Infections In Neutropenic Cancer Patients Research Articles

Effect of Neutropenic Diet on Infection Rates in Cancer Patients With Neutropenia: A Meta-analysis of Randomized Controlled Trials.

Neutropenic diets are commonly prescribed to cancer patients with neutropenia with the intention of reducing rates of infection. These diets are restrictive and are associated with lower patient satisfaction and possibly malnutrition. Further, it is unclear if these restrictive diets are effective in reducing infection. We performed a meta-analysis on the rates of infection reported in trials comparing the neutropenic diet to unrestricted diets in cancer patients with neutropenia. A comprehensive database search for all published randomized controlled trials comparing infection rates in cancer patients receiving a neutropenic diet versus an unrestricted diet was performed for all publications in English language from database's inception until September 12, 2017. The search strategy, study selection, and subsequent analysis adhered to PRISMA guidelines. Random effects modeling was used to obtain pooled relative risks. The primary outcome measure was the rate of infection. Five randomized controlled trials with a total of 388 patients were included in the final analysis. Patients mostly had acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or sarcoma. Infection was noted in 53.7% patients in the neutropenic diet group, as compared with 50% in the unrestricted diet group. No significant difference in infection rate was observed between the neutropenic diet versus unrestricted diet groups, pooled risk ratio (RR) 1.13 (95% CI, 0.98-1.30; P=0.10). This meta-analysis of randomized controlled trials suggests that the use of neutropenic diet was not associated with decreased risk of infection in neutropenic cancer patients. The continued use of neutropenic diets should be questioned.

Assessment of Initial Febrile Neutropenia Management in Hospitalized Cancer Patients at a Community Cancer Center

Fever may be the only sign of an underlying infection in neutropenic cancer patients. Unrecognized fever and untreated infections can lead to progressive sepsis and possibly death. The importance of early recognition, timely antibiotics, and treatment is crucial to favorable outcomes. The primary objective of this study was to evaluate the treatment of adult cancer patients with febrile neutropenia for compliance with National Comprehensive Cancer Network (NCCN) febrile neutropenia guidelines at our institution, UCHealth Memorial Hospital. Secondary objectives were to examine antibiotic selection, culture results, time to antibiotics, all-cause mortality, and length of hospital stay. This was a single-center, retrospective chart review of hospitalized neutropenic patients undergoing active chemotherapy. Neutropenia and fever were defined based on NCCN Guidelines. A total of 223 neutropenic patients were hospitalized between October 15, 2015, and December 31, 2016. Overall, 16 patients met the inclusion criteria for chemotherapy-induced neutropenia with fever. Compliance with the NCCN guideline standards was seen in seven (43.8%) patients. Antibiotics administered within 60 minutes of presentation was the lowest standard with adherence in eight (50%) patients. Empiric monotherapy antibiotic regimens were initiated in 11 (68.8%) patients; eight (50%) received cefepime and three (18.8%) received meropenem. At our institution, full compliance with the NCCN febrile neutropenia guidelines is not optimal. This study demonstrates the need for process improvement initiatives, including the addition of an electronic health record alert to flag patients undergoing active chemotherapy. It also warrants promoting the use of our institution's emergency department febrile neutropenia treatment pathway to providers to improve overall compliance.

How does fluconazole compare with amphotericin B for controlling fungal infections in neutropenic cancer patients?

How does fluconazole compare with amphotericin B for controlling fungal infections in neutropenic cancer patients?

Complete Genome Sequence of Streptococcus mitis Strain SVGS_061 Isolated from a Neutropenic Patient with Viridans Group Streptococcal Shock Syndrome.

Streptococcus mitis frequently causes invasive infections in neutropenic cancer patients, with a subset of patients developing viridans group streptococcal (VGS) shock syndrome. We report here the first complete genome sequence of S. mitis strain SVGS_061, which caused VGS shock syndrome, to help elucidate the pathogenesis of severe VGS infection.

