Cefepime monotherapy for the empirical treatment of fever in granulocytopenic cancer patients

In a pilot study, we evaluated the efficacy and the safety of cefepime, a new cephalosporin with extended-spectrum activity against both Gram-positive and Gram-negative bacteria, as empirical monotherapy for 108 febrile episodes in 84 granulocytopenic cancer patients. Cefepime (2 g tds) was given for a minimum of 7 days or until resolution of infection. Of the 108 episodes, 91 were evaluable. Microbiologically documented infections occurred in 25 patients (27%) (18 Gram-positive, 7 Gram-negative), of whom 18 had bacteraemia. Infection was clinically documented in 47 patients (52%) and fever was unexplained in 19 (21%). Overall, 71% (65/91) of the infections resolved. Response rates were 86% (6/7) for Gram-negative infections, 44% (8/18) for Gram-positive infections (57%%for cefepime-susceptible Gram-positive bacteria), 77% (36/47) for clinically documented infections and 79% (15/19) for unexplained fevers. Of the 26 patients (29%) whose primary infections did not improve with cefepime monotherapy, 23 responded after the addition of other antibiotics. Sixteen patients (18%) developed secondary infections of which 13 were microbiologically documented; Gram-positive bacteria were isolated from seven patients, Gram-negative bacteria from two, fungi from three and a virus from one. Adverse effects were mild and did not require premature discontinuation of therapy except for one patient who developed an immediate allergic reaction after the first dose of cefepime from which he recovered fully. The survival rate after resolution of granulocytopenia was 96%; three patients died of primary bacterial infection and one from secondary disseminated candidiasis. In this pilot study, cefepime monotherapy appeared safe and effective as empirical therapy for fever in cancer patients with granulocytopenia. Whether cefepime is superior to other advanced-generation cephalosporins for the treatment of Gram-positive infections will require evaluation in a larger comparative stud

Evidence-Based Guidelines for Empirical Therapy of Neutropenic Fever in Korea

Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broad-spectrum antibiotic or combination therapy with two antibiotics is recommended. At 3-5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patient's condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers

Empiric antibiotic therapy in a child with cancer and suspected septicemia

Improved outcome in the treatment of childhood cancer results not only from more aggressive and tailored cancer-directed therapy, but also from improved supportive therapy and treatment of life-threatening infectious complications. Prompt and aggressive intervention with empiric antibiotics has reduced mortality in this group of patients. Physical examination, blood tests, and blood cultures must be performed, and antibiotic therapy must be administered as soon as possible. Beta-lactam monotherapy, such as piperacillin-tazobactam or cefepime, may be an appropriate empiric therapy of choice for all clinically stable patients with neutropenic fever. An anti-pseudomonal beta-lactam antibiotic plus gentamicin is recommended for patients with systemic compromise

The Dutch Working Party on Antibiotic Policy (SWAB) Recommendations for the Diagnosis and Management of Febrile Neutropenia in Patients with Cancer

Introduction This guideline was written by a multidisciplinary committee with mandated members of the Dutch Society for Infectious Diseases, Dutch Society for Hematology, Dutch Society for Medical Oncology, Dutch Association of Hospital Pharmacists, Dutch Society for Medical Microbiology, and Dutch Society for Pediatrics. The guideline is written for adults and pediatric patients. Method The recommendations are based on the answers to nine questions formulated by the guideline committee. To provide evidence-based recommendations we used all relevant clinical guidelines published since 2010 as a source, supplemented with systematic searches and evaluation of the recent literature (2010-2020) and, where necessary, supplemented by expert-based advice. Results For adults the guideline distinguishes between high- and standard-risk neutropenia based on expected duration of neutropenia (> 7 days versus 7 days) and in children with neutropenia, ceftazidime, cefepime, and piperacillin-tazobactam are all first-choice options for empirical antibiotic therapy in case of fever. In adults with standard-risk neutropenia (duration of neutropenia <= 7 days) the MASCC score can be used to assess the individual risk of infectious complications. For patients with a low risk of infectious complications (high MASCC score) oral antibiotic therapy in an outpatient setting is recommended. For patients with a high risk of infectious complications (low MASCC score) antibiotic therapy per protocol sepsis of unknown origin is recommended.Immunogenetics and cellular immunology of bacterial infectious disease

