Cefpirome as empirical treatment for febrile neutropenia in patients with hematologic malignancies

Cefpirome, a fourth generation cephalosporin, was administered during 154 episodes of febrile neutropenia in 106 patients. We assessed the clinical efficacy of cefpirome and its activity against isolated pathogens in neutropenic patients with hematologic malignancies. In addition, the pharmacokinetics and optimal dosing regimen of cefpirome during neutropenia were investigated.     

Effect of hospitalwide change in clindamycin dosing schedule on clinical outcome

We compared clinical outcomes of 65 hospitalized patients receiving clindamycin before and 59 after a sudden hospitalwide shift in dosing schedules for this drug from 600 mg every 6 hours to 600 mg every 8 hours. Outcomes studied included the efficacy of antibiotic treatment, length of febrile period, and frequency of adverse effects. We also compared and controlled for patient characteristics such as age, sex, presence of multiple diagnoses, length of therapy, and concurrent use of other antibiotics. There were no differences in measured clinical outcomes between the two groups. Treatment was successful in 87% of both groups. The average number of febrile days was 5.1 in the first group and 3.9 in the second (P less than .05). Patients on 6-hourly therapy experienced a 12% rate of antibiotic-related adverse effects vs. 5% for the 8-hourly group (P greater than .05). These data support the clinical rationale and safety of a hospitalwide reduction in the frequency of clindamycin dosing. In addition to considerable pharmacy and nursing time saved, this change also saved greater than $40,000 annually in antibiotic costs.     

Pegfilgrastim use during chemotherapy: current and future applications

Chemotherapy-induced myelosuppression is the most common dose-limiting side effect of cancer chemotherapy. Neutropenia is a serious risk with chemotherapy, associated with infectious complications, use of intravenous antibiotics, hospitalization, and even death. The occurrence of febrile neutropenia can lead to dose reductions and delay in subsequent cycles of chemotherapy that may have a detrimental affect on overall survival and disease-free survival. Granulocyte colony-stimulating factors (G-CSF) can reduce the duration of severe neutropenia, the incidence of febrile neutropenia, and allow planned dosing and timing of chemotherapy. Filgrastim is a G-CSF that has demonstrated benefit for the treatment and prophylaxis of chemotherapy-induced neutropenia (CIN), but its short half-life requires repeated daily subcutaneous injection. Pegfilgrastim is a recombinant G-CSF created by attaching a polyethylene glycol (PEG) molecule to the filgrastim protein. Once-per-cycle dosing of pegfilgrastim has been evaluated in clinical trials using myelosuppressive chemotherapy in breast cancer, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. Trials have demonstrated that pegfilgrastim is comparable in safety and efficacy to filgrastim for decreasing the duration of severe neutropenia after chemotherapy in patients with nonmyeloid malignancy. This review will summarize recent clinical trial results and novel uses of pegfilgrastim.     

Flexible granulocyte colony-stimulating factor dosing in ovarian cancer patients who receive dose-intense taxol therapy

As has been reported with other chemotherapeutic agents, evidence is emerging to suggest that increased taxol dose intensity is associated with improved therapeutic efficacy. Granulocyte colony-stimulating factor (G-CSF) effectively protects the bone marrow from taxol-induced neutropenia and allows for higher taxol dose administration. This report addresses the optimal use of G-CSF as a supportive agent for dose-intense taxol therapy. Forty-seven patients were evaluated. Each ovarian cancer patient received taxol with G-CSF support, with starting doses of 250 mg/m2 per 21 days and 10 micrograms/kg/d, respectively. Five patients were treated with the same dose of G-CSF for multiple cycles. Forty-two patients were given "flexible" G-CSF dosing. Instead of reducing taxol dose after a cycle of therapy complicated by febrile neutropenia (F+N+), the G-CSF dose was increased. Only after a second episode of F+N+ was the taxol dose reduced. The initial 5 patients who developed F+N+ after taxol (250 mg/m2) and G-CSF (10 micrograms/kg/d) were retreated at the same doses of both drugs; subsequently, 4 of 5 patients had another episode of F+N+. With flexible G-CSF dosing, taxol dose intensity could be maintained at the target level in 34 of 42 patients (81% of the cohort). Sixteen of these patients (38% of the cohort) would have required taxol dose reductions for F+N+ if flexible G-CSF dosing had not been used. By increasing the G-CSF dose when indicated, patients at high risk for recurrence of F+N+, because they had already experienced one episode, appeared to have a lower risk of developing a recurrent episode. These data suggest that flexible G-CSF dosing may have merit and may allow the administration of more dose- intense taxol. A prospective, randomized, controlled clinical trial of flexible G-CSF dosing versus fixed-dose G-CSF appears warranted.     