Voriconazole versus amphotericin B or fluconazole in cancer patients with neutropenia.

Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy is used both empirically and therapeutically in these patients. To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia. Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 1 2014), MEDLINE (to January 2014). Letters, abstracts and unpublished trials were accepted. Contact was made with trial authors and industry. Randomised clinical trials comparing voriconazole with amphotericin B or fluconazole. Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted independently by two review authors. Three trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infection) in neutropenic cancer patients (849 patients, 58 deaths). The second trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). The third trial compared fluconazole to voriconazole for prophylaxis of fungal infections in patients receiving allogeneic stem cell transplantation (600 patients, number of deaths not stated). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the trial authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from the analysis by the trial authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication to counter side effects and replacement of electrolytes or use of salt water. This choice of comparator resulted in a marked difference in the duration of treatment on the trial drugs (77 days with voriconazole versus 10 days with amphotericin B) and precluded meaningful comparisons of the benefits and harms of the two drugs. The third trial failed to find a difference in fungal free survival or invasive fungal infections at 180 days when voriconazole was compared to fluconazole. Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of fungal infections in neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions. For prophylactic fungal treatment in patients receiving allogeneic stem cell transplantation, there was no difference between voriconazole and fluconazole regarding fungal free survival or invasive fungal infections.

Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients

Recent changes in the management of patients with haematological malignancies might have influenced the aetiology, characteristics, antimicrobial resistance and outcomes of bloodstream infection (BSI) during neutropenia. We compared 272 episodes of BSI in adult neutropenic patients with cancer prospectively collected from January 1991 to December 1996 (first period), when quinolone prophylaxis was used, with 283 episodes recorded from January 2006 to March 2010 (second period), when antibacterial prophylaxis was stopped. Patients in the second period were significantly older and were more likely to have graft-versus-host disease and a urinary catheter in place, whereas the presence of a central venous catheter, parenteral nutrition, corticosteroids and antifungal and quinolone prophylaxis, were more frequent in the first period. More patients in the first period had mucositis and soft-tissue infection as the origin of BSI, but an endogenous source was more common during the second. Gram-positive BSI was more frequent in the first period (64% versus 41%; p <0.001), mainly due to coagulase-negative staphylococci and viridans group streptococci. In the second period gram-negative BSI increased (28% versus 49%; p <0.001), quinolone susceptibilities were recovered, but multidrug-resistant gram-negative BSI also increased (1% versus 6%; p <0.001). Although patients in the second period were more likely to need admission to the intensive-care unit, overall case-fatality rate was similar in the two periods (19% versus 15%). The aetiology of BSI in neutropenic patients with cancer has shifted from gram-positive to gram-negative organisms. Multidrug resistance among gram-negative bacilli is emerging as a therapeutic challenge. Overall case-fatality rate remains high.

