Efficacy and Safety Assessment of Antifungal Sequential Therapy from Micafungin to Liposomal Amphotericin B for Antibiotics-Refractory Febrile Neutropenia in Patients with Hematologic Malignancies

Invasive fungal infections are a major challenging problem in the management of febrile neutropenia (FN) in patients with hematologic malignancies. Liposomal amphotericin B (L-AmB) or micafungin (MCFG) has been widely used as a first-line empirical antifungal therapy for suspected fungal infection in such patients. However, there are several issues in patients receiving these agents: drug related toxicities for L-AmB and breakthrough fungal infections for MCFG. In order to make the best use of these 2 agents, we conducted a prospective study of sequential therapy from MCFG to L-AmB, and evaluated the efficacy and safety of this strategy in FN patients with hematologic malignancies. A total of 18 patients were enrolled, and 11 patients who fulfilled the protocol defined criteria were evaluated. Underlying diseases consisted of acute leukemia (n = 9), non-Hodgkin lymphoma (n = 1), and myelodysplastic syndrome (n = 1). Treatment success was achieved in 8 patients (72.7%). Drug-related adverse events occurred in 8 patients (72.7%). All of those adverse events except one case were below grade 2. Three patients required discontinuation of L-AmB. Although our empirical antifungal sequential therapy seems to be encouraging for antibiotics-refractory FN in patients with hematologic malignancies, further investigation in large-scale studies is warranted.

Procalcitonin as a marker of infection in febrile neutropenia:A systematic review

Aim: Management of febrile neutropenia is challenged by lacking microbiological and clinical documentation of infection. Procalcitonin is emerging as a new promising biomarker of infection. We aimed to undertake a systematic review evaluating the diagnostic accuracy of procalcitonin as a marker of infection in febrile neutropenia. Methods: We performed a systematic re- view of the literature using the databases MEDLINE, EMBASE and Cochrane Library including a search of the grey literature (e.g. unpublished data, web sides of relevant societies). The methodological quality was assessed using predefined criteria. The relevant data were extracted and analyzed by two authors. Results: The literature search yielded a total of 193 studies of which nine were eligible for inclusion. There was a great variation in the quality of the methodological design. A notable heterogeneity exists regarding the studied populations and the definition of the reference standards. Among the nine included studies the sensitivity ranged from 42% to 72% and the specificity ranged from 64% - 89% at a cut off value ranging from 0.5 - 0.8 ng/ml. The studied endpoint was either microbiologically or clinically documented infection. Four studies found procalcitonin superior to Creactive protein in discriminating infection from the various other causes of fever. Conclusion: Procalcitonin appears to be a promising biomarker and might add new diagnostic information in the management of febrile neutropenia.

Decreased incidence of febrile neutropenia in Michigan following masking and social distancing orders for the COVID-19 pandemic: A population based cohort study

BACKGROUND It has been theorized that 75%-80%of febrile neutropenia(FN)is caused by endogenous pathogens,while up to 20%of cases are thought to be caused by a viral infection.It is unknown if precautions such as masking and social distancing reduce the risk of FN in susceptible populations.AIM To determine whether coronavirus disease 2019(COVID-19)infection mitigation efforts,namely masking and social distancing,were associated with a reduction in the incidence of FN.METHODS This was a retrospective population based cohort study comparing the incidence of FN in the 13 mo prior to(Year 0)and 13 mo following(Year 1)the public health executive orders(PHEO)in Michigan.Data was queried for all emergency department(ED)visits from April 1,2019 to March 31,2021 from the National Syndromic Surveillance Program,a program which collects data that is voluntarily submitted by approximately 89%of Michigan EDs.The primary study outcome was the incidence of FN as a proportion of ED visits in the 13-mo before and 13-mo after COVID-19 mitigations efforts,namely masking and social distancing.We hypothesized that there would be a significant decrease in the incidence of FN in the period following the PHEO aimed at reducing the spread of the severe acute respiratory syndrome coronavirus 2 virus.RESULTS There was a total of 8979221 total ED visits captured during the study period.In Year 0 there were 5073081 recorded ED visits and 3906140 in Year 1.There was a significant reduction in the proportion of total ED visits with a diagnosis of FN,decreasing 13.3%across periods(0.15%vs 0.13%,P=0.036).In patients with a hematologic malignancy a more impressive reduction in the incidence of FN was evident following PHEO(22%vs 17%,P=0.02).CONCLUSION We found a significant association between social distancing and mask guidelines implemented on a large public scale with decreased rates of FN,particularly in those with a hematologic malignancy.These findings may be useful in the design of future research and recommendations regarding the prevention of FN.