Quality of treatment for febrile illness among children at outpatient facilities in sub-Saharan Africa

For the prompt and effective management of malaria cases (a key strategy for reducing the enormous burden of the disease), healthworkers must prescribe antimalarial drugs according to evidence-based guidelines. In sub-Saharan Africa, the guidelines for use in outpatient settings generally recommend that febrile illness in children should be suspected to be malaria and be treated with an antimalarial drug. The quality of treatment offered to febrile children at outpatient facilities in this region has now been investigated in a literature review. The results of five methodologically comparable studies were also used to explore the determinants of malaria-treatment practices. The quality of treatment prescribed to febrile children was found to have been generally sub-optimal, with low levels of adherence to national guidelines, the frequent selection of non-recommended antimalarials, and the use of incorrect dosages. Several factors might be to responsible for these shortcomings. Although interventions such as the Integrated Management of Childhood Illness (IMCI) strategy can lead to improvements, a better understanding of the practices of the healthworkers responsible for treating febrile children will be needed before treatment is made much better. The failure to provide treatment of good quality will become an increasingly important problem as antimalarial policies involving drugs with more complex dosing regimens, such as artemisinin-based combination therapies (ACT), are implemented. If the malaria burden in Africa is to be greatly reduced, the deployment of ACT must be accompanied by interventions to ensure the correct treatment of children at the point of care. Some interventions, such as IMCI, can improve the treatment of not only malaria but also other potentially life-threatening illnesses.     

Prevalence of relative bradycardia in Orientia tsutsugamushi infection

We investigated 100 febrile patients infected with Orientia tsutsugamushi (the etiologic agent of scrub typhus) for the presence of relative bradycardia, defined as in increase in heart rate of < 10 beats/minutes/1 degree C increase in temperature. The median heart rate response for the entire febrile scrub typhus population was 9.3 beats/minute/degrees C and the prevalence of relative bradycardia was 53%. The occurrence of relative bradycardia was independent of patient age or gender. There were no differences in median basal temperature or febrile temperature between those patients exhibiting relative bradycardia and those with a normal febrile pulse increase. However, febrile patients with relative bradycardia had a significantly higher resting pulse rate following recovery from infection than did patients who had a normal pulse increase during their illness. These data demonstrate that relative bradycardia frequently accompanies mild infection with O. tsutsugamushi and that baseline cardiovascular parameters may affect the febrile heart rate response to scrub typhus.     

Relationship of serum antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy

Methicillin-resistant coagulase-negative staphylococci have become increasingly responsible for febrile episodes in cancer patients, often necessitating the addition of vancomycin to an aminoglycoside-containing broad-spectrum antibiotic regimen. A total of 229 courses of antibiotic therapy in 229 patients were evaluated for nephrotoxicity associated with the administration of an aminoglycoside and/or vancomycin. The incidence of nephrotoxicity observed in patients administered an aminoglycoside (Group A) was 18 percent; vancomycin (Group B) 15 percent; and an aminoglycoside concurrently with vancomycin (Group C) 15 percent. The following pharmacokinetic/dosing factors were significantly associated with increased nephrotoxicity in the groups: baseline serum creatinine level, mean daily dose during the first three days of therapy (Group B), and elevated serum trough aminoglycoside or vancomycin concentrations (2 micrograms/ml or more or 10 micrograms/ml or more, respectively). No cumulative nephrotoxicity was demonstrated with the concurrent administration of vancomycin and an aminoglycoside. A higher incidence of nephrotoxicity was seen in Group C (42 percent) and Group B (27 percent) patients, in whom trough serum vancomycin concentrations were 10 micrograms/ml or more.     