Editorial Commentary: Saving Lives With Optimal Antimicrobial Chemotherapy

The introduction of antimicrobial chemotherapy was an unprecedented advance in the practice of medicine. Previously fatal infections became treatable and antimicrobials were the agents of that salvage of life. In the more modern era, these agents also became the drugs that were permissive for many of the other modern medical miracles that we currently enjoy. The ability to treat serious infections in neutropenic cancer patients allowed the use of intensive oncologic chemotherapy. In the same vein, immunosuppressive therapy for organ and bone marrow transplants are made possible by antimicrobial therapy, as has the routine use of interventions that cross natural anatomic boundaries. In the early days of antimicrobial therapy, pioneers such as Harry Eagle recognized that certain administration profiles of drug prompted better therapeutic effect. This was demonstrated in a landmark paper published in the New England Journal of Medicine [1]. Certain agents such as penicillin had a better therapeutic effect when administered on very short administration intervals, whereas drugs such as the tetracyclines had antimicrobial effects that were somewhat independent of administration schedule. Unfortunately much of this information became lost in the 1960s and 1970s. In the late 1980s and early 1990s, these principles were rediscovered by the laboratory of William Craig [2–4]. These studies linked the effect of different antimicrobial classes, doses, and schedules to the reduction in colony-forming units (CFUs) in murine thigh or pneumonia models. Shortly thereafter, the burgeoning science of pharmacodynamics and pharmacometrics allowed identification of relationships between drug exposure indexed to the minimum inhibitory concentration (MIC) of the infecting pathogen and clinical and/ or microbiological outcomes [5–7]. The first study was a retrospective evaluation, but the last 2 were prospectively designed with analysis plans filed with the Food and Drug Administration (FDA). Such studies demonstrated conclusively that it was relatively straightforward to derive exposure-response relationships in the midst of clinical trials, employing a number of different mathematical techniques. The next step was to demonstrate the link between the animal model findings and the clinical trial pharmacodynamics relationships. Ambrose and colleagues [8] examined outcomes from clinical trials relative to the effect breakpoints determined from murine pharmacodynamic studies. They demonstrated a strong concordance between the preclinical and clinical pharmacodynamic studies for a number of different antimicrobial classes. Consequently, we can say that another brick was laid in the edifice of antimicrobial dynamics. While these data are convincing, it is also important to demonstrate that attainment of the “correct” antimicrobial targets has an impact on endpoints other than traditional clinical and microbiological outcomes in “real world” clinical practice settings. The clinical benefits of prolonged β-lactam infusion among critically ill patients were highlighted by the study performed at Albany Medical Center Hospital by Lodise and colleagues. Based on the results of a Monte Carlo simulation, prolonged infusion of piperacillin-tazobactam (3.375 g administered over a 4-hour period every 8 hours) was adopted as the standard hospital-wide piperacillin-tazobactam dosing scheme at their institution in February 2002. To evaluate the real-world effectiveness of this automatic dose substitution program, 14-day mortality and hospital length of stay after culture collection were Received 3 September 2012; accepted 11 September 2012; electronically published 16 October 2012. Correspondence: G. L. Drusano, MD, Professor and Director, Institute for Therapeutic Innovation, Department of Medicine, University of Florida, 6550 Sanger Boulevard, Lake Nona, FL, 32827 (gdrusano@ufl.edu). Clinical Infectious Diseases 2013;56(2):245–7 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cis863

Neutropenic Fever Syndromes in Patients Undergoing Cytotoxic Therapy for Acute Leukemia and Myelodysplastic Syndromes

Fever represents the major surrogate of infection in neutropenic cancer patients. A number of neutropenic fever syndromes have been recognized, the causes and significance of which will vary depending upon the clinical context. First neutropenic fever syndromes are typically of bacterial origin, the character of which may be influenced by whether antibacterial chemoprophylaxis has been administered. Persistent neutropenic fevers are documented during the empirical systemic antibacterial therapy for the first neutropenic fever, the cause of which is likely outside the spectrum of activity of the initial therapy. Recrudescent neutropenic fevers, defined by the appearance of a new fever after defervescence of the first fever, are often a function of invasive fungal infection or gram-positive infections outside the spectrum of the initial empirical antibacterial regimen. The myeloid reconstitution syndrome occurs in parallel with neutrophil recovery from aplasia and may not necessarily represent new infection. Recognition of these patterns can help the clinician make better clinical judgments and management plans.

