Neutropenic Leukemia Patients Research Articles

Anorectal Infections in Neutropenic Leukemia Patients: A Common Clinical Challenge.

Anorectal infections in neutropenic leukemia patients are a significant and potentially life-threatening complication. The pathogenesis of this condition is not entirely understood and believed to be multifactorial, including mucosal injury as a result of cytotoxic drugs, profound neutropenia and impaired host defense. Establishing an early diagnosis is key and often made clinically on the basis of signs and symptoms, but also from imaging studies demonstrating perianal inflammation or fluid collection. The management of anorectal infections in neutropenic leukemia patients is not straightforward, as there are no well-conducted studies on this entity. This review seeks to provide a framework into the pathophysiology and clinical presentation of anorectal infections in neutropenic leukemia patients, propose a diagnostic approach and to discuss controversies in the management of this condition.

Evolution of procalcitonin, C-reactive protein and fibrinogen levels in neutropenic leukaemia patients with invasive pulmonary aspergillosis or mucormycosis.

Unlike bacterial infections, the value of procalcitonin (PCT) in detecting fungal infections in leukaemia patients is not clear. To determine whether the monitoring of PCT coupled with C-reactive protein (CRP) and fibrinogen (Fib) could be helpful in the management of pulmonary aspergillosis (IPA) or mucormycosis (PM), we retrospectively analysed the evolution of PCT, CRP and Fib levels in 94 leukaemia patients with proven/probable IPA (n=77) or PM (n=17) from D-12 to D12 relative to IFI onset defined as D0. Overall, 2140 assays were performed. From D-12 to D0, 12%, 5% and 1.4% of patients had PCT >0.5, 1 and 1.5μgl(-1) , respectively, while CRP was >50, 75 and 100mgl(-1) in 84%, 70% and 57% and Fib was >4, 5 and 6gl(-1) in 96%, 80% and 61% of cases respectively (P<10(-7) ). The same trends were observed from D1 to D12. Overall, between D-12 and D12, only 6.4% of patients had PCT >1.5μgl(-1) , while CRP >100mgl(-1) and Fib >6gl(-1) were observed in 80% and 75% of cases respectively (P<10(-7) ). In leukaemia patients, IPA or PM was accompanied by a significant increase in CRP and Fib while PCT remained low.

Invasive Fusariosis in Patients with Hematologic Malignancies at a University Hospital