Garenoxacin Prophylaxis for Febrile Neutropenia after Chemotherapy in Hematological Malignancies

Background: Febrile neutropenia is one of the most serious adverse events in patients with hematological malignancies and chemotherapy. The routine use of fluoroquinolone prophylaxis in patients with hematological malignancies is controversial. Therefore, we prospectively evaluated the efficacy and safety of prophylactic use of garenoxacin for febrile neutropenia. Patients and Methods: Consecutive adult patients with hematological malignancies who were at risk for chemotherapy-induced neutropenia lasting more than seven days were eligible for present study. They received oral garenoxacin (400 mg daily) from the neutrophil count decreased to less than 1000/μl and continued until the neutropenia had resolved. The primary endpoint was incidence of febrile neutropenia, and the secondary endpoints were the type and incidence of adverse events. Results: We enrolled 46 consecutive patients (median age, 59 years). The underlying diseases comprised acute myeloid leukemia (n = 17), acute lymphoblastic leukemia (n = 3), malignant lymphoma (n = 23), and multiple myeloma (n = 3). There were 23 febrile neutropenia episodes and 2 episodes of bacteremia. There were no grade 3 or 4 adverse events;however serum creatinine levels were significantly elevated after garenoxacin administration. The overall prophylactic efficacy of garenoxacin was 50%, and there were no infection-related deaths. Conclusions: Prophylactic use of garenoxacin is effective and safe in patients with hematological malignancies. (Clinical trial registration number: UMIN000004979).

Caspofungin versus liposomal amphotericin B for treatment of invasive fungal infections or febrile neutropenia

Background Nowadays,there are published trials in regards to the comparison of caspofungin with liposomal amphotericin B （L-AmB）.However,these studies have a modest sample size and convey inconclusive results.The aim of this study was to review the efficacy and safety of caspofungin for the treatment of invasive fungal infections （IFIs）,compared with L-AmB.Methods Electronic databases （up to July 31,2013） PubMed and Embase databases,the Cochrane Library,and Google Scholar were searched to identify relevant trials of caspofungin and L-AmB.Analyses of efficacy and adverse outcomes were performed by relative risks （RRs） and 95% confidence intervals （C/s）.Heterogeneity was assessed by x2-test and the/2-statistic.Results Three trials were included in this meta-analysis with 1249 modified intention-to-treat （MITT） patients.The results showed that caspofungin produced equal efficacy in favorable overall response （RR=1.02,95% Cl 0.88-1.18; P=0.81） and mortality rate （RR=1.53,95% Cl 0.38-6.27,P=0.55）,safer in clinical adverse events （RR=0.20,95% Cl 0.08-0.54; P=0.001）,laboratory adverse events （RR=0.69,95% Cl 0.57-0.84; P=0.0002）,and discontinuation rate （RR=0.26,95% Cl 0.08-0.83,P=0.02）,compared with L-AmB in the treatment of patients with IFls.Conclusion Based on the results of this meta-analysis,it would appear that caspofungin was measured to have equal efficacy in clinical outcomes and safer in terms of adverse events.