Therapeutic drug monitoring of aminoglycosides in acute myeloid leukaemia patients

International guidelines limit the use of aminoglycosides in febrile neutropenia to severe situations. We retrospectively reviewed the use of aminoglycosides in adult acute myeloid leukaemia patients admitted in 2009. Our guidelines include precise indications (severe sepsis, shock, drug resistance), dosing regimens (once-daily 20 mg/kg/day amikacin, 5 mg/kg/day gentamicin), durations of treatment, drug monitoring timing, and target C(max) concentrations (40 mg/l amikacin, 20 mg/l gentamicin). Thirty-one patients received 46 aminoglycoside courses: 31 amikacin and 15 gentamicin. The mean prescribed dosage was 19 ± 2.8 mg/kg/day for amikacin and 4.7 ± 0.9 mg/kg/day for gentamicin. The mean duration of use was 2.9 days for both drugs. The mean C(max) for amikacin was 47 ± 13 mg/l and for gentamicin was 13.6 ± 7.5 mg/l. In compliant regimens, all amikacin patients and a third of gentamicin patients had adequate C(max). Among 23 isolated pathogens, 65.5% were susceptible to both drugs and 11.5% to amikacin only. This vindicates the 20 mg/kg/day amikacin dosage and suggests a need to increase the gentamicin dosage.     

Evaluation and management of febrile seizures in the out-of-hospital and emergency department settings

Febrile seizures are the most common seizures seen in children younger than 5 years old. Out-of-hospital and emergency department providers need to be familiar with the principles of the evaluation and management of this common disorder. Most febrile seizures are brief, do not require any specific treatment or extensive workup, and have a benign prognosis. Recognizing the pattern of a simple febrile seizure in young children is important to limit interventions and to reassure parents. Patients with febrile seizures are not at higher risk for serious bacterial illnesses than similarly aged febrile patients. Excluding meningitis and encephalitis are the primary clinical interventions through a thorough history and physical examination and, occasionally, a lumbar puncture. Reassuring parents of patients with febrile seizures and arranging primary care follow-up are important roles for the emergency physician.     

Diagnostic value of sTREM-1, IL-8, PCT,and CRP in febrile neutropenia after autologous stem cell transplantation

Infections and infectious complications are the major cause of morbidity and mortality in febrile neutropenic patients after autologous stem cell transplantation. Laboratory biomarkers are helpful for early identification of critically ill patients and optimal therapy management. Several studies in adult non-neutropenic patients proposed sTREM-1 as a superior biomarker for identification of septic patients as well as a predictor for survival in these patients compared with procalcitonin (PCT), C-reactive protein (CRP), or interleukin-8 (IL-8). Here, to assess the utility of PCT, CRP, IL-8, and sTREM-1 in febrile neutropenia, 44 patients presenting with febrile neutropenia after autologous stem cell transplantation were recruited in a single-center prospective pilot study. We analyzed PCT and CRP as well as IL-8 and sTREM-1 levels pre- and post-transplantation at defined time points. In 20 of 44 patients, concentration of sTREM-1 was under the detection level at appearance of febrile neutropenia. Mean levels of PCT, IL-8, and CRP were significantly increased in infections of critically ill patients who by dysfunction or failure of one or more organs/system depend on survival from advanced instruments of monitoring and therapy. However, all tested biomarkers could not distinguish between presence and absence of bloodstream infection. The combination of the biomarkers PCT and IL-8 achieved a high sensitivity of 90% and specificity of 74% for the identification of serious complications in febrile neutropenia, whereas the combination of CRP and PCT or IL-8 achieved a high sensitivity of 100%, but with the addition of a low specificity of 47or 41%. In conclusion, we found that the measurement of sTREM-1 concentration at presentation of febrile neutropenia is not useful to identify bacterial bloodstream infections and critically ill patients. PCT and IL-8 are useful biomarkers for the early identification of critically ill patients, compared to CRP and sTREM-1 in febrile neutropenia. PCT or IL-8 in combination with clinical parameters should be considered in routine measurement to identify critically ill patients as early as possible.     

