE patients the oral cavity or urinary tract was the probable source of infection in 50.0% of the patients. In about one third of HVE cases, there was strong evidence that the infection was related to a therapeutic procedure, whereas nearly half of the PVE patients had clinical evidence of an extracardiac infection at the time of open-heart surgery. We emphasize the need for good pre- and postoperative surveillance to eliminate possible predisposing infections and appropriate antibiotic prophylaxis in all patients with valvular disease at times of risk. The survival rate in patients with prosthetic valve endocarditis was highest in those patients who received "appropriate" antibiotics and, if significant congestive heart failure was present, surgical intervention was necessary.

Effect of the addition of ciprofloxacin on theophylline pharmacokinetics in subjects inhibited by cimetidine.

OBJECTIVE: Although the effect of individual enzyme inhibitors on hepatic microsomal enzyme activity has been studied extensively, little data exist on the effects of combinations of inhibiting agents. The purpose of this study was to investigate the effect of the addition of a second hepatic oxidative enzyme inhibitor on the inhibition of metabolism in subjects already maximally inhibited by cimetidine. Ciprofloxacin was used as the second inhibitor. DESIGN: In a randomized crossover sequence, subjects received theophylline 5 mg/kg on day 6 of therapy with cimetidine 2400 mg/d, ciprofloxacin 1 g/d, both drugs, or while drug-free. SETTING: National Institutes of Health-funded General Clinical Research Center. PARTICIPANTS: Eight normal volunteers (6 men, 2 women; mean age 25.2 y). OUTCOME MEASURES: Theophylline pharmacokinetic parameters after each treatment were determined by model independent pharmacokinetic analysis. Statistical analysis of the data for differences between treatments was assessed by ANOVA for repeated measures. RESEARCH: When administered alone, ciprofloxacin and cimetidine caused a significant increase in theophylline elimination half-life and a decrease in clearance. Theophylline elimination half-life was significantly longer during combined therapy compared with either drug alone. Theophylline clearance was lower during combined treatment, although this relationship did not reach statistical significance. CONCLUSIONS: The addition of a second enzyme inhibitor in subjects receiving maximally inhibiting doses of cimetidine can produce a further decrease in the hepatic metabolism of drugs that are metabolized by the cytochrome P-450 microsomal enzyme system. As cimetidine and ciprofloxacin are frequently used together for a variety of common clinical indications, clinicians should be aware of this drug interaction and should consider that a similar effect may occur when other enzyme inhibitors are used concomitantly.

Pharmacokinetics of ranitidine in morbidly obese women.

The pharmacokinetics of a single dose of ranitidine 50 mg iv were determined in ten normal-weight and ten morbidly obese (greater than 90 percent ideal body weight) age-matched female subjects. No significant difference between normal and obese subjects was found in ranitidine peak serum concentration, volume of distribution, clearance, and elimination rate constant. Ranitidine volume of distribution and clearance were significantly smaller in the obese subjects per kilogram of total body weight (1.45 vs. 0.80 L/kg and 0.59 vs. 0.33 L/h/kg, respectively; p less than 0.001) but not when normalized to ideal body weight (1.65 vs. 1.45 L/kg and 0.68 vs. 0.59 L/h/kg). We conclude that obese patients receiving ranitidine therapy should be treated with standard dosages or dosages based on ideal body weight.

Use of Sulesomab, a radiolabeled antibody fragment, to detect osteomyelitis in diabetic patients with foot ulcers by leukoscintigraphy.

Diabetic patients suspected of having osteomyelitis secondary to foot ulcers underwent scintigraphic imaging with Sulesomab, an anti-granulocyte antibody Fab' fragment labeled with technetium-99m. Among 122 patients who had osteomyelitis confirmed or excluded by histopathologic and/or microbiologic techniques, Sulesomab had a 91% sensitivity, a 56% specificity, and an accuracy of 80%. One planar imaging session was usually sufficient for diagnosis, typically requiring 20-30 minutes of camera time 1-2 hours after injection. Compared with ex vivo autologous white blood cell (WBC) scans, Sulesomab performed comparably but with significantly greater sensitivity (92% vs. 79%; P < .05). Sulesomab results were more sensitive than radiography (90% vs. 62%; P < .05) and more specific than bone scans (50% vs. 21%; P < .05) and would have altered management plans in most patients. No related adverse events occurred, and there was no induction of human anti-mouse antibody. Sulesomab is an effective and rapid imaging agent that is diagnostically comparable or superior to WBC scans in this setting, with significant advantages in safety and ease of use.

Effect of norfloxacin on theophylline metabolism.