Current management of chemotherapy-induced neutropenia in adults:key points and new challenges

Chemotherapy-induced neutropenia(CIN)is a potentially fatal and common complication in myelosuppressive chemotherapy.The timing and grade of CIN may play prognostic and predictive roles in cancer therapy.CIN is associated with older age,poor functional and nutritional status,the presence of significant comorbidities,the type of cancer,previous chemotherapy cycles,the stage of the disease,specific chemotherapy regimens,and combined therapies.There are many key points and new challenges in the management of CIN in adults including:(1)Genetic risk factors to evaluate the patient’s risk for CIN remain unclear.However,these risk factors urgently need to be identified.(2)Febrile neutropenia(FN)remains one of the most common reasons for oncological emergency.No consensus nomogram for FN risk assessment has been established.(3)Different assessment tools[e.g.,Multinational Association for Supportive Care in Cancer(MASCC),the Clinical Index of Stable Febrile Neutropenia(CISNE)score model,and other tools]have been suggested to help stratify the risk of complications in patients with FN.However,current tools have limitations.The CISNE score model is useful to support decision-making,especially for patients with stable FN.(4)There are still some challenges,including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN.In view of the current reports,our group discusses the key points,new challenges,and management of CIN.

Evaluation of febrile neutropenic patients hospitalized in a hematology clinic

Objective:To evaluate the febrile neutropenic patients with hematological malignancies hospitalized in hematology clinic with poor hygiene standards.Methods:A total of 124 patients with hematological malignancies(69 male,55 female)hospitalized in hematology clinic with poor hygiene conditions depending on hospital conditions,between January 2007 and December 2010,were evaluated,retrospectively.Results:In this study,250 febrile neutropenia episodes developing in 124 hospitalized patients were evaluated.Of the patients,69 were men(56%)and 55 women(44%).A total of 40 patients(32%)had acute myeloid leukemia,25(20%)acute lymphoblastic leukemia,19(15%)non-Hodgkin's lymphoma,10(8%)multiple myeloma,and 8(8%)chronic myeloid leukemia.In our study,56 patients(22%)were diagnosed as pneumonia,38(15%)invasive aspergillosis,38(15%)sepsis,16(6%)typhlitis,9(4%)mucormycosis,and 4(2%)urinary tract infection.Gram-positive cocci were isolated from 52%(n=20),while Gram-negative bacilli 42%(n=16)and yeasts from 6%(n=2)of the sepsis patients,respectively.The most frequently isolated Gram-positive bacteria were methicillin-resistant coagulase-negative staphylococci(n=18),while the most frequently isolated Gram-negative bacteria was Escherichia coli(n=10).Conclusions:Febrile neutropenia is still a problem in patients with hematological malignancies.The documentation of the flora and detection of causative agents of infections in each unit would help to decide appropriate empirical therapy.Infection control procedures should be applied for preventing infections and transmissions.

Role of urine studies in asymptomatic febrile neutropenic patients presenting to the emergency department

BACKGROUND: The role of urine studies in the detection of urinary tract infection(UTI) in febrile neutropenic patients with urinary symptoms(having a urinary catheter or having a positive urine analysis) is inarguable. However, the evidence is scarce regarding the indication for urine studies in asymptomatic(i.e., without urinary symptoms) patients with febrile neutropenia(FN) presenting to the emergency department(ED). The aim of this study is to evaluate the need for obtaining urine studies in asymptomatic febrile neutropenic patients.METHODS: This was a retrospective cohort study conducted on adult cancer patients who presented to the ED with FN and had no urinary symptoms. We included all ED presentations of eligible patients between January 2013 and September 2018. Student's t-test and Wilcoxon rank-sum test were used for continuous data, while Chi-square and Fisher's exact tests were used for categorical data. Participants were divided into two groups based on their urine culture(UC) results: negative and positive UCs. Two cut-offs were used for positive UC results: ≥10~5 cfu/m L and ≥10~4 cfu/m L.RESULTS: We included 284 patients in our study. The age of our patient population was 48.5±18.5 years. More than two-thirds(68.7%) of patients had severe neutropenia, while only 3.9% and 9.9% of the patients had positive UCs at ≥10~5 cfu/m L and ≥10~4 cfu/m L, respectively. UCs were expectedly positive in most patients with urinalysis(UA) abnormalities. However, 27.3% and 32.1% of patients with positive UCs at ≥10~5 cfu/m L and ≥10~4 cfu/m L respectively had a normal UA. CONCLUSIONS: In our study, the incidence of UTI in adult febrile neutropenic cancer patients who present to the ED without urinary symptoms is low. Consequently, routine urine testing may not be warranted in this population, as it adds unnecessary financial burdens on the patients and delays timely management.