Introduction: Fusarium species cause severe infections in patients with hematologic malignancies. The types of infection caused by Fusarium spp. in humans range from infections of nail, skin, and eye in immunocompetent host to invasive and disseminated infections in mainly immunocompromised patients.Methods: We retrospectively indentified patients with hematologic malignancy and positive cultures for Fusarium species at the University Hospital (1995-2014).Results: Thirteen cases were identified over study period. Patient demographic and underlying risk factors for fusariosis are presented in Table I. Most patients had uncontrolled hematological malignancy. All patients were neutropenic at diagnosis. Pulmonary involvement was evident in 3/13 patients (23%). Skin lesions were present in 2/13 (15%) patients. Fusariosis presented as a breakthrough infection in 8/13 (62%) of patients (Table II). Positive blood cultures were in the 6/13 (46%).Conclusions: Our study has several limitations due to its retrospective nature and its relatively small size. Fusariosis, althought uncommon, continues to have poor prognosis in neutropenic leukemic patients who present with fungemia. The optimal therapy for fusariosis remains undefined, because of its rarity and the complex clinical scenarious in patients with severe immunosupression.Table 1Characteristics of 13 patients with fusariosisNoSex/ageUnderlying diseaseDuration of neutropenia before/after (days)Fusarium spp.DiagnosisBreakthrough infectionsConcomitant infectionsTreatment of fusarium infectionOutcome of Fusarium infection1F/41AML/Ri15 /6F. verticillioidesBloodNoneNoneAmp- BEradicated, in 23 days2M/19Aplastic anemia67/54F. proliferatumBronchilavageNoneC. kefyr, C. glabrata, P. aeruginosaAmp- B, voriconazoleEradicated, in 51 days3M/38AML/RÝ31/1F. proliferatumBronchi lavageFluconazoleC. albicansAmp- B, voriconazoleEradicated, in 199 days4M/50ALL/RÝ25/0F. proliferatumBloodFluconazoleK. pneumoniaeAmp- BDied5M/43AML/consolidation37/9F. solani SC haplotype 6Skin biopsyFluconazoleC. bovis, S. arolisVoriconazoleDied6M/45Relapse AML/ RÝ37/5F. petroliphilumBlood + tissuebiopsyItraconazole, voriconazoleVRE, S. capitis, S. maltophiliaAmp- B, voriconazoleDied7M/65AML/ RÝ41/0F. andiyaziBloodPosaconazolA. baumaniiAmp - BDied8M/63MDS tr. AML/ RÝNoneF. petroliphilumNasalbiopsyFluconazoleHSV, C. albicans, alternans spp.Amp- B, voriconazoleDied9M/49Refractary MDS tr. AML/ RÝ67/94F. solaniss.NasalbiopsyNoneS. hominis, S. saprophyticusVoriconazoleEradicatedin 68 days10F/53Relapse MDS tr. AML/ RÝ25/27F. proliferatumNasalbiopsyPosaconazoleVRE, Klebsiella, EnterobactericeaAmp- B, voriconazoleEradicated, in 84 days11F/49ALL/ RÝ23/13F. petroliphilumNasalbiopsyNoneEnterococcus, S. epidermidis, E. faecalis, MRS, BLPSAmp- B, voriconazoleDied12M/50HCL65/4F. petroliphilumBloodNoneNoneAmp- BDied13M/52Relapse AML/ consolidation34/3F. petroliphilumBlood , skin biopsyPosaconazoleC. parapsilosis, C. meningosepticum, S. capitisEchinocandine, voriconazoleEradicated , in 90 daysTable 2Patient characteristicsDemographic and disease characteristicsNumber of patients, n=13 (%)Median age49(19-63)Male49,5(19-63)Female49(41-53)Female patient3 (23)Male patient10(77)AML/ MDS tr. AML9 (69)Relapse3Remission induction7Consolidation2Reinduction1ALL (remission induction)2 (15)Hairy cell leukemia1 (8)Aplastic anemia1 (8)Median duration of neutropenia before diagnosis (day)34 (15-67)Median duration of neutropenia after diagnosis (day)6 (0-94)History of DM0Albümin <3.5 mg/dLAllHýgh dose corticosteroid treatment within 30 days of diagnosis1Breakthrough infections8 (62)While receiving posaconazole3 (23)While receiving voriconazole1 (8)While receiving fluconazole4 (31)Concominant infectionBacterial, viral, fungal=11 (85)Exitus7 (54) DisclosuresNo relevant conflicts of interest to declare.

A Phase II Feasibility Study of Prophylactic White Cell Transfusions for the Prevention of Infection in AML Patients Undergoing Induction Therapy

▪Patients with acute myeloid leukemia (AML) experience sustained and profound neutropenia during induction chemotherapy; infections remain the leading cause of morbidity and mortality in myelosuppressed leukemia patients. The current standard of care is to provide patients with broad-spectrum antibiotic, antifungal and antiviral therapy; however resistance to available anti-infective agents is increasing. Transfusion of functional non-irradiated allogeneic granulocytes to neutropenic leukemia patients may treat, delay or prevent infections in patients with leukemia, and importantly may also have anti-leukemia benefits.Patients treated at MD Anderson Cancer Center with a diagnosis of AML undergoing front-line AML therapy were eligible. Patients were required to be free of signs and symptoms of infection at the time of study entry, and have sufficient volunteer donors to administer prophylactic white cell transfusions approximately twice a week for six weeks. Allogeneic white cell transfusions (≥ 4 x 10¹⁰ cells per transfusion) were administered every 3-4 days during the induction chemotherapy cycle, so long as patients remained neutropenic with an absolute neutrophil count < 500. Prophylactic transfusions continued until the time of sustained ANC recovery, initiation of a new treatment regimen, or after the completion of 6 weeks on protocol.Herein we provide the results of the first 21 patients. Median age was 67 (range 23-78); 12 patients were male and 9 were female. All patients were enrolled at the time of initiation of AML induction therapy. Seven patients had a diagnosis of therapy-related AML (6 with an antecedent hematologic disorder and 1 with prior solid malignancy). Various treatment regimens were administered and are displayed in Table 1, along with cytogenetic and MD Anderson prognostic model classification.Patients received a median of 5 transfusions (range 0 – 11). Of 21 patients, 1 withdrew consent prior to the first transfusion, and 3 patients discontinued transfusions prior to the end of study (due to a diagnosis of pneumonia in one with potential concern for increased pulmonary toxicity with continued transfusions, and two at patient requests due to fevers and myalgias post transfusions).Median time to ANC recovery was 38 days (range 14 – 137) and platelet recovery 29 days (range 12 – 160), consistent with the elderly population and the allotted treatment regimens. All patients experienced at least one neutropenic fever, often within 48 hours of white cell administration. Documented infections included 2 instances of bacteremia (1 streptococcal and 1 E. coli), 2 urinary tract infections (both coagulase negative staphylococci), 8 cases of pneumonia (1 documented E. coli, 7 culture-negative and presumed fungal pneumonia per imaging). There was one patient with neutropenic colitis per imaging. There were no induction-related deaths. 8-week mortality was 5% (n=1) and 12-week mortality was 20% (n=4). With a median follow-up time on study of 20.3 weeks, overall survival is 67% with a median survival which has not yet been reached (Figure 1). Overall response to initial induction chemotherapy was 67% (9 CR, 1 CRi, 4 PR). A total of 15 patients (71%) ultimately attained a CR (after the first cycle or with additional cycles of therapy), and 4 patients received a stem cell transplant at the time of CR/CRi.In conclusion, prophylactic transfusion of allogeneic non-irradiated white blood cells for newly diagnosed AML patients during induction chemotherapy was associated with a decreased incidence of life-threatening infections, decreased induction mortality (6-week OS of 100%), and may also lead to improved remission rates and overall survival. This feasibility study has been expanded to enroll a total of 50 patients, with updated results to be provided at the annual meeting. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Granulocyte concentrates from a single high-yield apheresis can be split to support multiple patients

