There should be no ESKAPE for febrile neutropenic cancer patients: the dearth of effective antibacterial drugs threatens anticancer efficacy.

The success of modern anticancer treatment is a composite function of enhanced efficacy of surgical, radiation and systemic treatment strategies and of our collective clinical abilities in supporting patients through the perils of their cancer journeys. Despite the widespread availability of antibacterial therapies, the threat of community- or healthcare facility-acquired bacterial infection remains a constant risk to patients during this journey. The rising prevalence of colonization by multidrug-resistant (MDR) bacteria in the population, acquired through exposure from endemic environments, antimicrobial stewardship and infection prevention and control strategies notwithstanding, increases the likelihood that such organisms may be the cause of cancer treatment-related infection and the likelihood of antibacterial treatment failure. The high mortality associated with invasive MDR bacterial infection increases the likelihood that many patients may not survive long enough to reap the benefits of enhanced anticancer treatments, thus threatening the societal investment in the cancer journey. Since cancer care providers arguably no longer have, and are unlikely to have in the foreseeable future, the antibacterial tools to reliably rescue patients from harm's way, the difficult ethical debate over the risks and benefits of anticancer treatments must now be reopened.

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.

Invasive fungal infection in haematopoietic stem cell transplant recipients: epidemiology from the transplant physician's viewpoint.

The practice of hematopoietic stem cell transplantation (HSCT) has undergone many changes that affect the likelihood that a given patient would develop an invasive fungal infection (IFI). The risks for IFI and the types of IFI that may occur are not continuous over the time course after transplantation. IFIs vary with the events that occur during the pre-engraftment neutropenic period, the early post-engraftment period until approximately day 100 post-transplant, and those in the late post-engraftment period after day 100. A number of well-recognized transplant recipient-, transplant procedure-, and transplant complication-related factors play a role in the likelihood of IFI. Important recipient-related factors include age, state of the underlying disease for which the HSCT is being done, and treatment-related history. Transplant procedure-related factors include the type of transplant (autologous or allogeneic), the use of and timing of anti-fungal prevention strategies including whether or not the transplant was conducted in a protected environment to minimize environmental exposure to mould conidia, the choice of conditioning (myeloablative or non-myeloablative), human leucocyte antigen-relatedness [autologous, matched related, mismatched related (including haploidentical pairings), unrelated (matched or mismatched)], stem cell source (bone marrow, peripheral, or cord blood), stem cell dosing, and stem cell product processing (red cell, plasma, or T-lymphocyte depletions, or CD34 selections). Transplant-related complications include duration of pre-engraftment period of neutropenia, graft failure or rejection, the degree of cytotoxic conditioning therapy-related intestinal mucosal damage, acute and chronic graft-versus-host disease (GvHD), the use of corticosteroids for the prevention or management of GvHD, the presence of cytomegalovirus infection and disease. The interaction of these factors over a given patient's journey through HSCT conspires to promote or reduce the overall IFI risk and set the conditions for the development of any given IFI. The following discussion attempts to look at this from the perspective of the transplant physician struggling to account for these interactions and their attendant risks for IFI.

Patient-driven hand hygiene audit process at a regional cancer center.

A patient-driven hand hygiene compliance audit strategy was piloted in a Canadian provincial cancer agency during routine provision of cancer outpatient care by health care providers (physicians, nurses, and health care aides) under conditions where the deployment of an independent external auditor was not feasible. The results of the audit suggest the feasibility of this approach as a routine institutional performance metric.

The First Case Report of West Nile Virus-Induced Acute Flaccid Quadriplegia in Canada.

The 1999 New York City outbreak of West Nile virus (WNV) was associated with a high incidence of West Nile virus neuroinvasive disease (WNVND) where the outcomes for these patients were very poor. We describe a case of West Nile virus neuroinvasive disease (WNVND) characterized by acute flaccid quadriplegia with a favorable outcome in Winnipeg, Manitoba, Canada.

Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia.

