Randomized, double-blind, multicenter trial comparing clinafloxacin with imipenem as empirical monotherapy for febrile granulocytopenic patients.

In a double-blind, multicenter trial, 541 febrile granulocytopenic patients were randomized to receive either intravenous (iv) clinafloxacin (200 mg every 12 h) or i.v. imipenem (500 mg every 6 h) as empirical monotherapy. More baseline pathogens were susceptible to clinafloxacin (259 [99%] of 262 organisms) than to imipenem (253 [95%] of 265; P=.03). Initial favorable clinical response rates for clinafloxacin (88 [32%] of 272 patients) and imipenem (89 [33%] of 269) were similar. After addition of other antimicrobial agents, overall response rates were 259 (95%) of 272 for clinafloxacin and 251 (93%) of 269 for imipenem. During the study, only 13 clinafloxacin (5%) and 18 imipenem (7%) recipients died. Both drugs were generally well tolerated. Drug-related skin rash occurred more often with clinafloxacin (11% vs. 6%; P=.07), whereas nausea (2% vs. 5%; P=.16), Clostridium-difficile-associated diarrhea (3% vs. 8%; P=.02), and seizures (0% vs. 2%; P=.06) occurred more often with imipenem. These results suggest that clinafloxacin and imipenem have similar efficacy as empirical monotherapy in febrile granulocytopenic patients.

A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer.

PURPOSE: To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer. PATIENTS AND METHODS: A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death. RESULTS: A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group. CONCLUSIONS: Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy.

A prospective, open-label study of single-dose ciprofloxacin absorption after chemotherapy in patients with malignancy.

The absorption of a single oral dose of ciprofloxacin 750 mg in patients with cancer who had chemotherapy-induced Cancer and Leukemia Group B grade I or II mucositis was evaluated. Ciprofloxacin was administered after an overnight fast. Plasma samples were collected before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the dose. Drug concentrations were determined by reverse-phase high-performance liquid chromatography with fluorescence detection. Pharmacokinetic values were characterized by noncompartmental methods. The mean +/- SD for area under the curve, mean peak concentration (C(max)), and time to C(max) (T(max)) were 18.7 +/- 5.03 mg/L x hour, 4.41 +/- 1.74 mg/L, and 1.81 +/- 0.843 hours, respectively. The absorption of oral ciprofloxacin in patients with chemotherapy-induced grade I or II mucositis compares with that in healthy volunteers. These findings may call for further pharmacokinetic evaluation of the drug in a similar patient population.

Empirical treatment of febrile neutropenia: evolution of current therapeutic approaches.

Administration of empirical antibiotic therapy is now standard practice in the management of febrile neutropenia, but there has been considerable debate about the selection of an efficacious empirical antimicrobial regimen over the past 2 decades. A variety of approaches, including both monotherapeutic and multidrug regimens, have been demonstrated to be effective, although no one regimen has been proven to be superior to another. Changes in the epidemiology of infectious organisms and the growing emergence of highly drug-resistant strains make it necessary to continually reevaluate the therapeutic options. Fortunately, the number of therapeutic options has also been broadening as new antimicrobial agents, including third-generation cephalosporins and carbapenem antibiotics such as imipenem and meropenem, become available. Optimal management is directed by the findings of a clinical evaluation of the patient as well as an awareness of institutional patterns of infection and susceptibility of likely infecting organisms.

Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells.

Freshly isolated acute non-lymphocytic leukemia (ANLL) cells were treated with the nitric oxide (NO)-liberating compounds sodium nitroprusside or S-nitrosoacetyl penicillamine and analyzed for viability, growth, and differentiation at 3-5 days. NO decreased the viability and the growth of freshly isolated ANLL cells in vitro. NO treatment significantly increased expression of CD14 in blast cells from patients with M5 ANLL, and increased at least one differentiation parameter in M4 or M5 cells. It had little or no effect on parameters of differentiation in other ANLL cells. We conclude that in vitro culture with NO decreases the growth and viability of most freshly isolated ANLL cells. NO also induces the differentiation of ANLL cells with a monocytic phenotype.

A pilot study of etoposide, vinblastine, and doxorubicin plus involved field irradiation in advanced, previously untreated Hodgkin's disease.