Allogeneic granulocyte transfusion has evolved into a viable therapeutic option for immunocompromised severely neutropenic leukemic patients and those with hematopoietic stem cell transplant with life-threatening bacterial and fungal infections. The collection of larger cell doses of granulocyte concentrates (GCs) has been facilitated by the stimulation of donors with granulocyte colony stimulating factor (G-CSF) and dexamethasone. The synergistic effect of G-CSF and dexamethasone has allowed the collection of larger cell doses of GCs and its use has increased steadily. This has allowed us to split the high-yield GC products and facilitated distribution of the split GC products to a second or third patient who needs GCs but lacks donors. The main objective of this article was to present our rationale for splitting GC products and how the split GC units were transfused to multiple patients. We believe that split GCs are as equally effective as unsplit GCs and that multiple patients benefit from splitting GCs.

The Reversed Halo Sign: Pathognomonic Pattern of Pulmonary Mucormycosis in Leukemic Patients With Neutropenia?

Pulmonary mucormycosis (PM) is a life-threatening fungal infection with an increasing incidence among patients with acute leukemia. In some immunocompromised hosts, the reversed halo sign (RHS) has been described on the pulmonary computed tomographic (CT) scan of patients with mucormycosis. This study reports a single-center experience with PM exclusively in patients with acute leukemia. Clinical records, laboratory results, and CT scans were retrospectively analyzed to evaluate the clinical usefulness of the RHS for the early identification and treatment of PM, with regard to outcomes in these patients. Between 2003 and 2012, 16 cases of proven PM were diagnosed among 752 consecutive patients receiving chemotherapy for acute myeloblastic or lymphoblastic leukemia. At the time PM was diagnosed, all patients but one were neutropenic. The study of sequential thoracic CT scans showed that during the first week of the disease, the RHS was observed in 15 of 16 patients (94%). Initially, other radiologic findings (multiple nodules and pleural effusion) were less frequent, but appeared later in the course of the disease (6% and 12% before vs 64% and 55% after the first week). After the diagnosis of PM, median overall survival was 25 weeks (range, 3-193 weeks), and 6 patients (38%) died before day 90. In the particular setting of neutropenic leukemia patients with pulmonary infection, the presence of the RHS on CT was a strong indicator of PM. It could allow the early initiation of appropriate therapy and thus improve the outcome.