Clinical guidelines for the management of cancer patients with neutropenia and unexplained fever

Neutropenia is a frequent complication in patients with malignancies undergoing cytostatic chemotherapy. It is also an important risk factor for infection. Fever is often the only sign of infection in neutropenic cancer patients. Although infections cannot be documented in a large proportion of febrile neutropenic cancer patients, empirical antimicrobial therapy based on clinical evidence and local data on microbiological epidemiology and susceptibility must be started immediately. The following recommendations for antimicrobial use in neutropenic patients with fever of unknown origin have been issued by a group of experts from countries belonging to the Asia–Pacific region. The task has been particularly challenging because of the significant differences among the participating countries, mainly in terms of microbiological epidemiology and resistance patterns. Indeed, in most countries of the region, and in contrast to the Western world, Gram-negative bacteria are the prevailing etiological agent of infections in febrile granulocytopenic patients. An additional difficulty has been the varying microbial susceptibility profiles and the high prevalence of methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, vancomycin-resistant enterococci, viridans group streptococci, ciprofloxacin-resistant Escherichia coli and Pseudomonas aeruginosa, among others. The recommendations that follow should be expected to provide general guidance to clinicians who care for febrile neutropenic cancer patients, rather than to operate as a substitute for their clinical judgment. 2. Definitions

Reappraisal with meta-analysis of the addition of Gram-positive prophylaxis to fluoroquinolone in neutropenic patients.

Past reports and meta-analyses indicate that fluoroquinolones are highly effective in preventing Gram-negative infections in neutropenic cancer patients, but offer inadequate coverage for Gram-positive infections. We evaluated by meta-analysis the efficacy of the addition of antimicrobial agents with enhanced Gram-positive activity to prophylaxis with quinolones. Randomized trials comparing fluoroquinolones alone (ciprofloxacin, ofloxacin, pefloxacin, or norfloxacin) with fluoroquinolone in combination with Gram-positive prophylaxis (rifampin, vancomycin, amoxicillin, roxithromycin, or penicillin) were retrieved. We pooled relative risks (RRs) using a fixed-effects model. Nine trials (1,202 patients) published between 1993 and 2000 meet inclusion criteria. Compared with fluoroquinolone alone, Gram-positive prophylaxis reduced total bacteremic episodes (RR, 1.54; 95% CI, 1.26 to 1.88), streptococcal infections (RR, 2.20; 95% CI, 1.44 to 3.37), coagulase-negative staphylococcal infections (RR, 1.46; 95% CI, 1.04 to 2.04), and rate of febrile patients (RR 1.08; 95% CI, 1.00 to 1.16). Occurrence of clinically documented infections, unexplained fever, and infectious mortality was similar in the two groups. The addition of Gram-positive prophylaxis, however, significantly increased side effects (RR, 0.46; 95% CI, 0.28 to 0.76). Rifampin use resulted in a higher incidence of undesirable effects. Considering the lack of cut-clear benefit on some parameters of morbidity and mortality, routine use of Gram-positive prophylaxis is not advisable. This strategy, however, should be particularly valuable in subgroups of patients at high risk of streptococcal infection (eg, those with severe and prolonged neutropenia or mucositis, and those receiving cytarabine). Problems of tolerability and the potential for the emergence of resistant microorganisms should be considered when prescribing prophylaxis with enhanced Gram-positive activity to neutropenic patients.

Fungal infections in neutropenic cancer patients.

Invasive fungal infections are important causes of morbidity and mortality in cancer patients with prolonged neutropenia following chemotherapy. Recent trends indicate a change toward infections by Aspergillus species, non-albicans species of Candida, and previously uncommon fungal pathogens. These have decreased susceptibility to current antifungal agents. In the last decade there has been much effort to find solution for these changing trends. This article reviews current approaches to prevention and treatment of opportunistic fungal infections in postchemotherapy neutropenic patients and discusses future antifungal approaches and supportive methods.

Bloodstream infection in neutropenic cancer patients related to short-term nontunnelled catheters determined by quantitative blood cultures, differential time to positivity, and molecular epidemiological typing with pulsed-field gel electrophoresis.