Intestinal barrier function was prospectively examined in the course of a clinical trial evaluating the efficacy and safety of lisofylline for reducing cytotoxic therapy-induced intestinal epithelial damage-related infectious morbidity in patients receiving standard remission-induction therapy for acute myeloid leukaemia. The absorption and permeation of oral D-Xylose, lactulose and mannitol were measured weekly from baseline until marrow recovery in adult recipients of idarubicin plus cytarabine for untreated acute myeloid leukaemia. These studies were correlated with non-haematologic chemotherapy-related toxicities reflecting mucosal damage, including nausea, vomiting, stomatitis, diarrhoea, abdominal pain and systemic infection. D-xylose absorption decreased and lactulose:mannitol ratio reflecting intestinal permeability increased from baseline until the second and third week after the beginning of the treatment followed by recovery. These measures correlated with infection rates, nausea, vomiting, diarrhoea and increased blood product utilization. Lisofylline was associated with increased intestinal permeability, nausea, vomiting and infection-related morbidity despite a reduction in the duration of neutropaenia. These surrogates of intestinal barrier function correlated well with clinically important outcomes despite the failure to demonstrate reduced morbidity with lisofylline and represent useful objective outcome measurements for future clinical trials of products for the amelioration of the effects of cytotoxic therapy on the intestinal mucosa.

A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies.

BACKGROUND: The empirical treatment of febrile, neutropenic patients with cancer requires antibacterial regimens active against both gram-positive and gram-negative pathogens. This study was performed to demonstrate the noninferiority of monotherapy with piperacillin-tazobactam, compared with cefepime. METHODS: We conducted a randomized-controlled, open-label, multicenter clinical trial among high-risk patients from 34 university-affiliated tertiary care medical centers in the United States, Canada, and Australia who were undergoing treatment for leukemia or hematopoietic stem cell transplantation and were hospitalized for empirical treatment of febrile neutropenic episodes. Patients received piperacillin-tazobactam (4.5 g every 6 h) or cefepime (2 g every 8 h) intravenously. The primary outcome was success (defined by defervescence without treatment modification) at 72 h of treatment, end of treatment, and test of cure in the modified intent-to-treat analysis. Secondary outcomes included time to defervescence, microbiological efficacy, the additional use of glycopeptide antibiotics, emergence of resistant bacteria, and safety. RESULTS: For 528 subjects (265 received piperacillin-tazobactam and 263 received cefepime), success rates were 57.7% and 48.3%, respectively (P = .04) at the 72-h time point, 39.6% and 31.6% (P = .06) at end of treatment, and 26.8% and 20.5% (P = .11) at the test-of-cure visit. The analyses demonstrated noninferiority for piperacillin-tazobactam at all time points (P< or = .0001). Treatment with piperacillin-tazobactam was independently associated with treatment success in multivariate analysis (odds ratio, 1.65; 95% confidence interval, 1.04-2.64; P = .035). Both regimens were well tolerated. CONCLUSIONS: This study demonstrates the noninferiority and safety of piperacillin-tazobactam monotherapy, compared with cefepime, for the empirical treatment of high-risk febrile neutropenic patients with cancer.

Totally implantable venous access ports systems for patients receiving chemotherapy for solid tissue malignancies: A randomized controlled clinical trial examining the safety, efficacy, costs, and impact on quality of life.

PURPOSE: To examine the safety, efficacy, costs, and impact on quality of life of venous access ports implanted at the outset of a course of intravenous cancer chemotherapy. PATIENTS AND METHODS: Adults beginning a course of intravenous chemotherapy at two university-affiliated hospitals were randomly allocated to have venous access using a surgically implanted venous access port (Port-a-Cath; Pharmacia, Canada Inc, Montreal, Québec, Canada) or using standard peripheral venous access. All accesses were documented by number, route, purpose, and procedure duration. Outcome measurements included port complications, access strategy failure, access-related anxiety and pain, quality of life (Functional Living Index-Cancer [FLI-C]), and costs. RESULTS: Port complication rates were low (0.23/1,000 days). Failure occurred in two (3.4%) of 59 port subjects and 16 (26.7%) of 60 controls (P =. 0004) at a median period of 26 days after randomization (95% confidence interval, 8 to 92). Peripheral accesses in port subjects took less time, had less access-related anxiety and pain, and were less costly to perform than in controls. Allocation had no effect on FLI-C scores. Peripheral access failure correlated with allocation to the control group (P =.007), higher pain scores with intravenous (IV) starts (P =.003), and anxiety with IV starts (P =.01). Venous accessing overall in port patients was four times more costly than that in controls ($2,178/patient v $530/patient, respectively). CONCLUSION: Ports were safe and effective but had no detectable impact on functional quality of life, despite less access-related anxiety, pain, and discomfort. Because only approximately one quarter of control patients ultimately required central venous access, economic considerations suggest that port-use policies should be based upon defined criteria of need.