Long-Term Follow-Up Of Invasive Aspergillosis In Allogeneic Stem Cell Transplantation Recipients and Leukemia Patients: Differences In Risk Factors and Outcoumes

Invasive aspergillosis (IA) remains a major concern among patients with hematological malignancies who receive cytotoxic chemotherapy or allogeneic stem cell transplantation (allo-SCT). With a view toward better understanding the differences in terms of clinical significance and outcomes of IA between allo-SCT recipients and patients treated for leukemia, we report a single-center study of 739 unselected consecutive patients treated in our unit between August 2000 and February 2004. IA episodes were classified according to the 2008 EORTC/MSG criteria. Patients were hospitalized either for allo-SCT (n=135), or for the treatment of acute leukemia (n=378), chronic lymphocytic leukemia (n=116), or myelodysplasic syndrome (n=105). Probable or proven IA were observed in 29 patients, among whom 7 were undergoing allo-SCT (5.2%), 20 were treated for acute leukemia (5.3%), 1 for chronic lymphocytic leukemia (0.8%), and 1 for myelodysplastic syndrome (0.95%). Most of the clinical signs were mild and nonspecific, especially in allo-SCT recipients. Chronologically, thoracic computerized tomography (CT) showed the first signs of IA in 38% of cases, and was positive the same day as at least one biological test (bronchoalveolar lavage [BAL] and serum galactomannan antigen) in 41% of cases. BAL was contributive to the diagnosis in 66% of the 29 cases. Comparison of patients undergoing allo-SCT to the others revealed significant differences. In allo-SCT recipients, the onset of IA occurred later than in the other patients, after the neutropenic period. The median time between the last hematologic treatment and the diagnosis of IA were 231 days (range, 68-341) in allo-SCT recipients and 17 days (6-57) in the other patients (p&lt;0.001). At the time of AI onset, the median absolute neutrophil count were 1.8 x 109 cells/L (0.7-5) and 0 x 109cells/L (0-2.1) in allo-SCT patients and the others, respectively (p&lt;0.0001). In addition, the median C-reactive protein level was lower in allo-SCT recipients (53 mg/L, 13-146) compared to the other patients (143.5 mg/L, 22.5-285), p=0.023. It is noteworthy that the 7 cases of IA in allo-SCT recipients occurred only in patients treated with corticosteroids for graft-versus-host disease (GVHD) (n=42). First line therapy was liposomal amphotericin B (n=22), caspofungin (n=8), voriconazole (n=6), or itraconazole (n=1), either alone (n=21) or in combination (n=8). Complete remission of IA on CT was observed in 12 cases, stable lesions in 8 cases and progression in 9 cases. Mortality directly related to IA was 24% in our study and occurred early after the onset of infection. The 100-day, 1-year, 2-year and 10-year overall survival (OS) were 42.9%, 28.6%, 0%, 0% for allo-SCT recipient, respectively, compared to 68.1%, 40.9%, 18.2%, 13.6% for the other patients, respectively (P-values ≥ 0.05). These poor outcomes were mainly attributable to the non-relapse mortality (NRM), especially in allo-SCT recipients, who had a 2-year NRM of 100% compared to 54.6% in the other patients, p=0.034 (2-year cumulative incidence of relapse were 0% and 70.2%, respectively). In conclusion, our data seem to distinguish 2 types of IA. One has an early onset in neutropenic leukemia patients. The second, observed in allo-SCT recipients, occurs later, after GVHD development and is associated with a very high NRM incidence, suggesting that those patients remain fragile. Thus, systematic broad-spectrum anti-fungal prophylaxis is highly recommended in patients undergoing allo-SCT who develop GVHD. Disclosures: Berthon: CELGENE: Research Funding.

Micafungin Versus Posaconazole Anti-Fungal Prophylaxis in Adult Patients with Acute Leukemia Undergoing Induction Chemotherapy

