Biomedical subjects
Publications and source records attributed to K V Rolston.
We examined an E-test-based strategy for testing the combination of itraconazole and amphotericin B, the latter given either sequentially or concomitantly, in isolates of Aspergillus fumigatus. An antagonistic interaction between the two drugs was noted, especially with the sequential administration of amphotericin B. This in vitro antagonism was reversible.
Risk prediction in patients with neutropenia and fever in a reliable and timely manner has only become possible in the last decade. Patients have been categorized as high risk or low risk based on certain presenting characteristics. Low-risk patients may be defined as hemodynamically stable, with responsive or controlled malignancies, brief (< or = 7-day) periods of neutropenia, and no significant comorbidities or serious documented infections. Such patients may be suitable for alternative treatment strategies, such as outpatient parenteral, sequential, or oral therapy. These approaches still need to be definitively evaluated, with safety being the primary concern. Substantial advantages may be gained from such strategies, including reduced exposure to resistant nosocomial pathogens, greater cost effectiveness, and enhanced quality of life.
BACKGROUND: Fever and neutropenia (F&N) is a common complication of cancer chemotherapy. It is conveniently managed by hospitalization and empiric administration of parenteral antibiotics. This study attempted to determine whether pediatric cancer patients with F&N identified as low risk for morbidity and mortality by clinical criteria at the time of presentation could be treated safely as outpatients. METHODS: Seventy-three episodes of F&N in 41 patients were studied prospectively over 2 years. Eligibility criteria included age > or =2 years, reliable caretakers, and residence within 1 hour of the hospital. Exclusion criteria included hemodynamic instability, dehydration, severe mucositis, pneumonia, leukemia/lymphoma induction therapy, bone marrow transplantation, or other serious comorbidity. Patients were evaluated, received a single dose of intravenous ceftazidime, and were observed for 3-16 hours. They were randomized to receive either oral ciprofloxacin or intravenous ceftazidime as outpatients. Patients were seen daily until they had been afebrile for at least 48 hours and had a rising absolute phagocyte count of >500 cells/microL. RESULTS: Sixty-three of 73 episodes (86%) were successfully managed on an outpatient basis. For 31 of 33 episodes in the ceftazidime arm, the patients remained outpatients, compared with 32 of 40 in the ciprofloxacin arm; this difference was not statistically significant. On average, patients remained febrile for 2.7 days and were treated for 4.7 days. Seventy-seven percent of episodes required no modification of initial antibiotic therapy. Of the 10 patients who were hospitalized, 4 had prolonged fever and 3 had emesis. Protracted neutropenia was associated with the need for hospitalization. There were no deaths, intensive care unit transfers, or serious complications. CONCLUSIONS: Carefully selected low risk children with fever and neutropenia can be treated safely as outpatients. Close daily medical scrutiny is required.
Gram-positive bacterial pathogens are important causes of disease in cancer patients and are becoming increasingly resistant to available antimicrobial agents. We examined the in vitro activity of gatifloxacin, a new fluoroquinolone, compared with other quinolones, ceftazidime, and traditional Gram-positive-active agents tested against pathogens isolated from patients at 10 cancer treatment hospitals in the United States. A total of 1,128 Gram-positive isolates were tested by the E-test method (AB BIODISK, Solna, Sweden) with results validated by concurrent quality control strain analysis. Gatifloxacin was more potent than either ciprofloxacin or levofloxacin against all Gram-positive species. Vancomycin was the most active agent tested against all species except Bacillus spp., which were more susceptible to the fluoroquinolones. When tested against these Gram-positive pathogens from patients with cancer, the spectrum of gatifloxacin was also greater than that of levofloxacin and ciprofloxacin. Gatifloxacin may have a role as part of prophylactic or therapeutic antimicrobial regimens for selected cancer patients with Gram-positive infections.
