Jeffrey J. Tarrand

Differential Time to Positivity: A Useful Method for Diagnosing Catheter-Related Bloodstream Infections

Context Diagnosing central venous catheterrelated bloodstream infections may be difficult. Contribution This prospective study from a tertiary care cancer center examined 191 infections with the same organism detected from simultaneously drawn central and peripheral blood cultures. Catheter-tip colonization or quantitative blood cultures defined catheter-related bloodstream infection. When the culture drawn from the catheter became positive at least 120 minutes earlier than the peripherally drawn culture, the odds of catheter-related bloodstream infection increased by a factor of 5.9. Implications Differential time to positivity of at least 120 minutes between centrally and peripherally drawn blood cultures helps diagnose catheter-related bloodstream infection. The Editors Catheter-related bloodstream infections are a common type of nosocomial bloodstream infections and are associated with the use of central venous catheters (1, 2). Kluger and Maki (3) estimated that more than 200 000 cases of catheter-related bloodstream infections occur annually in the United States, with an attributable mortality rate of 12% to 25% (3). However, despite their high frequency of occurrence and seriousness, such infections are often difficult to diagnose. Clinical manifestations of this type of infection, such as fever and chills, are sensitive but not specific for a diagnosis, whereas other manifestations, suchas catheter-site inflammation, are specific but not sensitive. For the past 25 years, semiquantitative (for example, the roll-plate technique) and quantitative (for example, sonication) methods of catheter culture have been used to establish the diagnosis of catheter-related bloodstream infection (4-6). However, because taking catheter cultures requires the removal or exchange of the catheter, it only minimally affects management of the infection (7). To avoid unnecessary removal of the central venous catheter, some researchers have suggested taking simultaneous quantitative blood cultures from the catheter and the peripheral vein (8, 9). This method has been limited because quantitative blood cultures are labor intensive and costly and therefore are not widely used in clinical microbiology laboratories. Recently, Blot and colleagues (10, 11) reported that the measurement of differential time to positivity between blood cultures drawn through the central venous catheter and those drawn from the peripheral vein is highly diagnostic of catheter-related bloodstream infection in patients with long-term catheters. The differential time to positivity was defined as the difference in the time it took for a blood culture drawn through the central venous catheter and a culture drawn from a peripheral vein to become positive. Other investigators did not show that this method is highly diagnostic of catheter-related bloodstream infection in patients with short-term (<30 days of dwell time) catheters. However, all of the studies reported so far have included a very small number of evaluable patients who had positive simultaneous blood cultures from both the central venous catheter and the peripheral vein (12-14). To investigate the diagnostic usefulness of differential time to positivity, we decided a priori to follow for a year patients who grew the same organism from blood cultures drawn simultaneously through the central venous catheter and peripheral vein. We hypothesized that the diagnostic utility of differential time to positivity would differ between patients who had short-term catheters and those who had long-term catheters. Methods Patients The study took place at the University of Texas M.D. Anderson Cancer Center, in Houston, Texas, between 1 September 1999 and 1 November 2000. We evaluated the results of all blood cultures drawn simultaneously from the central venous catheter and peripheral vein and prospectively followed patients who had positive simultaneous blood cultures that grew the same organisms. Information obtained on these patients included age, sex, underlying disease, duration of hospitalization, duration of stay in the intensive care unit, history of bone marrow transplantation, type of catheter, number of catheter lumen, catheter insertion site, and duration of catheterization. We also evaluated patients for neutropenia, thrombocytopenia, concomitant infections, therapy with antimicrobial agents, and outcome of infections. Definitions and Diagnosis We defined differential time to positivity as the difference in time needed for blood cultures drawn simultaneously through the central venous catheter and from a peripheral vein to become positive. As in previous studies, differential time to positivity was considered positive (that is, suggestive of catheter-related bloodstream infection) if the blood culture drawn through the central venous catheter became positive at least 120 minutes earlier than a positive culture drawn simultaneously from a peripheral vein. Significant colonization of the catheter tip was defined as a positive semiquantitative catheter culture by the roll-plate method, whereby at least 15 colony-forming units (CFUs) of an organism were cultured from the catheter tip (4). We used 3 definitions of catheter-related bloodstream infection in this study to evaluate the diagnostic accuracy of differential time to positivity. All of the definitions included the presence of clinical signs and symptoms of bacteremia, such as fever and chills, in the absence of sources for the bacteremia other than the catheter. The definitions were as follows: 1. Composite definition of catheter-related bloodstream infection as defined by the recent Infectious Disease Society of America (IDSA) guidelines (15): Positive simultaneous blood cultures from the central venous catheter and peripheral vein yielding the same organism in the presence of either significant catheter-tip colonization with 15 CFUs or more of the same organism (same species and antibiogram) isolated from the blood cultures, or simultaneous quantitative blood cultures in which the number of CFUs isolated from the blood drawn through the central venous catheter was at least 5-fold greater than the number isolated from blood drawn percutaneously. 2. Partial definition based on simultaneous quantitative blood cultures: The presence of at least 5 times the number of CFUs from the central venous catheter blood culture compared with that the number from the peripheral vein blood culture. 3. Partial definition based on semiquantitative catheter culture: Catheter-tip culture with at least 15 CFUs of the same organism isolated from the peripheral vein blood culture. A bloodstream infection originating from a noncatheter source was defined as one with positive blood cultures from the central venous catheter and peripheral vein that did not fulfill any of the criteria of quantitative catheter-related bloodstream infection or tip culturebased bloodstream infection, as defined earlier. Evaluable cases of bloodstream infection were those with positive simultaneous blood cultures of the same organisms from the central venous catheter and peripheral vein, in which it was possible to determine the source of the bloodstream infection (catheter or otherwise) on the basis of the definitions outlined earlier. Short-term central venous catheters were those with a dwell time of less than 30 days, and long-term central venous catheters were those with a dwell time of 30 days or more. The principal investigator determined whether infections were catheter related and had no knowledge of differential time to positivity at the time of adjudication of the reference standard definitions. Culture Techniques After rigorous antiseptic cleansing of the skin and the hub with 70% alcohol, we drew quantitative and qualitative blood cultures from the peripheral vein and central venous catheter hub simultaneously (maximum of 15 minutes apart). From the central venous catheter, we drew 7 to 10 mL of blood and then discarded the sample to avoid contamination with previously administered agents that could have antimicrobial activity. We subsequently drew 20 mL of blood through the central venous catheter and divided the sample into 2 portions. We placed 10 mL in isolator tubes (isolator 10, Wampole, Cranbury, New Jersey) for quantitative culturing by using the lysis centrifugation method, as described elsewhere (16). Another 10 mL of blood was placed in a regular aerobic blood culture bottle (aerobic 26+, Becton Dickinson DIS, Sparks, Maryland). We also drew 20 mL of blood percutaneously and processed the sample in the same manner as the blood culture from the central venous catheter. All blood culture bottles were taken promptly to the microbiology laboratory and placed in an automatic culture detector (Bactec 9240, Bactec Plus Aerobic/F, Becton Dickinson DIS, Sparks, Maryland), which records culture positivity every 15 minutes according to changes in fluorescence related to microbial growth. Catheters were removed aseptically, at the discretion of primary care physicians, if they were no longer needed or if infection was suspected. A 5-cm segment of the removed catheter tip was aseptically cut and delivered to the microbiology laboratory for culture by the semiquantitative roll-plate method (4). Statistical Analysis We divided the study sample into 2 groups, those with catheter-related bloodstream infection and those without, on basis of the composite definition of catheter-related bloodstream infection according to IDSA guidelines (15). We determined the significance of the differences between the 2 study groups using the chi-square test or the Fisher exact test, as appropriate, for categorical variables. The Student t-test or MannWhitney test was used for continuous variables. All P values were based on 2-tailed tests (level of significance, P 0.05). Sensitivity, specificity, and likelihood ratios, along with associated 95% CIs, were determined for differential time to positivity o

Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center.

Abstract: Community respiratory viruses (CRVs) have been recognized as a potential cause of pneumonia and death among hematopoietic stem cell transplantation (HSCT) recipients and patients with hematologic malignancies. We reviewed the Microbiology Laboratory records dated from July 1, 2000, to June 30, 2002, to identify patients who had respiratory specimens positive for influenza, parainfluenza, respiratory syncytial virus, or picornavirus. We identified 343 infections among patients with underlying hematologic malignancies and HSCT. We collected data on type of disease, age, sex, type of infection, neutrophil and lymphocyte counts, therapy, and outcome. Influenza, parainfluenza, and respiratory syncytial virus accounted for most cases and were approximately equal in frequency. Most infections occurred predominantly among recipients of allogeneic transplants. Infection progressed to pneumonia in 119 patients (35%) and occurred with similar frequency for the 3 viruses. Patients at greatest risk for developing pneumonia included those with leukemia, those aged more than 65 years, and those with severe neutropenia or lymphopenia. Lack of respiratory syncytial virus-directed antiviral therapy (p = 0.025) and age (p = 0.042) were associated with development of respiratory syncytial virus pneumonia, and an absolute lymphocyte count ≤200 cells/mL (p = 0.049) was associated with development of influenza pneumonia. The overall mortality rate for CRV pneumonia was 15%. The only independent predictor of fatal outcome was an absolute lymphocyte count ≤200 cells/mL (p = 0.03) in patients with influenza pneumonia. HSCT recipients and patients with hematologic malignancies who develop upper respiratory infection due to CRVs should be considered for antiviral therapy of proven efficacy to reduce the risk of pneumonia and death. Abbreviations: CRV = community respiratory virus; HSCT = hematopoietic stem cell transplantation; RSV = respiratory syncytial virus; URI = upper respiratory infection.

Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001-2007): stable incidence but changing epidemiology of a still frequently lethal infection.

The incidence, epidemiology, Candida species distribution, resistance patterns, and outcome of candidemia in high‐risk hematologic malignancy and/or stem cell transplantation patients have not been extensively described since the introduction of new antifungal agents.

Common Emergence of Amantadine- and Rimantadine-Resistant Influenza A Viruses in Symptomatic Immunocompromised Adults

The importance and significance of amantadine- or rimantadine-resistant influenza viruses in immunocompromised patients was studied in a population of adult bone marrow transplant (BMT) recipients and patients with leukemia prospectively cultured for respiratory viruses. Influenza A viruses were isolated from 29 patients with acute respiratory illness (14 BMT recipients and 15 patients with leukemia). Fifteen patients (52%) received amantadine (n = 4) or rimantadine (n = 11) therapy. All influenza isolates recovered from six patients shedding virus for > or = 3 days were screened for antiviral susceptibility; resistant isolates were further genetically characterized. Initial influenza isolates were susceptible to amantadine or rimantadine, but subsequent isolates from five of six patients were resistant. Influenza-associated mortality was similar among patients with and without documented antiviral resistance (2 of 5 vs. 5 of 24). We conclude that development of antiviral resistance in immunocompromised individuals should be considered when they have been treated with antivirals and have shed influenza virus for a prolonged period. Isolation procedures should be instituted for all immunocompromised patients with influenza, both during and after therapy with amantadine or rimantadine.

Impact of central venous catheter removal on the recurrence of catheter-related coagulase-negative staphylococcal bacteremia.

OBJECTIVE To determine the impact of catheter management on the acute and long-term outcome of catheter-related coagulase-negative staphylococcal bacteremia. DESIGN Retrospective surveillance of catheter-related sepsis using quantitative blood and catheter cultures. SETTING University-affiliated tertiary cancer center. PATIENTS AND METHODS Seventy patients with catheter-related coagulase-negative staphylococcal bacteremia were studied by retrospective chart review. The clinical characteristics of the patients and the management of the bacteremias were determined. The impact of immunosuppressive risk factors, antibiotic therapy, and catheter management on the recurrence of the bacteremia was investigated. RESULTS Acute sepsis-related morbidity and mortality were not related to catheter management. However, during a 12-week followup period, the bacteremia recurred in 20% of the patients whose catheters remained in place, compared with only 3% of those whose catheters were removed (p less than .05). By multivariate analysis, patients whose catheters remained in place were 2.9 times more likely to experience a recurrence than those whose catheters were removed (odds ratio = 2.9, 95% confidence interval = 1.2-8.8, p = .03). All other potential risk factors were equally distributed between patients, with and without a recurrence. CONCLUSIONS Although patients with catheter-related coagulase-negative staphylococcal bacteremia could be treated successfully while the catheter remains in place with the majority remaining free of recurrence, catheter retention results in a significantly higher risk for the recurrence of the bacteremia.

Late Cytomegalovirus Pneumonia in Adult Allogeneic Blood and Marrow Transplant Recipients

To assess the impact of antiviral prophylaxis during the first 3 months after transplantation on the frequency, timing, and outcome of cytomegalovirus (CMV) pneumonia during the first year, 541 adult allogeneic blood and marrow transplant recipients were evaluated. Thirty-four patients (6.3%) developed 35 episodes of CMV pneumonia at a mean of 188 days after transplantation, with an associated mortality rate of 76%. Twenty-six episodes (74%) occurred late (after day 100). Of the patients with late CMV pneumonia almost all (92%) had chronic graft vs. host disease or had received T cell-depleted transplants. Fourteen late CMV pneumonias (54%) were associated with serious concurrent infections, and 100% of these episodes were fatal. In conclusion, although the frequency of CMV pneumonia in the early posttransplantation period may be substantially reduced by prophylaxis, CMV continues to be a major cause of morbidity and mortality in the late period. Some subsets of patients need more prolonged surveillance and prophylaxis and/or preemptive therapy.