AbstractAbstract 3556 Introduction:Posaconazole has been shown to be effective in reducing the incidence of invasive fungal infections (IFI) in high-risk, neutropenic leukemia patients following induction chemotherapy. Its clinical utilization, however, may be limited by decreased oral absorption secondary to mucositis and other adverse events that occur during therapy. Micafungin is a broad spectrum antifungal agent approved for prophylaxis in stem cell transplant recipients. Nonetheless, its safety and efficacy in neutropenic leukemia patients has not been established. We therefore designed a prospective randomized study comparing micafungin to posaconazole as anti-fungal prophylaxis in patients with acute leukemia undergoing induction chemotherapy. The aim of this interim analysis is to compare (1) the total time on study drug between the micafungin and posaconazole treatment groups and (2) the percentage of patients completing the planned treatment course between the two groups. Methods:Patients > 18 years of age were eligible for study with newly diagnosed acute leukemia (either AML or ALL) or MDS who were to receive myeloablative therapy with an anticipated neutropenic period of at least 7 days following anthracycline-based chemotherapy. Patients with first relapse of AML and ALL were also eligible. Patients who were pregnant, unable to swallow, hypersensitive to azoles, taking medications known to interact with posaconazole, and those receiving dasatinib were excluded from the study. Patients with a history of invasive fungal infection requiring therapy within 30 days of randomization, prolonged QTc interval on EKG, and moderate or severe liver dysfunction were also excluded.Participants were randomized to receive micafungin (100 mg IV daily) or posaconazole (400 mg orally twice daily). The absolute neutrophil count (ANC) was monitored daily. Neutrophil recovery was defined as ANC ≥500 cells/μl for two consecutive days. Prophylaxis completion was defined as continuation of treatment until neutrophil recovery or 28 days after treatment initiation, whichever was earlier. Prophylaxis failure was defined as discontinuation of study drug due to adverse event, persistent neutropenic fever requiring change to an alternative antifungal agent, or withdrawal from the study before 28 days. Fungal markers (Galactomannan, BD glucans) were followed weekly from randomization to neutrophil recovery. Continuous and categorical variables were tested with Wilcoxon rank-sum test and chi-square tests, respectively. Kaplan-Mayer method was used to measure the completion rates of anti-fungal prophylaxis, and the log-rank test was used to compare the completion between two groups. Results:From March 2011 to May 2012, 46 patients were randomized to prophylaxis with either micafungin (n=23) or posaconazole (n=23). The two groups did not differ in age, sex, race, neutropenic duration, or liver dysfunction (p=0.35, 0.56, 0.36, 0.07 and 0.4366, respectively). Nineteen patients (83%) completed micafungin therapy while only eight (35%) completed posaconazole (p=0.001). Median number of days on prophylaxis was 18.2 days for the micafungin group and 14.8 days for the posaconazole group (p=0.0584). Eight patients (34.8%) were removed from study in the posaconazole group after developing colitis or being made NPO by the treating physician. There were no positive fungal markers during the study period. Nine patients (20%) underwent bronchoscopy because of new chest CT abnormalities while on study drug. Bronchoalveolar lavage was sent for routine cultures, cytology, Galactomannan, and pan-fungal PCR (University of Washington). Two patients (one from each treatment group) had IFI identified by PCR (Rhodotorula nothofagi and Cryptococcus species). Conclusions:For patients undergoing myeloablative therapy for the treatment of acute leukemia or MDS, micafungin prophylaxis is associated with a superior completion rate and longer time to failure of prophylaxis compared to posaconazole. In addition, there is no difference in breakthrough fungal infections between the two treatment groups. Micafungin as antifungal prophylaxis is well tolerated and appears as effective as posaconazole prophylaxis for leukemia patients with prolonged neutropenia from induction chemotherapy. Our ongoing clinical study will continue to assess the efficacy of micafungin in this patient population. Disclosures:No relevant conflicts of interest to declare.

Invasive fusariosis in patients with hematologic malignancies at a cancer center: 1998–2009

Fusarium species cause severe infections in patients with hematologic malignancies. Few data are available concerning the outcome of fusariosis in the era of the expanding antifungal armamentarium. We retrospectively identified patients with hematologic malignancy and positive cultures for Fusarium species at the MDACC (1998-2009). The diagnosis of proven or probable fusariosis was made according to modified EORTC/MSG criteria. Forty-four cases (75% proven) were identified over study period. Most (71%) patients had uncontrolled hematological malignancy and 21 patients (47%) received hematopoietic stem cell transplantation (85% allogeneic). Most patients (82%) were neutropenic at diagnosis (75% < 100/mm(3)). Patients had overlapping clinical syndromes: sinus 27%, pulmonary 75%, skin 68%, fungemia 36% and disseminated infection 70%. Bacterial (54%), fungal (36%) and viral (27%) co-infections were common. Most patients (84%) received combination therapy (typically a lipid formulation of amphotericin B and a triazole) with a mean duration of 28 days. Mortality at 12 weeks was 66%; 50% of deaths were attributable to Fusarium. Factors associated with increased likelihood of death at 12 weeks, included albumin <3.5 mg/dL, fungemia, and ICU admission; neutrophil recovery and fusariosis limited to skin were associated with improved survival (P < 0.05). Fungemia with Fusarium spp (OR 15.9; 1.1-231; P = 0.042) was the only risk factor independently associated with 12-week mortality with only 1/17 (6%) of patients still alive at 12 weeks. Fusariosis, although uncommon, continues to have poor prognosis in neutropenic leukemic patients who present with fungemia.