BACKGROUND: Advanced stage Hodgkin's disease (HD) usually is treated with combination chemotherapy with or without supplemental irradiation. The risk of significant acute and long term toxicity when the chemotherapy regimen contains alkylating agents has provided the impetus for the development of systemic combinations that do not include alkylating agents. This trial was designed to assess the toxicity and efficacy of a regimen of etoposide, vinblastine, and doxorubicin (EVA) as part of a combined modality approach in patients with moderate to high risk HD. METHODS: This was a prospective pilot study that included 26 previously untreated patients. They received 6 cycles of EVA, and complete responders received low dose (1500-2500 cGy) involved field radiation. RESULTS: Four patients were hospitalized for sepsis during chemotherapy. Complete response was achieved in 54% of patients, and 46% patients experienced induction failures. Two year failure-free survival is 44%, while 2 year overall survival is 86%. Median follow-up is 27 months. CONCLUSIONS: The EVA regimen is no more efficacious than other programs already in use and may be less so. It also is potentially leukemogenic because of the presence of etoposide. New combinations that do not contain etoposide should be explored in therapy programs for advanced HD in the hopes of discovering an efficacious treatment program that has minimal long term side effects.

Critical appraisal of antimicrobials for prevention of infections in immunocompromised hosts.

Infections remain a common cause of morbidity and mortality among patients receiving antineoplastic chemotherapy. Over the past 30 years a number of techniques have been evaluated in an attempt to reduce the incidence of bacterial, fungal, and viral infections. Protective isolation, oral nonabsorbable antibiotics, and selective decontamination of the gastrointestinal tract have all been extensively evaluated. More recently, newer antimicrobial agents have been employed, such as quinolones, imidazoles, and recombinant monoclonal agents for modulation of the immune cascade. A critical review of the advantages and disadvantages of each of these methodologies is presented.

Survival of patients with carcinoma of the esophagus treated with combined-modality therapy.

Since 1985, 229 cases of carcinoma of the esophagus have been considered for entry into a protocol with the use of preoperative chemotherapy and radiation therapy followed by surgical intervention as the primary element of treatment. One hundred sixty-five patients (93 with adenocarcinoma and 72 with squamous cell carcinoma) had esophagogastrectomy. The 5-year survival of the protocol patients who underwent resection was 25% for both groups--squamous cell carcinoma and adenocarcinoma. Of the protocol patients with squamous cell carcinoma who underwent resection, 40% had a sterilized specimen, whereas of those with adenocarcinoma, 20% had a sterilized specimen. If the patient had a sterilized specimen, the 5-year survival was approximately 60% for adenocarcinoma and 40% for squamous cell carcinoma. Those patients with adenocarcinoma and Barrett's esophagus had a 5-year survival of 55%. Of the patients who underwent only esophagectomy and esophagogastrectomy and had not been entered into the protocol, none lived beyond 3 years. The operative mortality rate for those who had esophagogastrectomy was 5%. Sixty-four patients completed the radiation therapy and chemotherapy but did not undergo surgical procedures because of progressive disease or refusal. Of those patients who completed chemotherapy and radiation therapy without surgical intervention, 5-year survival was 18% in patients with squamous cell carcinoma, whereas no patients with adenocarcinoma survived beyond 3 years. The finding of a sterilized specimen after esophagectomy is a favorable prognostic factor in patients with adenocarcinoma or squamous cell carcinoma. The finding that patients with Barrett's esophagus and adenocarcinoma have an improved chance for survival is perhaps related to an earlier diagnosis. It is clear that some patients with squamous cell carcinoma who did not undergo surgical procedures did have a sterilized specimen, because the survival in this group approached 20% at 5 years.

Detection of circulating candida enolase by immunoassay in patients with cancer and invasive candidiasis.

BACKGROUND: Invasive candidiasis is a major nosocomial infection that is difficult to diagnose. Few biochemically defined markers of invasive candidiasis are known. Initial findings suggested that the presence of candida enolase in the blood may be a novel marker for invasive candidiasis. METHODS: We tested 170 patients at high risk for invasive candidiasis for candida enolase antigenemia. All the patients had cancer and neutropenia. We detected antigen using a double-sandwich liposomal immunoassay for candida enolase in serially collected serum samples. Invasive candidiasis was proved by finding candida species in deep nonmucosal tissue, blood cultures, or both. Antigen testing was performed with the investigator blinded to tissue or culture diagnosis. RESULTS: Among 24 patients with proved invasive candidiasis, 149 serum samples were tested for enolase antigenemia; 80 were positive and 69 negative (sensitivity per sample, 54 percent). Multiple sampling improved the detection of antigenemia, which was found in 11 of 13 proved cases of deep tissue infection (85 percent) and in 7 of 11 proved cases of fungemia (64 percent). Specificity was 96 percent as measured against control groups including patients with mucosal colonization, bacteremia, and other deep mycoses. Antigenemia was detected in the absence of fungemia in 5 cases of deep tissue candidiasis, but was not detected in 6 cases of fungemia alone. CONCLUSIONS: Candida enolase antigenemia is a novel marker for invasive candidiasis. It may be a useful indicator of deep infection in patients with cancer and neutropenia and may complement the diagnostic usefulness of blood cultures.

Empirical antibiotics for febrile neutropenic cancer patients.