Collateral damage and what the future might hold. The need to balance prudent antibiotic utilization and stewardship with effective patient management

Increased severity of illness among hospitalised patients and an ageing population have led to an increased incidence of hospital acquired infections and represent a significant challenge to the clinician in terms of managing infections. The collateral damage which can occur with antibiotic therapy is also an important consideration when initiating empirical antibiotic therapy, particularly in patients who are seriously ill or immunocom-promised. Collateral damage is the term used to describe the adverse ecological effects of antibiotic therapy, such as the selection of drug-resistant organisms, and the adverse events associated with antibiotic therapy such as Clostridium difficile disease. Antibiotic use and ineffective infection control have been implicated in the development and spread of resistant Gram-positive and Gram-negative bacterial pathogens which are associated with increased mortality and morbidity, prolonged hospitalisation and increased costs. Carbapenem consumption and mechanical ventilation have been linked to colonisation or infection with problematic organisms including methicillin-resistant Staphylococcus oureus, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, while cephalosporin use has been associated with evolution of infections due to vancomycin-resistant enterococci (VRE) and Gram-negative bacilli producing extended-spectrum β-lactamases (ESBL), and to colonisation or superinfection with Clostridium difficile. The safety profile of antibiotics must also be taken into consideration when selecting therapy, and single broad-spectrum agents may provide excellent coverage with a low risk of adverse events. The use of single agents may be associated with lower costs, improved ease of administration and fewer drug-drug interactions. However, in an environment of increasing resistance, initial aggressive therapy may be required to avoid excessive mortality and morbidity. Ideally antibiotic therapy should be directed by culture and knowledge of local susceptibility patterns. Before culture results are available therapy may need to be initiated empirically to cover the likely pathogens. In neutropenic patients with fever the current guidelines recommend the use of empirical therapy at the onset of fever for all patients. Where no aetiology is identified, antibiotic therapy should continue for at least 2 weeks while aggressive attempts are made to define the source of fever. When the aetiology of infection has been identified, therapy should be adjusted to provide optimal treatment with the best safety profile and lowest cost. The principal of avoiding collateral damage provides a useful framework for selecting antibiotics for empirical therapy in today's changing environment

APPLICATION OF WISCA (WEIGHTED-INCIDENCE SYNDROMIC COMBINATION ANTIBIOGRAM) TO GUIDE THE CHOICE OF EMPIRIC ANTIBIOTIC TREATMENT IN ONCOLOGICAL PAEDIATRIC PATIENTS WITH FEBRILE NEUTROPENIA: AN ITALIAN MULTICENTER STUDY