Prevention of mould infections

Isolation of patients at risk of invasive mould infection might be suitable for the reduction of invasive aspergillosis or zygomycosis, if combined with high-efficiency particulate air filtration. Prophylactic wearing of filtering masks of N95 or FFP2 standards has not yet been demonstrated to be efficacious in reducing invasive mould infections outside of scenarios with excessive contamination of room air by fungal spore-loaded dust. The oral broad-spectrum antifungal azoles posaconazole and voriconazole offer protection against invasive Aspergillus infections in severely neutropenic leukaemia patients and allogeneic haematopoietic stem cell transplant recipients; however, their routine use might result not only in considerable side effects, but also in the spread of multi-azole-resistant Aspergillus species, so that careful selection of suitable high-risk patient populations is mandatory.

Candida kefyr as an Emerging Pathogen Causing Nosocomial Bloodstream Infections in Neutropenic Leukemia Patients

Candida kefyr as an Emerging Pathogen Causing Nosocomial Bloodstream Infections in Neutropenic Leukemia Patients

Biologic effects of leukocytes present in transfused cellular blood products

A considerable literature has accumulated over the past decade indicating that leukocytes present in allogeneic cellular blood components, intended for transfusion, are associated with adverse effects to the recipient. These include the development of febrile transfusion reactions, graft-versus-host disease, alloimmunization to leukocyte antigens, and the immunomodulatory effects that might influence the prognosis of patients with a malignancy. Moreover, it has become evident that such leukocytes may be the vector of infectious agents such as CMV, HTLV-I/II, and EBV as well as other viruses. An interesting development that has occurred coincidentally in transfusion medicine is that agencies responsible for the provision of blood products are being designated manufacturers of biologicals. The trend among manufacturers of biologicals is to try to produce pure products to provide for the specific therapeutic need of patients. Thus, with the realization that allogeneic leukocytes and their products may have adverse biologic activities, there is increasing pressure from various sources for the reduction of the leukocyte content in allogeneic blood components to minimize the occurrence of their adverse effects. Although the threshold leukocyte number below which these effects might no longer occur is still to be determined, a 2 to 3 log10 leukocyte reduction, provided by the currently available commercial leukocyte filters, has been shown to reduce the frequency of many of such reactions. On the other hand, the immunosuppressive effects produced by the infusion of allogeneic leukocytes might be beneficial for some patients, ie, for the maintenance of kidney allografts, in possibly reducing the relapse rate in patients with inflammatory bowel diseases, and in ameliorating recurrent spontaneous abortion. Moreover, therapeutic granulocyte transfusions may be of benefit in certain well-defined categories of patients infected with bacteria, yeast, and/or fungi. These include neonates with bacterial sepsis associated with bone marrow failure as well as severely neutropenic leukemic patients with an infection unresponsive to appropriate and specific antibiotic therapy. Many of the results obtained with the use of leukocyte depletion filters are tantalizing, but the actual clinical benefit of leukodepletion has not been established in most instances, because much of the available data are retrospective or from uncontrolled clinical trials. Moreover, issues of cost-effectiveness and quality control have not been considered adequately. Properly designed prospective clinical trials are essential to provide data with which to answer such questions and also to help define the optimal conditions required for the preparation of blood components ultimately destined for clinical use. Only with the availability of such data can sound decisions be made about the clinical value of leukodepletion.