Evaluation of Prophylaxis with Norfloxacin and Ceftriaxone versus Ciprofloxacin during the Period of Neutropenia after Haematopoietic Stem Cell Transplantation:Retrospective Analysis of Two Sequencial Cohorts

Background: The aim of this study was to evaluate the occurrence of febrile neutropenia (FN) during aplasia after haematopoietic stem cell transplantation (HSCT) in patients who received anti-bacterial prophylaxis with norfloxacin/ceftriaxone or ciprofloxacin, between September 2006 and May 2009. Methods: We retrospectively examined all patients undergoing HSCT at S?o Paulo Hospital during the study period. Results: Of the 107 studied patients, 71 (66.3%) were included in the analysis. The exclusion criteria were as follows: occurrence of fever or infection before the transplantation (17), prophylactic use of norfloxacin (6), fever of probable non-infectious aetiology (2), and absence of prophylaxis during the aplasia period (11). Thirty-eight patients received norfloxacin and ceftriaxone as prophylaxis (Group I) and 33 received ciprofloxacin (Group II). The groups were comparable with respect to age, underlying diseases, comorbidities, and status of the underlying disease. Patients in Group II used antibiotics in a significantly higher frequency than those in Group I (66.7% vs 33.8%, p = 0.017), for 30 days before transplantation. The number of previous hospitalisations, length of hospitalisation until transplantation, type of transplant, progenitor cells used, number of CD34 cells infused, type of conditioning, and graft-versus-host disease prophylaxis were similar in both groups. After the transplantation, 28.9% and 39.4% of the patients in Groups I and II, respectively, presented Grade III and IV mucositis (p = 0.448). Neutropenia of <500 neutrophils/mm3 lasted an average of 9.5 and 9.3 days in Groups I and II, whereas neutropenia of <100 neutrophils/mm3 lasted between 6.6 and 5.7 days. FN occurred in 78.9% of patients in Group I and 81.8% in Group II, with no significant difference in the classification of these episodes. Six patients (15.8%) in Group I and five (15.2%) in Group II had bacteraemia. All patients who did not receive prophylaxis developed FN. Conclusions: The high incidence and classification of FN episodes were similar between groups;however, the frequency was lower than in those patients who did not receive prophylaxis.

Neutropenic Fever in Lung Cancer:Clinical Aspects Related to Mortality and Antibiotic Failure

Background and objectives:Lung cancer(LC)is the leading cause of cancer death.Patients treated with chemotherapy are at risk of developing chemotherapy-induced febrile neutropenia(FN),a potentially life-threatening complication.The aims of this study were(1)to characterize FN admissions of patients with LC in a pulmonology department,and(2)to determine associations between patient profiles,first-line antibiotic failure(FLAF)and mortality.Methods:Retrospective observational case-series,based on the analysis of medical records of LC patients that required hospitalization due to chemotherapy-induced FN.Results:A total of 42 cases of FN were revised,corresponding to 36 patients,of which 86.1%were male,with a mean age of 66.71±9.83 years.Most patients had a performance status(PS)equal or less than 1,and metastatic disease was present in 40.5%(n=17).Respiratory tract infections accounted for 42.9%(n=18)of FN cases,and multidrug-resistant Staphylococcus aureus was the most isolated agent.The mortality rate was 16.7%(n=7),and the FLAF was 26.2%(n=11).Mortality was associated with a PS≥2(P=0.011),infection by a Gram-negative agent(P=0.001)and severe anemia(P=0.048).FLAF was associated with longer hospitalizations(P=0.020),PS≥2(P=0.049),respiratory infections(P=0.024),and infection by a Gram-negative(P=0.003)or multidrug-resistant agent(P=0.014).Conclusions:Lower PS,severe anemia,and infections by Gram-negative or multi-resistant agents seem to be associated with worse outcomes in FN patients.

