Philip A. Pizzo

2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer

Walter T. Hughes, Donald Armstrong, Gerald P. Bodey, Eric J. Bow, Arthur E. Brown, Thierry Calandra, Ronald Feld, Philip A. Pizzo, Kenneth V. I. Rolston, Jerry L. Shenep, and Lowell S. Young St. Jude Children’s Research Hospital, Memphis, Tennessee; Memorial Sloan-Kettering Cancer Center, New York, New York; University of Texas M. D. Anderson Cancer Center, Houston; Harvard Medical School, Boston, Massachusetts; Stanford University School of Medicine, Palo Alto, and Kuzell Institute for Arthritis, San Francisco, California; University of Manitoba, Winnipeg, and Princess Margaret Hospital, Toronto, Canada; and Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline

PURPOSE To update the 2000 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSF). UPDATE METHODOLOGY The Update Committee completed a review and analysis of pertinent data published from 1999 through September 2005. Guided by the 1996 ASCO clinical outcomes criteria, the Update Committee formulated recommendations based on improvements in survival, quality of life, toxicity reduction and cost-effectiveness. RECOMMENDATIONS The 2005 Update Committee agreed unanimously that reduction in febrile neutropenia (FN) is an important clinical outcome that justifies the use of CSFs, regardless of impact on other factors, when the risk of FN is approximately 20% and no other equally effective regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. CSF use allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.

Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia

Abstract Since early diagnosis of even a disseminated fungal infection is difficult and treatment often ineffective in a patient with persistent granulocytopenia, we have prospectively evaluated continued antibiotic therapy and early empiric antifungal therapy in patients with prolonged fever and granulocytopenia. Between November 1975 and December 1979, all patients with fever (oral temperature >38 °C three times per 24 hours or >38.5 °C once) plus granulocytopenia (polymorphonuclear leukocytes 3 ), were evaluated and began an empiric antibiotic regimen consisting of Keflin ® , gentamicin and carbenicillin (KGC). Of the 652 episodes of fever and granulocytopenia (in 271 patients), initial evaluation failed to define an infectious etiology in 323 (49.5 percent). In 50 of the patients in whom initial evaluation did not demonstrate an infectious etiology, fever and granulocytopenia continued after seven days of therapy with KGC, without evidence for the etiology of their persistent fever. These patients were randomized to either discontinue receiving KGC (Group 1); continue receiving KGC (Group 2); continue receiving KGC with the addition of empiric amphotericin B (Group 3). The duration of granulocytopenia was comparable in the three groups (median 24 days, range 8 to 51 days). Clinically or microbiologically demonstrable infections occurred in nine of 16 patients who discontinued the KGC regimen (Group 1) (six also experienced shock, p Empiric amphotericin B therapy was also evaluated for its effectiveness in patients whose initial evaluation revealed an infectious etiology with fungal colonization throughout their alimentary tract but in whom fever and granulocytopenia remained despite at least seven days of therapy with appropriate antibiotics. In addition, the postmortem records of all patients dying between 1970 and 1979 were reviewed to ascertain the cause of death and the type of antimicrobial therapy received prior to death. Only one death due to fungal invasion occurred, when therapy with amphotericin B was instituted after one week of broad-spectrum antibiotic therapy. Collectively, these data suggest that continuing antibiotic therapy reduces early bacterial infections in patients with persistent fever and granulocytopenia and that empiric antifungal therapy also appears necessary to prevent fungal superinfections and to control clinically undetected fungal invasion.

Pneumocystis carinii Pneumonia: A Comparison Between Patients with the Acquired Immunodeficiency Syndrome and Patients with Other Immunodeficiencies

Clinical features of 49 episodes of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome were compared with those of 39 episodes in patients with other immunosuppressive diseases. At presentation patients with the syndrome were found to have a longer median duration of symptoms (28 days versus 5 days, p = 0.0001), lower mean respiratory rate (23.4 versus 30, p = 0.005), and higher median room air arterial oxygen tension (69 mm Hg versus 52 mm Hg, p = 0.0002). The survival rate from 1979 to 1983 was similar for the two groups (57% and 50% respectively). Patients with the syndrome had a higher incidence of adverse reactions to trimethoprim-sulfamethoxazole (22 of 34 versus 2 of 17, p = 0.0007). Survivors with the syndrome at initial presentation had a significantly lower respiratory rate, and higher room air arterial oxygen tension, lymphocyte count, and serum albumin level compared to nonsurvivors. Pneumocystis carinii pneumonia presents as a more insidious disease process in patients with the syndrome, and drug therapy in these patients is complicated by frequent adverse reactions.

1997 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Unexplained Fever

This is the first in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of these guidelines is to provide assistance to clinicians when making decisions on treating the conditions specified in each guideline. The targeted providers are internists, pediatricians, and family practitioners. The targeted patients and setting for the fever and neutropenia guideline are hospitalized individuals with neutropenia secondary to cancer chemotherapy. Panel members represented experts in adult and pediatric infectious diseases and oncology. The guidelines are evidence-based. A standard ranking system was used for the strength of the recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary, algorithms, and tables highlight the major recommendations. The guideline will be listed on the IDSA home page at http://www.idsociety.org.

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.