A Pilot Study of Piperacillin and Ciprofloxacin as Initial Therapy for Fever in Severely Neutropenic Leukemia Patients

We studied the efficacy of piperacillin and ciprofloxacin as initial parenteral therapy in 41 adult patients with leukemia who developed 47 febrile episodes during severe neutropenia following chemotherapy. 40 patients (98%) survived their febrile episode(s), whereas 1 patient died of infection. When assessed at 72 h after initiation of treatment (early evaluation), 24/47 episodes (51%) had been successfully treated. These 24 favourable responses were seen in 15/24 (63%) microbiologically documented infections and 9/19 (47%) fever of unknown origin (FUO). At the resolution of fever (late evaluation) 46 episodes were evaluable, and 28 (61%) had responded successfully to piperacillin and ciprofloxacin. Successful treatment was most frequently observed in microbiologically defined infections, 18/23 (78%). Three of 5 (60%) Gram-positive, 11/12 (92%) Gram-negative and 1 of 2 mixed bacteremias were successfully treated. In contrast, only 10/19 (53%) FUO and none of 4 clinically defined infections had responded. Thus, this pilot study indicates that piperacillin and ciprofloxacin may be a safe and effective combination for the treatment of febrile episodes in severely neutropenic leukemia patients, which merits further investigation in randomized trials.

Septicemia due toStreptococcus mitis in neutropenic patients with acute leukemia

SummaryEight neutropenic patients with acute lymphocytic or nonlymphocytic leukemia had septicemia due to different strains ofStreptococcus mitis (St. mitis), a microorganism not commonly recognized as a special pathogen in leukemic patients. Four of the patients had been treated with high-dose cytosine arabinoside as part of the cytostatic regimen, six had a central venous line and four patients had oral lesions prior to the infection. Selective gut decontamination consisted of co-trimoxazole/colistin in five patients and quinolones in three patients. The first three patients died, either due to interstitial pneumonia with the adult respiratory distress syndrome (ARDS), or due to infection-triggered disseminated intravascular coagulation despite prompt empiric antibiotic therapy including vancomycin. The other patients improved after empiric supplementation of penicillin G (30 Mega/day) to the antibiotic regimen. Beginning ARDS in two of these patients dramatically responded to high-dose steriods. We conclude thatSt. mitis is a major pathogen in neutropenic leukemic patients. Infection appears to occur independently of acute leukemic cell type, regimen of selective gut decontamination, venous access, visible oral lesions or treatment with highdose cytosine arabinoside. The clinical course of our patients raises questions about the value of commonly recommended empiric antibiotic regimens, which were clearly ineffective to control infections withSt. mitis in this patient group. Our data indicate that immediate antibiotic therapy with penicillin G is indicated and may be life-saving for suspectedSt. mitis infections in neutropenic leukemic patients.

Emergence of Ciprofloxacin-Resistant Coagulase-Negative Staphylococcal Skin Flora in Immunocompromised Patients Receiving Ciprofloxacin

Seven septicemias in neutropenic leukemia patients (two with fatal outcome) caused by ciprofloxacin-resistant coagulase-negative staphylococci were diagnosed in the hematologic unit of Turku University Central Hospital in 1988 soon after the introduction of the drug. Coagulase-negative staphylococcal skin flora of 28 neutropenic patients receiving ciprofloxacin prophylaxis and therapy for gram-negative bacterial infections were compared with those of 31 untreated patients and 33 hospital personnel working in the same unit. In ciprofloxacin-treated patients the flora were almost completely ciprofloxacin-resistant, whereas in the control groups resistant flora were detected only occasionally. Similarities in the plasmid profile patterns were found in 91% of the ciprofloxacin-resistant coagulase-negative staphylococci, suggesting an epidemiologic relation between these strains. It seems evident that cross-infection is responsible for the spread of ciprofloxacin-resistant coagulase-negative staphylococci in these patients.

Adult respiratory distress syndrome in neutropenic leukemia patients.

Seven episodes of adult respiratory distress syndrome, occurring in leukemic patients with longstanding (average 11 days) and severe neutropenia (less than 0.1 x 10(9)/1) are described. Pathological and clinical data give further support to the view that the complement-neutrophil pathway is not the only mechanism in generating clinical ARDS in leukemia patients.

A Randomized Trial Comparing Ketoconazole and Nystatin Prophylactic Therapy in Neutropenic Patients