The empirical institution of broad spectrum antibiotics for febrile neutropenic cancer patients has become standard medical practice. Traditionally, the antibiotics consisted of a combination of agents selected to maximize activity against the most commonly isolated pathogens, and often employed agents with synergistic antimicrobial activity. Recent additions to the antibiotic armamentarium, however, have provided single agents with equivalent spectra of activity, thus potentially allowing a 'monotherapeutic' alternative to the combination regimens. The empirical utilization of antibiotics for the febrile, neutropenic episode is reviewed, with emphasis on recent clinical studies evaluating select monotherapeutic 'agents'.

Gram-positive infections and the use of vancomycin in 550 episodes of fever and neutropenia.

STUDY OBJECTIVE: To determine the appropriate role for vancomycin in neutropenic patients with cancer. To review the incidence, types, and outcome of gram-positive infections in a series of neutropenic patients with cancer. DESIGN: Retrospective review. SETTING: Inpatient units of the Medical and Pediatric Oncology Branches of the National Cancer Institute. PATIENTS: Five hundred and fifty consecutive episodes of fever and neutropenia in patients with cancer randomized prospectively on another study to receive either ceftazidime alone or combination antibiotics for initial empirical therapy. INTERVENTION: Intravenous vancomycin (dosage adjusted by serum levels). MEASUREMENTS AND MAIN RESULTS: Gram-positive organisms were the commonest of the bacterial pathogens isolated (63%). Of the 53 gram-positive organisms accounting for primary infections (isolated at initial presentation), there were 36 staphylococcal isolates (19 coagulase-negative and 17 coagulase-positive), 13 streptococcal isolates (8 non-group D and 5 group D), and 4 polymicrobial isolates. Of the 22 secondary gram-positive infections (occurring after institution of initial antibiotics), there were 10 streptococcal isolates (9 group D and 1 non-group D), 7 staphylococcal isolates (6 coagulase-negative and 1 coagulase-positive), and 5 polymicrobial isolates. Vancomycin was used to treat 26 of the 53 primary infections, but was begun only after knowledge of the isolate in 25. Vancomycin was used to treat 17 of the 22 secondary infections, and begun only after knowledge of the isolate in 14. This approach resulted in no treatment failures for the primary infections, and a single microbiological failure for the secondary infections. There was a tendency towards a greater proportion of secondary gram-positive infections in the monotherapy group compared to the combination therapy group (16 of 282 compared with 6 of 268 respectively, P2 = 0.04 by the chi-squared test); but all were treated successfully. CONCLUSION: Vancomycin need not be included in routine empirical therapy for febrile neutropenic patients, but should be added when clinical or microbiological data suggest the need.

A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia.

To assess the efficacy of single-agent therapy relative to standard combination antibiotic therapy for the initial management of fever and neutropenia in cancer patients, we conducted a randomized trial comparing ceftazidime alone with a combination of cephalothin, gentamicin, and carbenicillin. Of 550 evaluable episodes of fever and neutropenia, 282 were treated with ceftazidime alone and 268 with the combination. All episodes were evaluated for responses at 72 hours after the start of treatment and at resolution of the neutropenia. Of the patients with unexplained fever who were given ceftazidime alone, 99 percent were alive at 72 hours and 98 percent were alive when the neutropenia resolved, as compared with 100 percent and 98 percent, respectively, of those given combination therapy. Of the patients with documented infection who were given ceftazidime alone, 98 percent were alive at 72 hours and 89 percent when the neutropenia resolved, as compared with 98 percent and 91 percent, respectively, of those given combination therapy. The majority of episodes of documented infection in both treatment groups necessitated additional antimicrobial treatment or other modifications of the initial regimen, as compared with only 22 percent of the episodes of unexplained fever. We conclude that initial single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment.

Is there a role for monotherapy with beta-lactam antibiotics in the initial empirical management of febrile neutropenic cancer patients?

In empirical antimicrobial chemotherapy for febrile neutropenic cancer patients, drug combinations are commonly used, and aminoglycosides are usually included for their excellent activity on Gram-negative organisms and for potential synergism. However, new beta-lactams have at least as good a spectrum and in many ways better pharmacology. More Gram-positive infections are now being reported and the sensitivity of the causative organisms varies. This provides reasons for examining alternatives to aminoglycosides, and the use of monotherapy. Clinical results suggest that the emergence of resistance may be a problem with ureidopenicillins used alone, and that double beta-lactams may be as good as but not better than standard regimens. New cephalosporins have been used alone in 14 trials (not all of them well designed) with results as good as those of standard regimens in many, although superinfection with resistant organisms has been a problem in some. It is possible that early supplementation, with aminoglycosides, of empirical monotherapy with such agents as ceftazidime may solve some of the problems posed by resistant organisms.