Effect of Continuous Intravenous Infusion of Zidovudine (AZT) in Children with Symptomatic HIV Infection

Abstract To produce concentrations of zidovudine (AZT) in plasma and cerebrospinal fluid that would provide constant inhibition of the replication of human immunodeficiency virus (HIV), we gave AZT by continuous intravenous infusion to 21 children ranging in age from 14 months to 12 years who had acquired HIV infection through transfusions or perinatally. All patients were symptomatic before AZT treatment (Class P2 of the Centers for Disease Control); 13 (62 percent) had evidence of neurodevelopmental abnormalities. The mean CD4/CD8 ratio was 0.18; 11 patients had CD4 counts below 0.2X109 per liter. We administered AZT at four dose levels: 0.5, 0.9, 1.4, and 1.8 mg per kilogram of body weight per hour. The plasma drug concentrations achieved at the respective dose levels were 1.9±0.3, 2.8±1.4, 3.1 ±1.1, and 4.5±1.0 μM. The steady-state cerebrospinal fluid:plasma ratio was 0.24±0.07. The only evidence of toxicity was bone marrow suppression. Transfusion was required in 14 patients because of low levels of ...

A Double-Blind Comparison of Empirical Oral and Intravenous Antibiotic Therapy for Low-Risk Febrile Patients with Neutropenia during Cancer Chemotherapy

BACKGROUND Among patients with fever and neutropenia during chemotherapy for cancer who have a low risk of complications, oral administration of empirical broad-spectrum antibiotics may be an acceptable alternative to intravenous treatment. METHODS We conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to 74 years) who had fever and neutropenia during chemotherapy for cancer. Neutropenia was expected to be present for no more than 10 days in these patients, and they had to have no other underlying conditions. Patients were assigned to receive either oral ciprofloxacin plus amoxicillin-clavulanate or intravenous ceftazidime. They were hospitalized until fever and neutropenia resolved. RESULTS A total of 116 episodes were included in each group (84 patients in the oral-therapy group and 79 patients in the intravenous-therapy group). The mean neutrophil counts at admission were 81 per cubic millimeter and 84 per cubic millimeter, respectively; the mean duration of neutropenia was 3.4 and 3.8 days, respectively. Treatment was successful without the need for modifications in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group (difference between groups, 3 percent; 95 percent confidence interval, -8 percent to 15 percent; P=0.48). Treatment was considered to have failed because of the need for modifications in the regimen in 13 percent and 32 percent of episodes, respectively (P<0.001) and because of the patients inability to tolerate the regimen in 16 percent and 1 percent of episodes, respectively (P<0.001). There were no deaths. The incidence of intolerance of the oral antibiotics was 16 percent, as compared with 8 percent for placebo (P=0.07). CONCLUSIONS In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective.

Abnormal CT Scans of the Brain in Asymptomatic Children with Acute Lymphocytic Leukemia after Prophylactic Treatment of the Central Nervous System with Radiation and Intrathecal Chemotherapy

Abstract Thirty-two asymptomatic patients with acute lymphocytic leukemia, who had received prophylactic cranial radiation (2400 rads) and either intrathecal methotrexate or cytosine arabinoside were studied by computed tomography of the brain 19 to 67 months after initiation of prophylaxis. Seventeen of 32 (53 per cent) had one or more abnormal findings. Dilatation of the ventricles (eight patients) and widening of the subarachnoid spaces (nine patients) were equally distributed among patients in both intrathecal-chemotherapy groups. Areas of decreased attenuation coefficient (hypodense, abnormally radiolucent regions) (four patients) and intracerebral calcification (one patient) — lesions previously described in methotrexate leukoencephalopathy —were found only in those who had received intrathecal methotrexate. Mild Central-nervous-system dysfunction was detected in seven patients but did not correlate with the presence of tomographic abnormalities. Nevertheless, these tomographic findings may represen...

Lysis-centrifugation blood cultures in the detection of tissue-proven invasive candidiasis : disseminated versus single-organ infection

Several studies have demonstrated significantly higher frequency and more rapid detection of candidemia with blood culture methods performed by lysis-centrifugation (LC) in comparison with other techniques. Little is known, however, about the ability of LC blood culture methods to detect tissue-proven invasive candidiasis. We therefore investigated the sensitivity of LC blood cultures in the detection of tissue-proven invasive candidiasis. Between 1985 and 1991, invasive candidiasis was detected in 41 (5.1%) of 803 autopsies at the Clinical Center of the National Institutes of Health (Bethesda, MD, USA). Cases were classified as single-organ (SO) candidiasis (n = 20) and as disseminated candidiasis (DI) (n = 21). Patients with DI were more likely than those with SO to have a hematologic malignancy (71% vs 15%, P < 0.001) and to have gastrointestinal mucosal candidiasis (76% vs 25%, P = 0.003). LC detected fungemia in 16 (43%) of all 37 cases with blood cultures. When analyzed by classification, Candida spp. were isolated from blood in 11 (58%) of 19 patients with DI and in five (28%) of 18 patients with SO (P = 0.13). When analyzed by number of organs infected, blood cultures were positive in seven (78%) of nine patients with > 3 organs infected by Candida in comparison to five (28%) of 18 patients with one organ infected (P = 0.024). The mean recovery time for Candida in blood cultures was 2.6 days in DI and 3.2 days in SO (P = 0.017). There was no difference in colonies of organisms per LC tube between patients with DI and those with SO.(ABSTRACT TRUNCATED AT 250 WORDS)