The efficacy and safety of piperacillin-tazobactam for febrile neutropenic patients in Japan

The IDSA guideline for management of febrile neutropenic patients updated in 2010 recommends monotherapy with anti-pseudomonal-lactam agents, including piperacillin-tazobactam (PIPC/TAZ) for high-risk patients. However, clinical studies of PIPC/TAZ are limited in Japanese patients. In this study, we conducted an open-labeled non-randomized prospective trial to examine the efficacy and safety of PIPC/TAZ as an empirical treatment for Japanese patients with febrile neutropenia. Forty-nine febrile episodes in neutropenic patients excluding those undergoing allogeneic stem cell transplantation (high risk 36, low risk 13) were analyzed. The overall response rate was 71%, and no significant differences between the high-risk and the low-risk group were observed (high risk 72%, low risk 69%). Neither PS nor usage of G-CSF affected the response rate. No major side effects were observed in the study. The efficacy and the safety profile of PIPC/TAZ treatment were comparable to those in other previous Western studies. In conclusion, this study suggests PIPC/TAZ is effective and well tolerated as an initial empirical treatment for febrile neutropenic Japanese patients.     

Granulocyte Transfusion Therapy

The effect of granulocyte transfusions on the course of infection in patients under treatment for acute leukemia was evaluated by comparing 19 febrile episodes in 15 patients receiving antibiotics alone with 18 febrile episodes in 13 patients receiving antibiotics in combination with granulocyte transfusions from ABO-matched donors. Both groups had a similar age, sex distribution and duration of disease prior to the febrile episode. About two-thirds of the patients in both groups had acute myeloblastic leukemia. 94% of the patients in the transfused group and 74% of the control group survived the febrile episode. In patients with positive blood cultures all transfused patients survived as compared to only 57% in the control group (p=0.05). In patients with persistent bone marrow failure 92% of the transfused patients survived as compared to 73% in the control group. Granulocyte transfusions had no effect on the outcome of febrile episodes in patients with negative blood cultures or early recovery of marrow function. These data appear to support the contention that granulocyte transfusions are beneficial in patients with blood culture-proved sepsis with persistent neutropenia.     

Treatment of febrile neutropenia: what is new?

PURPOSE OF THE REVIEW: To identify the more recent challenges in the treatment of patients with febrile neutropenia following antineoplastic chemotherapy or bone marrow transplant published in the English language in the period late 2000-early 2002 regarding: changes in etiology of bacteremia in neutropenic patients; new options for initial empirical antibacterial therapy; factors associated with the risk of developing infection in cancer patients; prediction of prognosis in febrile neutropenia; oral therapy; need for a specific anti-Gram-positive coverage in persistently febrile and neutropenic patients. RECENT FINDINGS: Findings may be summarized according with the identified topics as follows: many centers are reporting an increase in the incidence of Gram-negative bacteremias; piperacillin-tazobactam could be safely administered as monotherapy of febrile neutropenia; congenital factors and intensity of chemotherapy and other medical interventions, such as antifungal prophylaxis, are recognized as of increasing importance in the determination of infectious risk; it is now possible to identify patients with a good prognosis (low risk) by means of validated scoring systems; oral therapy is feasible in low risk patients; the empirical addition of a glycopeptide in persistently febrile neutropenic patients is not indicated. SUMMARY: Many of the identified points may have a great impact in the daily management of febrile granulocytopenic patients. However, all recent epidemiological and therapeutical studies underline the absoloute need for the knowledge of the pattern of infecting organisms in each center.     