To determine the rate of catheter-related bloodstream infection (CRBSI) among cases of primary bloodstream infection (BSI) in febrile neutropenic cancer patients with short-term nontunnelled catheters, quantitative paired blood cultures (Isolator) from the central venous catheter (CVC) and peripheral vein were obtained between November 1999 and January 2001. Bactec blood culture bottles were obtained to determine the differential time to positivity (DTP). CRBSI was defined as a quantitative blood culture ratio of >5:1 (CVC versus peripheral) with proven identity of isolates from positive peripheral and CVC blood cultures as confirmed by pulsed-field gel electrophoresis. Forty-nine episodes of primary BSI were detected among 235 cancer patients with febrile neutropenia. Of these, 18 episodes (37%) were CRBSI and 31 (63%) were BSI with an unknown portal of entry. Coagulase-negative staphylococci were present in nine cases of CRBSI (50%). The identity of isolates from peripheral and CVC blood cultures was confirmed in all cases. Earlier positivity (>2 h) of CVC-drawn versus peripheral blood cultures was observed in 18 of 22 CRBSI-associated blood cultures (sensitivity, 82%; specificity, 88%; positive predictive value, 75%; negative predictive value, 92%). In summary, CRBSI accounted for 37% of cases of primary BSI in this population of neutropenic cancer patients. DTP compares favourably with quantitative blood cultures for the diagnosis of CRBSI and may be particularly useful for patients in whom catheter salvage is highly desirable.

Periodontal infection in cancer patients treated with high-dose chemotherapy.

The infected and inflamed periodontium can act as a focus for systemic infection in neutropenic cancer patients. The incidence of these oral infections is unknown, but probably underestimated. Periodontal infections can easily be overlooked, primarily because symptoms of gingival inflammation may be minimal and the infection may be located in deeper parts of the periodontium. Assessment of a patient's periodontal condition before the onset of profound neutropenia is critical to the diagnosis and the management of these potentially life-threatening infections. This review article is aimed at informing supportive care providers of recent insights into the pathogenesis of periodontal diseases and the role of subgingival microorganisms, with the emphasis on these infections in cancer patients treated with high-dose chemotherapy. Furthermore, a multidisciplinary approach to the management of periodontal infections and the need for future research is discussed.

Infections in neutropenic cancer patients

Infections in neutropenic cancer patients

Infections in Neutropenic Cancer Patients

Infections in Neutropenic Cancer Patients

Anaerobic Bacteremia in a Neutropenic Patient with Oral Mucositis

An increasing number of anaerobic bloodstream infections in neutropenic cancer patients have been reported in the last decade. The type of anaerobes isolated from most of these patients suggests an oral source of infection. We describe a case of anaerobic bacteremia in a neutropenic patient with oral mucositis that highlights the importance of considering these organisms when selecting empiric prophylactic or therapeutic antimicrobial regimens, especially in the setting of periodontal disease or oral mucositis.

A Retrospective Review of the Frequency of Infections and Patterns of Antibiotic Utilization on a Palliative Care Unit

Various disease-related and therapy-induced factors make cancer patients susceptible to infections. The epidemiology and management of infections in neutropenic cancer patients and patients with primary hematological malignancies has been widely reported, but very few studies have characterized infections and their management in palliative care patients. We conducted a retrospective review of 100 consecutive admissions to an acute palliative care unit with the objective of assessing overall and site-specific frequencies of infections, the pathogens involved and their antibiotics sensitivities, and the pattern of antibiotic utilization. The mean age was 64 ± 11.5 years, the mean length of stay was 29.8 ± 28.2 days, and 70% of patients died on the unit. Only one case of neutropenia was identified. Fifty-five of the 100 patients were diagnosed with a total of 74 separate infections. The most frequent sites of infections were the urinary tract (39.2%), the respiratory tract (36.5%), skin and subcutaneous tissues (12.2%), and blood (5.4%). Fifty-four culture-positive infections were identified. Overall, the most common organisms were Escherichia coli (22.9%), Staphylococcus aureus (20%), and Enterococcus (11.4%). Fifty-three of the74 (71.6%) infections were treated with antibiotics. The decision-making process regarding treatment versus nontreatment of an infection can be complex in terminally ill patients and needs to be individualized. Symptom control is the primary objective in the majority of cases. The appropriate management of infections, with specific attention to measures that would improve patients’ quality of life, should be a research priority in patients with advanced cancer.