Meropenem and imipenem/cilastatin, currently the only available carbapenem agents in Europe and the United States, are characterised by a broad spectrum of antimicrobial activity and stability to beta-lactamase-mediated resistance mechanisms. A guide to the use of carbapenems in clinical practice is presented; the role of carbapenems in the treatment of several types of serious bacterial infection and an up-to-date account of their clinical efficacy and safety profiles are discussed. The good clinical efficacy and favourable safety profiles of the carbapenems make them valuable as initial empirical therapy in the treatment of ventilator-associated pneumonia, sepsis of unknown origin, post-operative peritonitis, paediatric meningitis, and febrile neutropenia. However, to maintain superior efficacy, the carbapenems should be used appropriately for definitive therapy.
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Standard management of febrile neutropenia includes the prompt administration of empirical, broad-spectrum, parenteral antibiotic therapy. This is generally done in a hospital-based setting. Although effective (overall survival of >90%), such therapy leads to prolonged hospitalization, excessive resource utilization, and increased costs. Recently, risk-assessment models have been developed that reliably differentiate febrile patients with neutropenia that are at low risk for morbidity and/or mortality. This has enabled clinicians to administer risk-based treatment to such patients. High-risk patients still receive standard, hospital-based, parenteral treatment. Many patients, however, defervesce promptly and can be discharged home with parenteral or oral antibiotics. Low-risk patients need not be hospitalized at all and can be safely treated with parenteral or oral antibiotics in the outpatient or home setting. Careful risk assessment and patient selection, appropriate antimicrobial regimen(s), and meticulous monitoring for response or the development of complications or toxicity are essential for the success of risk-based therapy.
We report the in vitro activities of broad-spectrum beta-lactam antimicrobials tested against 1,128 gram-positive pathogens recently isolated from cancer patients. Cefepime and imipenem were more active than ceftazidime and ceftriaxone against these organisms. Only vancomycin demonstrated reliable activity against oxacillin-resistant staphylococci, Enterococcus spp., and Corynebacterium spp. The spectrum of gram-positive organisms against which cefepime and imipenem have activity provides an advantage over ceftazidime as empiric therapy for cancer patients, potentially reducing the need for the empiric addition of glycopeptides.
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BACKGROUND: Discrepancies between the severity of toxicities reported in early clinical trials and recent clinical experience with vancomycin have led to confusion regarding the need for routine serum vancomycin level monitoring and discontinuation of vancomycin when toxicities occur. Therefore, the authors examined the incidence, outcomes, and predictive factors of vancomycin-associated toxicities in general oncology practice with the goal of developing clinically relevant prediction rules and guidelines. METHODS: All 742 consecutive cancer patients who received vancomycin at a comprehensive cancer center during a 3-month period were followed prospectively for the development and outcome of phlebitis, rash, ototoxicity, and nephrotoxicity. Logistic regression was used to derive a multiple variable model of the risk of nephrotoxicity. A clinical prediction rule, the Nephrotoxicity Risk Score, was developed from the risk model and validated prospectively. RESULTS: Phlebitis occurred in 3% of patients (95% confidence interval [95% CI], 2-4%), predominantly those with recently inserted central venous catheters. Rashes occurred in 11% of patients (95% CI, 9-13%); however, all but 4 patients also were receiving beta-lactam antibiotics. Clinical evidence of ototoxicity developed in 6% of patients (95% CI, 4-9%) who were receiving vancomycin plus other ototoxic agents and only 3% of patients (95% CI, 2-5%) not receiving other ototoxic agents (P = 0.08). Nephrotoxicity occurred in 17% of patients (95% CI, 15-20%). Logistic regression revealed that factors associated with an increased risk of nephrotoxicity included administration of other mild to moderate (P = 0.01) or severely nephrotoxic agents (P < 0.001) or an acute physiology and chronic health evaluation (APACHE) score > 40 (P = 0.002). Elevated serum vancomycin peak levels did not reliably predict subsequent nephrotoxicity. CONCLUSIONS: Vancomycin-associated toxicities usually are mild and self-limiting. Some patients are at a significantly higher risk of nephrotoxicity but the authors believe these individuals can be identified reliably with the Nephrotoxicity Risk Index using information available at vancomycin initiation. Further testing of the Nephrotoxicity Risk Index is ongoing.