Nei pazienti oncologici la neutropenia febbrile (NF) è associata alla presenza di infezioni batteriche e fungine, le più frequenti e gravi complicanze della chemioterapia antitumorale, correlate ad alta morbilità e mortalità.Deve essere tempestivamente trattata con una terapia antibiotica empirica ad ampio spettro.Le linee guida raccomandano un beta-lattamico anti-pseudomonas in monoterapia.Con l’aumento dell’incidenza di germi multiresistenti, la scelta della terapia empirica dovrebbe essere guidata dall'epidemiologia locale, solitamente descritta dagli antibiogrammi cumulativi ospedalieri, che forniscono informazioni generali sulla sensibilità di singole specie batteriche a determinati antibiotici, senza ulteriori stratificazioni.WISCA è uno strumento sindrome-specifico che tenta di soddisfare la necessità di ottenere dati sulla sensibilità locale sindrome-specifici con il fine di guidare la prescrizione empirica di antibiotici.Mira a sviluppare un modello WISCA per informare la selezione di regimi antibiotici empirici per la NF nei bambini, utilizzando i dati dei reparti di Oncoematologia Pediatrica degli ospedali di Padova e Genova.Identificare quale combinazione di antimicrobici sia più efficace nella copertura dei principali patogeni che causano batteriemie in pazienti pediatrici oncologici o sottoposti a trapianto di cellule staminali ematopoietiche (TCSE), che si presentano con NF.Sono state incluse le emocolture dei pazienti con diagnosi di batteriemia in concomitante neutropenia, ricoverati presso il reparto di Oncoematologia Pediatrica del Dipartimento di Salute della Donna e del Bambino di Padova e dell’Ospedale Gaslini di Genova da gennaio 2016 a dicembre 2021.I modelli WISCA sono stati sviluppati stimando la copertura di 20 antibiotici in monoterapia e di 21 regimi antibiotici combinati, utilizzando un modello Bayesiano stratificato per centro di appartenenza, fascia d’età, patologia di base e TCSE.È stato creato un secondo modello considerando solo le batteriemie da gram-negativi.Sono state raccolte 350 emocolture (196 gram-negativi e 154 gram-positivi) con età mediana al momento dell’episodio infettivo di 8,6 anni.Le due popolazioni di Padova e Genova si sono rivelate omogenee, con tuttavia differenze statisticamente significative riguardanti il genere e la patologia di base.Considerando le combinazioni antibiotiche più utilizzate come PI-TZ ed amikacina, la copertura mediana è del 78%.Con l’aggiunta del glicopeptide, la copertura mediana è aumentata ulteriormente all’89%, mentre la sostituzione di PI-TZ con meropenem, mantenendo l’associazione con l’amikacina, non ha fornito benefici.Considerando solo i batteri gram-negativi, la monoterapia con PI-TZ ha dimostrato un’efficacia leggermente inferiore rispetto a meropenem; tuttavia, se combinati con amikacina, entrambi hanno raggiunto lo stesso livello di copertura.WISCA applicato alle emocolture ha dimostrato come la monoterapia non offra un adeguato tasso di copertura, e ha confermato la validità dei regimi terapeutici empirici utilizzati in entrambi i centri.Pur essendo dati incoraggianti, la significatività statistica non è stata raggiunta a causa della ristrettezza campionaria.WISCA fornisce un approccio innovativo per orientare la scelta del trattamento antibiotico empirico nei pazienti oncologici pediatrici con NF. La sua applicazione in uno studio multicentrico offre la possibilità di massimizzare l'utilità clinica dei dati di sorveglianza microbiologica derivati da centri maggiori per informare la terapia empirica anche per altri ospedali minori presenti nel territorio, contribuendo al risparmio degli antibiotici ad ampio spettro e aumentando la fiducia nella selezione di regimi a spettro ristretto.In oncological patients febrile neutropenia (FN) is the hallmark of bacterial and fungal infections, the most frequent and severe complications of cancer chemotherapy, correlated to high morbidity and mortality.FN should be promptly treated with broad-spectrum empirical antibiotic therapy.Guidelines recommend an anti-pseudomonal beta-lactam in monotherapy.However with the increasing number of multidrug-resistant organisms, the best empiric therapy should be driven by local epidemiology, usually described by cumulative hospital antibiograms, which provide general information on the sensitivity of individual bacterial species or genera to certain antibiotics with no further stratifications.WISCA is a syndrome-specific tool that attempts to satisfy the unmet need to obtain syndrome-specific local susceptibility data to guide empirical antibiotic prescribing, providing estimates for several treatment regimens as a weighted average of pathogens' susceptibilities.This study aims to develop a WISCA model to inform empirical antibiotic regimens selection for FN in children using data from the Paediatric Onco-haematological wards of Padua and Genoa Hospitals.The second aim is to identify which combination of antimicrobials is more effective in the coverage of the main bacteria causing bloodstream infections (BSIs) in paediatric patients with cancer or undergoing haematopoietic stem-cell transplantation (HSCT) presenting with FN.The study cohort included blood cultures of patients with a diagnosis of BSI and neutropenia admitted to the Paediatric Onco-haematological wards of the Department for Women’s and Children’s Health in Padua and of Gaslini Hospital in Genoa from January 2016 to December 2021.WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined antibiotics regimens, using a Bayesian model stratified by centre, age group, underlying pathology and HSCT.A second model considering only gram-negative bacteria was created.We collected 350 blood cultures (196 gram-negative and 154 gram-positive) with median age at the time of the infectious episode of 8,6 years. In both centres, most BSIs (28%) occurred at age 9-14.The two populations of Padua and Genoa turned out homogeneous, with statistically significant differences concerning sex and underlying pathology.Considering most used antibiotic combinations such as PI-TZ plus amikacin, the median coverage was 78%.Adding a glycopeptide, the median coverage further increased to 89%, while the replacement of PI-TZ with meropenem, maintaining the association with amikacin, did not provide benefits.When considering only gram-negative bacteria, monotherapy with PI-TZ showed a slightly inferior coverage compared with meropenem; however, when combined with amikacin, both reached the same coverage level.WISCA applied to blood cultures showed how monotherapy did not offer an adequate coverage rate for the identified pathogens and confirmed the validity of the empirical therapeutic regimens used in both centres.Albeit encouraging data, the statistical significance was not reached because of the small sample size.WISCA provides an innovative approach to pool information from different sources, guiding the choice of empirical antibiotic treatment in oncological paediatric patients with FN. Moreover, its application in a multicenter study offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from larger hospitals to inform the selection of the most appropriate empiric therapy also for other minor hospital settings in the same area while contributing to spare broad-spectrum antibiotics and increasing confidence in the selection of narrow-spectrum regimens