The purpose of this study was to investigate the effect of norfloxacin on theophylline elimination. Ten normal volunteers were studied. In a randomized crossover sequence, each subject received 6 mg of aminophylline per kg of body weight by a 30-min intravenous infusion on day 4 of taking norfloxacin (400 mg every 12 h) or while drug free. Mean theophylline clearance decreased and mean elimination half-life increased after norfloxacin administration (from 0.036 +/- 0.006 to 0.033 +/- 0.004 liter/h per kg and from 8.7 +/- 1.2 to 9.5 +/- 1.5 h, respectively; P less than 0.05, Wilcoxon signed-ranks test). We conclude that norfloxacin taken in recommended doses for 3 days has a small inhibitory effect on theophylline metabolism that would probably not cause clinically important elevations in theophylline concentrations in most patients.

Teicoplanin in the treatment of bone and joint infections. Teicoplanin Bone and Joint Cooperative Study Group, USA.

Teicoplanin is a new glycopeptide antibiotic with activity against Gram-positive bacteria, including methicillin-resistant organisms. Teicoplanin is administered once daily, either intravenously or intramuscularly. Teicoplanin was given once daily, intravenously or intramuscularly, in the treatment of hospitalized or ambulatory patients with Gram-positive bone or joint infections. A total of 90/98 patients were evaluated for efficacy; 41 had acute osteomyelitis, 41 had chronic osteomyelitis, and 8 had septic arthritis. At the end of therapy, 37 acute osteomyelitis patients were cured/improved with a 90% cure rate at 6-month follow-up; 2 relapsed and 1 failed. At the end of therapy 30 chronic osteomyelitis patients were cured/improved with an 88% cure rate at 6-month follow-up; 2 relapsed and 1 failed. 100% of the septic arthritis patients were cured at the end of therapy and at 1-month follow-up. The most common bacterial isolates cultured from bone were S. aureus (39 isolates), S. epidermidis (11 isolates), other coagulase-negative staphylococci (20 isolates), enterococci (6 isolates), and other streptococcal species (20 isolates). The most common bacterial isolates cultured from joint fluid were S. aureus (6 isolates) and S. epidermidis (2 isolates). All patients tolerated the intramuscular or intravenous routes of administration well. Adverse reactions were mild and most cases did not require discontinuation of therapy. The majority of therapy was administered on an outpatient basis. Teicoplanin was safe, effective, convenient and relatively well tolerated in patients with acute or chronic osteomyelitis or septic arthritis.

A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group.

OBJECTIVE: To evaluate the safety and efficacy of E5, a murine, monoclonal antibody directed against endotoxin, in the treatment of patients with Gram-negative sepsis. DESIGN: A multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Fifty-three hospitals across the United States, including university medical centers, Veterans Affairs Medical Centers, and community hospitals. PATIENTS: 847 patients were randomized into this study. Enrolled patients met criteria for three conditions: a) known or suspected Gram-negative infection; b) clinical evidence of sepsis; and c) signs of end-organ dysfunction. Patients with refractory shock were excluded from the study. INTERVENTIONS: Two doses of E5 (2 mg/kg/day by intravenous infusion 24 hrs apart), or placebo that was identical in appearance were administered. In addition, all patients received standard supportive therapy and broad-spectrum antibiotics. MEASUREMENTS AND MAIN RESULTS: The primary end point was mortality over 30 days. Secondary outcome measures included the resolution and prevention of organ failure in the same two populations. Additionally, the safety of E5 was evaluated. There was no significant improvement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received placebo (n = 530; p = .21). In addition, E5 did not improve survival for patients with Gram-negative sepsis and organ failure (n = 139; p = .3). However, a significantly greater percentage of patients with Gram-negative sepsis experienced resolution of major organ failure if they received E5, compared with those patients who received placebo (n = 139; 48% E5 vs. 25% placebo; p = .005). This result extended to all patients who entered the study with one or more major organ failures, regardless of the etiology of the infection (n = 225; 41% E5 vs. 27% placebo; p = .024). E5 also provided protection against the development of some organ failures, but significant prevention was only observed for adult respiratory distress syndrome (p = .007) and central nervous system dysfunction (p = .050). Hypersensitivity reactions attributable to E5 occurred in 2.6% of patients. An asymptomatic antibody response occurred in 44% of the E5-treated patients and in 12% of the patients who received placebo. CONCLUSIONS: In this study, E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those patients also had organ failure. However, E5 did result in greater resolution of organ failure in patients with Gram-negative sepsis. This benefit extended to those patients with suspected Gram-negative etiology. This finding is important because patients with suspected Gram-negative sepsis and organ failure can be identified without waiting for culture results. In addition, E5 resulted in the prevention of adult respiratory distress syndrome and central nervous system organ failure. However, more studies are needed to determine if this result can be extended to organ failure in general. E5 is safe as a treatment for patients with Gram-negative sepsis.