Cytotoxic therapy-induced D-xylose malabsorption and invasive infection during remission-induction therapy for acute myeloid leukemia in adults.

PURPOSE: To study the sequential changes in the intestinal absorption of an oral pentose probe, D-xylose, in patients receiving therapy for untreated acute myeloid leukemia (AML), and to correlate these changes to infectious morbidity. PATIENTS AND METHODS: Serial D-xylose absorption studies were conducted in 110 consecutive adult patients admitted to a university-affiliated tertiary care hospital for remission-induction therapy for untreated newly diagnosed AML. Serial serum D-xylose levels were obtained 1 hour after a 5-g oral dose of D-xylose at baseline and weekly for 4 weeks until marrow recovery. These results were correlated with invasive infection using multivariate techniques. RESULTS: The mean (+/- SEM) serum D-xylose levels were 0.88 +/- 0.03, 0.69 +/- 0.03, 0.58 +/- 0.02, 0.53 +/- 0.02, and 0.73 +/- 0.02 mmol/L at baseline and weeks 1 to 4, respectively (P < .0001, analysis of variance [AN-OVA]). Time to malabsorption varied with induction regimen (P = .007, log-rank test). Bloodstream infections during week 2 correlated with malabsorption (P = .007). Neutropenic enterocolitis correlated independently with induction regimen (P = .009), malabsorption at week 2 (P = .02), and the development of candidemia (P = .005). Hepatosplenic fungal infection correlated with induction regimen (P = .03), malabsorption at week 2 (P = .02), and fever at diagnosis (P = .003). Malabsorption was unrelated to the duration of severe neutropenia and the administration of parenteral nutrition. CONCLUSION: Serial D-xylose absorption studies in subjects with AML produced a characteristic profile of cytotoxic therapy-related damage to the functional integrity of the intestinal epithelium that was regimen dependent, myelosuppression independent, and predictive for invasive infectious complications. Further study to validate these observations appears warranted.

Therapy of untreated acute myeloid leukemia in the elderly: remission-induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide.

PURPOSE: The University of Manitoba Adult Acute Leukemia Study Group sought to examine the safety, efficacy, and impact on quality of life of a non-cytarabine-containing remission-induction regimen followed by intermediate-dose cytarabine (IDARA-C) postremission therapy for the management of untreated acute myeloid leukemia (AML) in patients age 60 to 80 years. PATIENTS AND METHODS: Eligible patients received mitoxantrone 10 mg/m2 and etoposide 100 mg/m2 on days 1 to 5. Complete remitters received a single course of cytarabine 0.5 mg/m2 every 12 hours on days 1 to 6. Cytogenetic and immunophenotyping studies were performed at diagnosis and were examined for prognostic importance. The Functional Living Index-Cancer (FLI-C) was used in the longitudinal assessment of quality of life. RESULTS: A total of 37 (55%) of 67 eligible patients achieved remission, 34 (92%) of whom did so with a single course. The induction mortality rate was 12%. The median disease-free and overall survival times were 8.4 and 9.2 months, respectively. CD34 stem-cell phenotype, poor performance status, and high cytogenetic complexity score were independent covariates of failure to achieve remission. Very complex karotype combined with CD34 stem-cell phenotype to predict induction death in 67% of cases (P = .0003). Cytotoxic therapy-related gut epithelial damage was maximal during weeks 2 and 3 of therapy. Complete remitters and partial responders exhibited significantly improved global FLI-C scores following completion of therapy. CONCLUSION: Mitoxantrone plus etoposide was an effective and well-tolerated first-line induction regimen for AML in the elderly that should be studied further in comparison to the standard cytarabine/anthracycline-based therapy.

Management of the febrile neutropenic cancer patient: lessons from 40 years of study.

Almost forty years ago the relationship between the circulating neutrophil count and the risk of pyogenic infection was established. Since that time, through the vehicle of clinical trials, much has been learnt about the etiologies, risk factors, pathogenesis, and natural history of first and subsequent febrile neutropenic episodes. Refinements to the empirical antibacterial management has reduced infection-related mortality to less than 10 percent. Algorithmic approaches to persistent fever in the setting of severe neutropenia have been developed. Circumstances wherein preventative strategies are most efficacious have been defined. Clinicians have learned that neutropenic patients comprise a heterogeneous population that does not encounter the same risks for infection-related morbidity and mortality. Tailored stratified approaches to management of the febrile neutropenic patient have been developed that are safe and cost-effective.