Cefepime monotherapy for the empirical treatment of fever in granulocytopenic cancer patients.

In a pilot study, we evaluated the efficacy and the safety of cefepime, a new cephalosporin with extended-spectrum activity against both Gram-positive and Gram-negative bacteria, as empirical monotherapy for 108 febrile episodes in 84 granulocytopenic cancer patients. Cefepime (2 g tds) was given for a minimum of 7 days or until resolution of infection. Of the 108 episodes, 91 were evaluable. Microbiologically documented infections occurred in 25 patients (27%) (18 Gram-positive, 7 Gram-negative), of whom 18 had bacteraemia. Infection was clinically documented in 47 patients (52%) and fever was unexplained in 19 (21%). Overall, 71% (65/91) of the infections resolved. Response rates were 86% (6/7) for Gram-negative infections, 44% (8/18) for Gram-positive infections (57% for cefepime-susceptible Gram-positive bacteria), 77% (36/47) for clinically documented infections and 79% (15/19) for unexplained fevers. Of the 26 patients (29%) whose primary infections did not improve with cefepime monotherapy, 23 responded after the addition of other antibiotics. Sixteen patients (18%) developed secondary infections of which 13 were microbiologically documented; Gram-positive bacteria were isolated from seven patients, Gram-negative bacteria from two, fungi from three and a virus from one. Adverse effects were mild and did not require premature discontinuation of therapy except for one patient who developed an immediate allergic reaction after the first dose of cefepime from which he recovered fully. The survival rate after resolution of granulocytopenia was 96%; three patients died of primary bacterial infection and one from secondary disseminated candidiasis. In this pilot study, cefepime monotherapy appeared safe and effective as empirical therapy for fever in cancer patients with granulocytopenia. Whether cefepime is superior to other advanced-generation cephalosporins for the treatment of Gram-positive infections will require evaluation in a larger comparative study