BACKGROUND: Imipenem-cilastatin (referred to hereafter as imipenem) is administered at different doses as monotherapy or with other agents. Limited comparisons of the alternatives exist. The authors compared the efficacy and safety of several imipenem-containing regimens (ICRs) to determine the appropriate dose and the need for combination therapy. METHODS: Between 1985 and 1994, febrile neutropenic patients were given ICRs according to the same methodology on prospective trials at a referral cancer center. The ICRs were high dose imipenem (HIP), high dose imipenem and amikacin (HIPA), high dose imipenem and vancomycin (HIPV), and low dose imipenem and vancomycin (LIPV). RESULTS: The overall response rates were comparable (70-77%). There was a univariate trend toward better response among patients with pneumonia and documented infections with unidentified organisms who received HIPV versus LIPV (P=0.06), as well as a significantly better response among patients with gram positive infections who received HIPV versus HIP (P=0.02) and HIPA (P=0.002). HIPV was a more effective treatment for documented infections with identified organisms (P=0.05) and bloodstream infections (P=0.04) than HIP; there was a univariate trend toward better response among patients infected with gram negative organisms who received HIPA versus HIP (P=0.12). Multivariate adjustment for baseline and prognostic factors did not reveal a relative advantage for any regimen. No differences in overall toxicities were observed between HIPV and LIPV. CONCLUSIONS: Imipenem monotherapy is adequate treatment for most febrile neutropenic cancer patients. Low dose imipenem could be effective and safe in uncomplicated cases without pneumonia. Further studies are needed to establish the usefulness of low dose imipenem in this context.
BACKGROUND: The aim of this study was to determine the efficacy of novobiocin and rifampin as oral antibiotic prophylaxis for the prevention of catheter-related infection in melanoma patients treated with interleukin-2 (IL-2) plus interferon-alpha and chemotherapy (biochemotherapy). METHODS: Patients with advanced melanoma who were treated with biochemotherapy at the University of Texas M. D. Anderson Cancer Center were randomized in a crossover study to receive either oral antibiotic prophylaxis consisting of novobiocin and rifampin or observation alone over a 35-day course period. Patients were subsequently "crossed over" to the opposite arm of the study for an additional 35-day period, with each serving as his or her own control. RESULTS: Twenty-six patients were enrolled. Nine patients (35%) failed to tolerate oral antibiotics because of severe nausea and vomiting; 17 patients (65%) were crossed over and considered evaluable. During the control patient courses, 71% of evaluable patients had infectious complications, 41% had a catheter-associated bacteremia, and 53% had a local catheter infection. In contrast, of the patients treated with antibiotic prophylaxis, only 12% had an infectious complication (P = 0.001), 12% had a local catheter infection (P = 0.008), and 6% had catheter-associated bacteremias (P = 0.04). Thirty-six episodes of catheter infections occurred during the 17 control courses, whereas only 3 episodes occurred during antibiotic prophylaxis (P < 0.001). CONCLUSIONS: Although more than one-third of patients receiving IL-2 treatment with biochemotherapy failed to tolerate novobiocin and rifampin, this oral antibiotic regimen was efficacious in preventing the infectious complications, especially those associated with vascular catheters, in this high risk patient population.
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Immunocompromised patients with varicella-zoster virus (VZV) infection are at greater risk for dissemination and the development of complications than immunocompetent individuals. Consequently, they are generally hospitalized in strict isolation rooms and treated with parenterally administered acyclovir. Although effective, this approach is expensive and creates logistic difficulties in the hospital. We treated 38 immunosuppressed cancer patients presenting to our ambulatory treatment center with VZV infections with intravenous acyclovir (500 mg/m2 8-hourly) in an ambulatory/home setting. Patients were monitored for success or failure of therapy, progression of infection, development of complications or drug toxicity, and satisfaction/compliance with therapy. Most patients (33, or 87%) responded to therapy. Among the failures, 2 patients had progressive VZV infection, 2 were hospitalized due to renal toxicity, and 1 developed a superinfection. All patients eventually responded and there were no deaths on this study. Two patients relapsed within 1 month of initial response. Both responded to retreatment with acyclovir, without hospitalization. The median duration of parenteral therapy with acyclovir was 7.5 days. Seven patients (18%) had to be switched to oral acyclovir (800 mg, 5 times a day) before complete response, owing to problems with venous access. All 7 completed therapy successfully. Overall, patients expressed a high level of satisfaction with outpatient therapy, and there were no instances of noncompliance or patient requests for withdrawal from study. The results of this study indicate that VZV infections in clinically stable immunosuppressed cancer patients are relatively benign and do not require hospitalization. Parenterally administered acyclovir in an ambulatory setting is effective therapy for such infections.