Assessment of measuring circulating levels of interleukin-6, interleukin-8, C-reactive protein, soluble Fc gamma receptor type III, and mannose-binding protein in febrile children with cancer and neutropenia.

Circulating levels of interleukin (IL)-6, IL-8, soluble Fc gamma receptor type III (sFc gammaRIII), mannose-binding protein (MBP), and C-reactive protein (CrP) were assessed among febrile children with cancer and neutropenia. Levels of IL-6, IL-8, sFc gammaRIII, MBP, and CrP were measured in serum from 56 pediatric cancer patients at the time of admission for 121 episodes of febrile neutropenia (88 febrile episodes without identifiable source, 5 clinically documented infections, 20 episodes of bacteremia due to gram-positive and 5 due to gram-negative organisms, and 3 fungal infections). IL-6 and IL-8 levels were higher in patients with either bacteremia due to gram-negative organisms or fungal infections than in patients with febrile episodes without an identifiable source (P < .00001 for each). IL-6 and IL-8 levels were higher in children with bacteremia due to gram-negative organisms than in those with bacteremia due to gram-positive organisms (P = .0011 and P = .0003, respectively). The measured levels of CrP, MBP, and sFc gammaRIII were not useful for identifying the type of infection. These preliminary results show the potential usefulness of IL-6 and IL-8 as early indicators for life-threatening infections in febrile cancer patients with neutropenia.     

Improving efficacy of antifungal therapy by polymerase chain reaction-based strategy among febrile patients with neutropenia and cancer.

Early detection of fungal infections in and corresponding early treatment of febrile patients with neutropenia and cancer have been important issues and continue to be major challenges for clinicians. The use of nested PCR to make therapeutic decisions was studied. Sequential blood samples obtained from 42 patients with neutropenia and cancer were tested by nested PCR and culture. Instead of the empirical antifungal therapy strategy, amphotericin B treatment was initiated only for patients who had 2 consecutive positive results by nested PCR. A reduced mortality rate was observed for febrile patients with neutropenia and cancer who had fungal infections. Thus, this strategy, combined with the nested PCR for early detection of fungal infection in febrile patients with neutropenia, may be used as a guideline for antifungal therapy.     

Elevated IgA and IgM anticardiolipin antibodies in acute Kawasaki disease

There is marked activation of the endothelium and immune system in Kawasaki disease. Anticardiolipin antibodies (aCL) can cause activation of the endothelium. We measured aCL levels in acute Kawasaki disease patients and compared them to other febrile patients to see whether their aCL responses were different. Twenty-one patients with acute Kawasaki disease and 16 patients with an acute febrile illness were recruited. The aCL levels were measured in the sera of febrile patients and in Kawasaki disease patients prior to immunoglobulin therapy. There was no significant difference between the IgG aCL levels (p = 0.87) between the Kawasaki disease and febrile patients. However, the IgM (p = 0.01) and IgA (p = 0.03) aCL were significantly higher in patients with acute Kawasaki disease than in febrile children. Elevation of IgA aCL has been reported in association with other vasculitides and IgA-secreting plasma cells have been demonstrated in the vascular tissue in Kawasaki disease.     