A multicenter comparative trial of tobramycin and ticarcillin vs moxalactam and ticarcillin in febrile neutropenic patients.

During a multicenter prospective randomized trial in febrile neutropenic patients (neutrophil count, less than 1,000/cu mm), 103 episodes were treated with tobramycin sulfate plus ticarcillin disodium (TT) while 117 were treated with moxalactam plus ticarcillin disodium (MT). The majority of patients had an underlying diagnosis of leukemia (60%) and most (62.8%) had granulocyte counts of less than 100/cu mm at the start of therapy. The response rates for clinically or microbiologically documented episodes were 38 of 60 (55.1%) for TT and 38 of 64 (59.4%) for MT. The MT regimen appeared to be more effective for gram-positive infections (56% vs 33%) while TT appeared more effective for gram-negative infections (64% vs 40%). Nephrotoxicity attributable to study drugs occurred in only 2.3% of cases (one on each treatment arm). Prolongation of the prothrombin time was observed in only six of 78 (7.7%) in the TT arm as compared with 39 of 103 (38%) in the MT arm. Neither regimen was adequate for the unusually high frequency of gram-positive pathogens seen during this study.

Comparison of norfloxacin with cotrimoxazole for infection prophylaxis in acute leukemia. The trade-off for reduced gram-negative sepsis.

A total of 63 neutropenic patients receiving cytotoxic therapy for acute leukemia were randomly allocated to receive norfloxacin (400 mg every 12 hours) or cotrimoxazole (160/800 mg every 12 hours) to prevent bacterial infection. Compliance was more than 95 percent and no adverse effects attributable to the study drugs were observed. The overall incidence of febrile illness (67 percent) was similar between the groups; however, no gram-negative bacillary infections were observed in 31 norfloxacin recipients compared with four of 32 cotrimoxazole recipients. Furthermore, nine norfloxacin recipients had 17 gram-positive bacteremias compared with two in two cotrimoxazole recipients (p = 0.0034). Norfloxacin was more effective than cotrimoxazole for preventing acquisition of aerobic gram-negative bacilli in surveillance cultures. Neither study drug allocation nor the presence of an indwelling central venous catheter influenced outcome among the 42 patients who subsequently received empiric systemic antibiotics for suspected infection. Although gram-positive infection remains an unsolved problem, norfloxacin appears to be a safe, effective, well-tolerated alternative to cotrimoxazole for preventing gram-negative infection in neutropenic patients with acute leukemia.

Randomized controlled trial comparing trimethoprim/sulfamethoxazole and trimethoprim for infection prophylaxis in hospitalized granulocytopenic patients.

The clinical and microbiologic efficacy of trimethoprim alone and trimethoprim/sulfamethoxazole for infection prevention was evaluated in 75 patients during 92 episodes of granulocytopenia. Ultimately, 60 patients were evaluable during 77 episodes of granulocytopenia, 36 episodes in the trimethoprim group and 41 episodes in the trimethoprim/sulfamethoxazole group. The incidence of infection was higher in the trimethoprim group (50 percent) than in the trimethoprim/sulfamethoxazole group (39 percent), but this did not reach statistical significance. Trimethoprim did not appear to be as protective as trimethoprim/sulfamethoxazole when the granulocyte count was less than 100/mm3. In patients receiving trimethoprim/sulfamethoxazole, aerobic gram-negative bacilli cleared from fecal surveillance cultures more often and new aerobic gram-negative bacilli were acquired less often than in those receiving trimethoprim alone (p less than 0.05). More myelosuppression was observed among patients receiving trimethoprim/sulfamethoxazole (p less than 0.001). These observations suggest that trimethoprim alone may not be optimal for preventing colonization and infection in granulocytopenic patients and that combination with other agents may be necessary to increase the spectrum of activity. Trimethoprim/sulfamethoxazole itself may predispose toward an increased risk of infection by prolonging myelosuppression.

Invasive aspergillosis in cancer patients.