An analysis of interleukin-8, interleukin-6 and C-reactive protein serum concentrations to predict fever, gram-negative bacteremia and complicated infection in neutropenic cancer patients.

A prospective study was performed to assess the potential value of interleukin (IL)-8, IL-6, and C-reactive protein (CRP) serum levels to predict fever, gram-negative bacteremia and complicated infection in neutropenic patients with cancer. Serum samples were obtained three times a week during 208 neutropenic episodes following cytotoxic chemotherapy. Fever of any cause developed during 104 out of 191 evaluable episodes. Serum levels of neither cytokine nor CRP were predictive of fever within more than 24 h before its onset. Unlike CRP, both IL-6 and IL-8 serum levels were significantly different between microbiologically documented infections and unexplained fevers. The highest values of IL-6 and IL-8 were observed in episodes of gram-negative bacteremia. Using receiver-operating-characteristic curves, the analysis of cytokine levels measured around the onset of fever indicated that IL-8 is potentially useful for predicting gram-negative bacteremia, with a high negative predictive value of > 90% and a moderate positive predictive value of 50% (sensitivity, 70%; specificity, 91%). In patients with persistent fever, predictions of further clinical complications, defined as prolonged fever of more than 7 days' duration, pneumonia, shock and/or death due to infection, were best predicted by IL-6. With an IL-6 cutoff value of 250 pg/ml in samples obtained 8 to 32 h after onset of fever, the positive predictive value was 92%, the negative predictive value 91% (sensitivity, 85%; specificity, 95%). The positive predictive value of IL-6 in samples obtained another 24 h later from patients still febrile remained > 90%, but the negative predictive value dropped to 47%. In any of the analyses, the predictive values of CRP levels were poor and inferior to either cytokine. These findings may have clinical value in identifying subgroups of patients requiring different therapeutic approaches.

How should imipenem‐cilastatin be Used in the treatment of fever and infection in neutropenic cancer patients?

How should imipenem‐cilastatin be Used in the treatment of fever and infection in neutropenic cancer patients?

How should imipenem-cilastatin be Used in the treatment of fever and infection in neutropenic cancer patients?

Imipenem-cilastatin (referred to hereafter as imipenem) is administered at different doses as monotherapy or with other agents. Limited comparisons of the alternatives exist. The authors compared the efficacy and safety of several imipenem-containing regimens (ICRs) to determine the appropriate dose and the need for combination therapy. Between 1985 and 1994, febrile neutropenic patients were given ICRs according to the same methodology on prospective trials at a referral cancer center. The ICRs were high dose imipenem (HIP), high dose imipenem and amikacin (HIPA), high dose imipenem and vancomycin (HIPV), and low dose imipenem and vancomycin (LIPV). The overall response rates were comparable (70-77%). There was a univariate trend toward better response among patients with pneumonia and documented infections with unidentified organisms who received HIPV versus LIPV (P=0.06), as well as a significantly better response among patients with gram positive infections who received HIPV versus HIP (P=0.02) and HIPA (P=0.002). HIPV was a more effective treatment for documented infections with identified organisms (P=0.05) and bloodstream infections (P=0.04) than HIP; there was a univariate trend toward better response among patients infected with gram negative organisms who received HIPA versus HIP (P=0.12). Multivariate adjustment for baseline and prognostic factors did not reveal a relative advantage for any regimen. No differences in overall toxicities were observed between HIPV and LIPV. Imipenem monotherapy is adequate treatment for most febrile neutropenic cancer patients. Low dose imipenem could be effective and safe in uncomplicated cases without pneumonia. Further studies are needed to establish the usefulness of low dose imipenem in this context.