Once-daily and twice-daily dosing of p-aminosalicylic acid granules

The study objective was to determine the minimum frequency of dosing for standard 4-g doses of p-aminosalicylic acid (PAS) granules. Two sequential six-patient pharmacokinetic studies are described, followed by clinical data from 40 subsequent patients. All patients had multidrug-resistant tuberculosis (MDR-TB). Serum was collected at two to three time points after dosing, and assayed by a validated high performance liquid chromatography (HPLC) assay. Data were analyzed using noncompartmental methods. In six patients, twice-daily dosing produced median serum concentrations at 4, 8, and 12 h post-dose of 25.8, 23.2, and 16.4 microgram/ml. In six patients, once-daily dosing produced median serum concentrations at 6, 12, and 24 h post-dose of 23.4, 3.7, and 0 microgram/ml. In 40 patients, twice-daily dosing produced median serum concentrations at 4 to 8 and 9 to 12 h post-dose of 24.8 and 20.6 microgram/ml. Unlike once-daily dosing, twice-daily PAS maintained serum concentrations in excess of 1 microgram/ml, the typical minimal inhibitory concentration against Mycobacterium tuberculosis, for the entire dosing interval. We now use twice-daily PAS granules for our patients with MDR-TB.     

Seroprevalence of Q-fever in febrile individuals in Mali

OBJECTIVES: We conducted a serological survey for Q-fever among febrile patients in Bamako and Mopti (Mali) and investigated the main risk factors for seroconversion. METHODS: Blood samples from 156 febrile patients were collected in healthcare facilities of Bamako and Mopti and examined with the microimmunofluorescence test. RESULTS: Forty per cent (n = 63) were seropositive for Q-fever, 28% in Bamako and 51% in Mopti. A more recent infection was suspected in 9.5% (n = 6) of all seropositive patients. This is the first time that Q-fever seropositivity is reported in febrile individuals in Mali. The patients' symptoms and diagnoses spanned a wide range of conditions; none had been diagnosed with Q fever by their treating physician. No risk factors for seropositivity could be identified with the exception of the city of residence and none could be identified with a logistic regression model with 'city' taken as random effect. CONCLUSION: A high rate of seropositivity to C. burnetii was found among febrile urban patients in Mali but no risk factors for seropositivity could be identified in this study.     

Febrile pharyngitis as the primary sign of HIV infection in a cluster of cases linked by sexual contact

Three cases of febrile pharyngitis were recorded retrospectively in a cluster of 5 men and 1 woman linked by sexual contact to a human immunodeficiency virus (HIV) carrier. In all 3 patients, a progression into clinical HIV disease was noted during an observation period of 20-25 months. The febrile pharyngitis developed similarly in each patient after an incubation time of 3-5 weeks. High fever of sudden onset and a sore bright red throat were accompanied by extreme lethargy and, in 2/3 patients, a morbilliform rash. The acute illness lasted 4-7 days and was followed by mild lymphadenopathy. All 3 patients were HIV seropositive 17-19 months later, when they first entered the study. By contrast, those 2 cases who did not fall ill, continued to be seronegative for 19-39 months after the exposure. Seroconversion of HIV could retrospectively be demonstrated in 1 of the 3 patients 2 weeks after the onset of the febrile illness. A simultaneous lack of rise in the EBV and CMV titres suggests HIV as the causative agent for this febrile mononucleosis-like pharyngitis.     

Shifting guidelines for myeloid growth factors: applications in cancer chemotherapy

Neutropenia is a frequent dose-limiting complication of chemotherapy. Although myeloid growth factors decrease the risk of febrile neutropenia and the resulting complications of hospitalizations, dose delays, and dose reductions, not all patients need or benefit from the prophylactic administration of myeloid growth factors. A recent risk model showed that the predictors of febrile neutropenia include anthracycline use, poor performance status, and low pretreatment blood counts. These predictors may be used in addition to the intensity of the chosen chemotherapy regimen to determine whether a patient warrants primary prophylaxis with myeloid growth factors. The 2005 guidelines of the National Comprehensive Cancer Network call for primary prophylactic use in all patients with a risk of febrile neutropenia above 20%. Other recent studies show that pegylated filgrastim is also effective at preventing febrile neutropenia in patients receiving intermediate- risk chemotherapy.