The incidence of invasive aspergillosis is increasing parallel to the intensity of immunosuppressive and myelosuppressive anticancer treatments. Successful management is linked to an understanding of the pathogenesis and recognition of risk factors. Identifying the patients and clinical circumstances associated with the highest risk for invasive aspergillosis and managing patients in protected environments remain the most effective means of prevention. Early accurate diagnosis continues to be a challenge; however, newer non-culture-based methods are encouraging and have been incorporated into standardized case definitions. Unacceptably high mortality rates persist with current treatment of established infection. Among the newer potentially less toxic antifungal therapies are the triazoles, and lipid-based polyene-formulations that target the fungal cell membrane and 1,3-beta-D-glucan synthase inhibitors that target the fungal cell wall. These agents are currently in clinical trials. Host defense augmentation using hematopoietic growth factors with or without other cytokines such as interferon-gamma or hematopoietic growth factor-stimulated neutrophil transfusions remain controversial strategies that have yet to be tested in well-designed randomized controlled trials.

A case of group A streptococcal meningitis in an adult.

Group A streptococci are an important cause of soft tissue infections but have rarely been reported as the cause of pyogenic meningitis since the advent of antibiotics. A case of group A streptococcal meningitis in an adult is presented along with a review of similar cases reported in the literature. This case serves to illustrate the virulent nature of this pathogen in infections of the meninges, the potential for associated complications, and the need for rapid diagnosis and appropriate treatment. The source of infection in this and many other cases in the literature is the upper respiratory tract. The case presented responded well to antibiotics but resulted in permanent auditory-vestibular dysfunction.

Thrombotic thrombocytopenic purpura associated with the acquired immune deficiency syndrome.

A bisexual male presented with acute thrombotic thrombocytopenic purpura (TTP) in association with established acquired immune deficiency syndrome. The patient had classic clinical and laboratory findings of TTP and responded well to plasmapheresis therapy. Previously reported cases of TTP in association with human immunodeficiency virus (HIV) infection are briefly reviewed. Basic concepts in the pathogenesis of TTP are examined in reference to HIV infection.

Antimicrobial regimens prescribed by Canadian physicians for chemotherapy-induced febrile neutropenic episodes.

OBJECTIVE: To study the antimicrobial management of cancer patients with chemotherapy-induced neutropenia by Canadian physicians. SETTING: A cohort of 274 cancer patients with severe neutropenia (ie, less than 0.5×10(9) neutrophils/L) who participated in a prospective double-blind, placebo controlled study on antifungal prophylaxis conducted in 14 Canadian university-affiliated centres. Antifungal prophylaxis (oral fluconazole 400 mg daily) was administered to 153 of 274 (56%) patients. RESULTS: Antibacterial prophylaxis with a quinolone was given to 87 patients (32%) at the onset of chemotherapy whereas trimethoprim/sulphamethoxazole was given to 56 (20%) patients. Fever (ie, 38°C or over) occurred in 216 (79%) patients after a median duration of neutropenia of four days (range one to 31 days). Empirical antibacterial antibiotics were administered in 214 febrile patients. In 164 (77%) patients antibiotics were started during the first 24 h of fever. Monotherapy with a third generation cephalosporin and duotherapy with a antipseudomonal beta-lactam and an aminoglycoside were prescribed in 69 (32%) and 61 (28%) of the febrile patients, respectively. Inclusion of vancomycin in the initial empirical regimen was noted in 32 (15%) patients. Modifications of the initial regimen occurred in 187 (87%) patients after a median of five days (range one to 28 days). Empirical systemic amphotericin B was added after a median duration of nine days (range one to 34 days) of the empirical antibacterial regimen. CONCLUSIONS: Overall, the antimicrobial management of cancer patients with chemotherapy-induced neutropenia by Canadian physicians follows the current guidelines promulgated by the Infectious Diseases Society of America.

Reduction in clinical response to empiric antimicrobial therapy of febrile granulocytopenic patients receiving TMP/SMX infection prophylaxis.

In the course of a multicentre clinical trial evaluating two antibacterial regimens for the empiric treatment of suspected infection in febrile neutropenic cancer patients, a suboptimal response was noted among recipients of antibacterial prophylaxis with trimethoprim/sulphamethoxazole (TMP/SMX). Multivariate analysis identified TMP/SMX prophylaxis as a predictor of poor outcome independent of other variables such as classification of infection, marrow recovery, neutrophil count at first fever, indwelling central venous catheter use, and underlying disease. This effect appeared to be restricted to recipients of tobramycin plus ticarcillin (TT). TMP/SMX suppresses potentially pathogenic aerobic Gram-negative bacilli and allows colonization and subsequent infection by Gram-positive microorganisms against which TT-like regimens have limited activity. Recognition of this phenomenon may permit a more appropriate selection of antibacterial agents for the therapy of suspected infection in the neutropenic patient.