A randomized trial was conducted comparing ketoconazole and nystatin in the prevention of oral candidiasis and appearance of invasive fungal infections in 51 neutropenic leukemic patients undergoing induction chemotherapy. Ketoconazole was administered in a 200 mg dose twice daily. Nystatin oral suspension was given in doses of 500,000 units four times daily. Surveillance cultures of the throat and urine were obtained prior to treatment and conducted weekly. Patients were enrolled in the study if the absolute granulocyte count was less than 1500/microliter, if physical examination revealed no evidence of oral candidiasis, no evidence of urinary tract infection, and there was no pulmonary infiltrate on chest x-ray. Patients were continued on study until the absolute granulocyte count reached 1500/microliter, evidence of oral candidiasis appeared, or presumed or proven invasive fungal infections appeared. Of the 46 evaluable patients, 22 received ketoconazole, 3 (14%) developed oral candidiasis, and 5 developed suspected systemic fungal infections (23%). Of 24 patients who received nystatin, 4 (17%) developed oral candidiasis and 8 (33%) developed systemic fungal infections, 4 proven and 4 suspected. Significantly more patients on the nystatin arm progressed to invasive fungal infections. Ketoconazole was not superior to nystatin in reducing the frequency of oral candidiasis but possibly reduced the frequency of invasive fungal infections.

A Randomized Trial Comparing Ketoconazole and Nystatin Prophylactic Therapy in Neutropenic Patients

A randomized trial was conducted comparing ketoconazole and nystatin in the prevention of oral candidiasis and appearance of invasive fungal infections in 51 neutropenic leukemic patients undergoing induction chemotherapy. Ketoconazole was administered in a 200 mg dose twice daily. Nystatin oral suspension was given in doses of 500,000 units four times daily. Surveillance cultures of the throat and urine were obtained prior to treatment and conducted weekly. Patients were enrolled in the study if the absolute granulocyte count was less than 1500/μl, if physical examination revealed no evidence of oral candidiasis, no evidence of urinary tract infection, and there was no pulmonary infiltrate on chest x-ray. Patients were continued on study until the absolute granulocyte count reached 1500/μl, evidence of oral candidiasis appeared, or presumed or proven invasive fungal infections appeared. Of the 46 evaluable patients, 22 received ketoconazole, 3 (14%) developed oral candidiasis, and 5 developed suspected systemic fungal infections (23%). Of 24 patients who received nystatin, 4 (17%) developed oral candidiasis and 8 (33%) developed systemic fungal infections, 4 proven and 4 suspected. Significantly more patients on the nystatin arm progressed to invasive fungal infections. Ketoconazole was not superior to nystatin in reducing the frequency of oral candidiasis but possibly reduced the frequency of invasive fungal infections.

Bacterial translocation and gram-negative bacteremia in patients with hematological malignancies.

Between 1976 and 1982, Enterobacteriaceae and Pseudomonas aeruginosa were prospectively counted in fecal specimens from leukemic patients with gram-negative bacteremia. The strains isolated from the blood and feces of 55 patients were compared. Translocation of the dominant fecal strain of Enterobacteriaceae or P. aeruginosa was observed in 45 cases (82%) and was strongly associated with granulocytopenia of less than 10(2) cells/microliter (P less than .0001). Thirteen (81%) of 16 patients with bacteremia caused by P. aeruginosa were intestinal carriers of the same strain, whereas only 2 (5%) of 39 patients with bacteremia caused by Enterobacteriaceae were carriers of P. aeruginosa. Bacterial translocation of Enterobacteriaceae was not associated with an abnormally high fecal population of the translocating strain. Prospective quantitative and qualitative analyses of fecal flora were useful in forecasting the most probable translocating gram-negative organism in neutropenic leukemic patients with clinical signs of bacteremia.

The effect of amphotericin B lozenges on the presence and number of Candida cells in the oropharynx of neutropenic leukemia patients.

A retrospective evaluation was made on the value of amphotericin B lozenges in the selective elimination of yeasts from the oropharynx. Four different groups of severely granulocytopenic patients were studied. All 77 patients received amphotericin B orally as a suspension or as tablets. Four amphotericin B lozenges were also administered daily for topical antimycotic decontamination of the oropharynx. This was done in the presence of colonization-resistance decreasing factors such as a nasogastric tube (Group I, 19 patients) or mucosal damage (Group III, 25 patients) and in patients with four or more consecutive throat swab cultures with yeasts (Group IV, 11 patients). The 22 patients in Group II did not receive lozenges. The addition of lozenges resulted in a decrease in the mean "growth density" of Candida cells in the oropharynx. This reduction was significant in Group III (p less than 0.01) and Group IV (p less than 0.02) and became evident during the first week of treatment. In patients with a nasogastric tube, however, 51.8% of the throat swab cultures revealed yeasts. Increasing the dose of the lozenges might improve the results in these patients. Topical treatment of the oropharynx with amphotericin B lozenges is advocated for patients who are susceptible to Candida infections.