Non-Hodgkin’s Lymphoma Associated with Metastatic Lung Cancer: Case Report

Lymphomas are neoplastic transformations that affect lymphoid cells. Diffuse large B-cell non-Hodgkin’s lymphoma has a high degree of cell proliferation, accounting for 30% of all lymphomas. Lung cancer is the leading cause of death worldwide and the recommended treatment is chemotherapy. Among the main complications resulting from non-Hodgkin’s lymphoma, lung cancer and chemotherapy used in their treatment, we can mention sepsis, acute kidney injury and febrile neutropenia. Febrile neutropenia can occur by suppressing the production of neutrophils. Sepsis, a widespread infection, is the main cause of acute kidney injury, which can also be caused by hydroelectrolytic complications or by nephrotoxicity. This is a report of a smoking patient with metastatic lung cancer who sought care due to progressive dysphagia, cough with chest pain, fever, and lower airways critical obstruction due to mediastinal lymphadenopathy, being diagnosed with diffuse large B-cell non-Hodgkin’s lymphoma. The patient evolved to death because of a significant worsening of the ventilatory pattern of multifactorial cause, mainly due to sepsis, acute kidney injury, and febrile neutropenia. The patient had mostly classic characteristics of her comorbidities, however, the overlapping of interrelated comorbidities led to the outcome of death. What is unusual about the present case report is that the patient’s characteristics, such as age, sex, and ethnicity, are opposite to those described as risk factors for diffuse large B-cell non-Hodgkin’s lymphoma.

Efficacy and safety of itraconazole as empirical antifungal therapy in febrile neutropenic patients with hematologic malignancies： an open-lable, multicenter, observational trial in a Chinese cohort

Background Invasive fungal infection （IFI） is a common and fatal complication in neutropenic patients with hematological malignancy. Empirical antifungal therapy is widely used in practice due to the difficulty of pathogens determination and illness of the hosts. The aim of this study was to evaluate the efficacy and safety of itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematologic malignancies. Methods Two hundred and seventy-four patients with hematologic malignancies who had suspected fungal infections were enrolled in 18 centers across China between April 2008 and April 2009. Empirical antifungal therapy with intravenous itraconazole 200 mg twice daily was given for the first two days, followed by 200 mg once daily for the next 12 days. Oral itraconazole solution was sequential for follow-up therapy if necessary. Five composite end points were evaluated for the response, which was more restrictive and adopted for the first time in such study in China. Results The intent-to-treat analysis included data from 274 patients （full analysis set, FAS）, of whom 248 were included as the per-protocol population （PPS）. As the composite end point of five indices was concerned, the overall response rate was 43.4%. Seperately, defervescence was achieved in 90% of patients in which 55.5% occured during neutropenia. The mean time to defervescence was 2.71 days. Absence of breakthrough IFI during drug administration or within the first 7 days after study completion was observed in 71.5% of patients. Fifty-five point five percent patients with IFI at baseline was successfully treated. Ninety point five percent patients survived for at least 7 days after completing the study. PPS analysis revealed that the duration of neutropenia 〉10 days was a statistically significant negative predictor for the response. The withdrawal rate due to drug-related toxicity or lack of efficacy was 11.0%. The incidence of adverse events was 22.6%, in which 11.6% was study drug related. The most frequent adverse events were mild to moderate liver toxicity. Conclusion Itraconazole shows desirable efficacy and safety as empirical antifungal therapy for febrile neutropenic patients with hematologic malignancies.