Fever in neutropenic cancer patients is often due to the development of an infection. The standard management of febrile neutropenic patients involves the administration of empiric, hospital-based, parenteral antibiotic therapy. Although this treatment strategy has evolved from experience in high-risk patients with hematological malignancies, in whom bacterial infection can result in substantial morbidity and mortality, it has been adopted for all patients with febrile neutropenia, largely because of the inability of clinicians to reliably distinguish between patients who are at high risk for developing such morbidity/mortality and those who are not. The development of risk-assessment models has facilitated the recognition of high-, moderate-, and low-risk subgroups among febrile neutropenic patients and allows the administration of outpatient antibiotic therapy to the moderate- and low-risk groups, with the same degree of efficacy and safety as hospital-based therapy. Monotherapy with the carbapenems (imipenem/cilastatin and meropenem), with their broad spectrum of activity and established efficacy in high-risk patients, represents realistic options for risk-based treatment of febrile neutropenic patients within and outside the hospital setting.
Twenty-nine cases of neutropenic enterocolitis (NEC) were identified from 1992 to June 1996, and their clinical, microbiological, and radiologic characteristics were reviewed. Eighteen of 29 episodes were considered to be definite NEC since abdominal computed tomographic or ultrasonographic findings (n = 14) and/or pathological findings (n = 7) were consistent with the diagnosis, whereas 11 were classified as possible NEC since these findings were normal or nondiagnostic. Abdominal pain, diarrhea, and fever occurred in nearly all cases in both groups, whereas bloody stools were more frequent and the duration of diarrhea was longer in definite cases. Other clinical, laboratory, and microbiological findings were of variable frequencies, with no apparent differences between groups. All 29 patients received medical/supportive treatment, and only five deaths were related to NEC. We conclude that NEC has a broad spectrum of clinical presentation, but patients whose imaging studies are positive appear to have a more serious form of the disease. Medical management appears appropriate in most cases, as the associated mortality rate is < 20%.
Pulmonary infections can mimic or occasionally co-exist with pulmonary neoplasms. In order to determine the frequency and nature of these infections, we conducted a retrospective analysis, covering a 3-year period, of patients who were referred to our center with presumed lung cancer but turned out to have pulmonary infection instead. The overwhelming majority of patients (93.3%) referred to "rule out" lung cancer were documented as having a neoplastic process, and only 1.3% had an infection. Fungal infections (histoplasmosis, cryptococcosis, coccidiomycosis) accounted for 46%, mycobacteria for 27%, bacteria for 22%, and parasitic lesions (dirofilariasis) for 5% of these infections. The most common clinical manifestations were cough and chest pain, and the most common radiographic finding was a solitary pulmonary nodule. There were no specific clinical or radiographic features predictive of either infection or neoplastic disease. All patients responded to specific anti-infective therapy with or without surgical excision. Our data indicate that pulmonary infections mimic neoplasms very infrequently. However, establishing a specific diagnosis is critical, since the management and outcome of these two processes are entirely different.
The care of the febrile neutropenic patient has undergone a shift in the last 10 years with the realization that neutropenic patients presenting with fever do not constitute a homogeneous group. Strategies of risk assessment have allowed the testing of novel therapies including outpatient treatment with oral and intravenous antibiotics, either in combination regimens or as monotherapy; the addition of growth factors to hasten the return of the absolute neutrophil count; and the possibility of self-initiation of antibiotics by cancer patients when they develop fever. The clinical trials data regarding these new approaches will be reviewed, and areas requiring further research will be discussed.