Candidemia in a Tertiary Care Cancer Center: In vitro susceptibility and its association with outcome of initial antifungal therapy

Since the 1990s, changing trends have been documented in species distribution and susceptibility to bloodstream infections caused by Candida species in cancer patients. However, few data are available regarding the association between in vitro antifungal susceptibility and outcome of candidemia in this patient population. We therefore evaluated the association of in vitro antifungal susceptibility and other risk factors with failure of initial antifungal therapy in cancer patients with candidemia. Candidemia cases in cancer patients from 1998 to 2001 (n = 144) were analyzed retrospectively along with their in vitro susceptibility to amphotericin B, fluconazole, and itraconazole (National Committee for Clinical and Laboratory Standards M27-A method). Patients were evaluable for outcome analysis if they received continuous unchanged therapy with either fluconazole or amphotericin B for ≥5 days. We excluded cases of mixed candidemia. In vitro susceptibility testing data of the first Candida bloodstream isolate were analyzed. Appropriate therapy was defined as that using an active in vitro antifungal for ≥5 days. For fluconazole susceptible-dose dependent Candida species, we defined appropriate therapy as a fluconazole dose of ≥600 mg/day. The Candida species distribution was 30%Candida albicans, 24%Candida glabrata, 23%Candida parapsilosis, 10%Candida krusei, 9%Candida tropicalis, and 3% other. Overall, amphotericin B was the most active agent in vitro, with only 3% of the isolates exhibiting resistance to it (>1 mg/L). Dose-dependent susceptibility to fluconazole and itraconazole was seen in 13% and 21% of the isolates, respectively, while resistance to fluconazole and itraconazole was seen in 13% and 26%, respectively.Eighty patients were evaluable for outcome analysis. In multivariate analysis, the following factors emerged as independent predictors of failure of initial antifungal therapy: leukemia (p = 0.01), bone marrow transplantation (p = 0.006), and intensive care unit stay at onset of infection (p = 0.02). Inappropriate antifungal therapy, as defined by daily dose and in vitro susceptibility, was not shown consistently to be a significant factor (it was significant in multivariate analysis, p = 0.04, but not in univariate analysis), indicating the complexity of the variables that influence the response to antifungal treatment in cancer patients with candidemia.

Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: A 20-year autopsy study

Autopsy studies remain an essential tool for understanding the patterns of fungal disease not detected ante mortem with current diagnostic approaches. We collected data concerning the microbiological trends, patient clinical characteristics and sites of involvement for invasive fungal infections (IFIs) identified at autopsy in a single large cancer treatment centre over a 20‐year period (1989–2008). The autopsy rate and IFI prevalence both declined significantly during the study period. The prevalence of Aspergillus spp. decreased significantly from the first 15 years of the study (from 0.12 to 0.14 cases per 100 autopsies to 0.07 in 2004–2008; P = 0.04), with only Mucorales accounting for a greater proportion of IFIs over the duration of the study period (0.06 to 0.2 cases per 100 autopsies, P = 0.04). After 2003, moulds accounted for the majority of infections identified at autopsy in the spleen, kidney, heart and gastrointestinal tract. Despite a trend of decreasing prevalence from 1989 to 2004, invasive candidiasis increased in prevalence during later periods 2004–2008 (0.02–0.05 per 100 autopsies) with decreasing kidney, heart and spleen involvement. Despite a declining autopsy rate, these data suggest a decreasing prevalence overall of IFIs with changing patterns of dissemination in patients with haematological malignancies.

Rapid and accurate identification of mycobacteria by sequencing hypervariable regions of the 16S ribosomal RNA gene.

We developed a method to identify mycobacteria by sequencing hypervariable regions of the polymerase chain reaction-amplified 16S ribosomal RNA gene. This method is nearly specific for mycobacteria and uses positive culture from liquid or solid medium without the needfor lengthy subculture. It shortens identification time to 3 days, which is much faster than the conventional biochemical method (mean, 8 weeks). It applies to all mycobacteria (approximately 100 species), unlike current nucleic acid hybridization methods, which probe only 4 species. The identifications are the same or are species specific for the well-characterized mycobacteria (59/68 [87%]) or more accurate for recently proposed species (9/68 [13%]). The method requires a single sequencing reaction, which is efficient and cost-effective. Therefore, this method is clinically and academically useful.

Serious complications of vascular catheter-related Staphylococcus aureus bacteremia in cancer patients

Over the period 1986 to 1989, 53 cancer patients were identified with catheter-relatedStaphylococcus aureus bacteremia at the University of Texas M.D. Anderson Cancer Center. Septic thrombosis was diagnosed in 12 (23 %) patients and was suspected in another 3 (6 %). Of the 12 patients, five developed deep-seated infections (septic emboli, endocarditis, meningitis, abscess), compared with 2 of the 38 other patients with no septic thrombosis (p<0.01). Fever persisted for more than three days after antibiotic initiation in 52 % of the patients with complications (septic thrombosis and/or deep-seated infections), compared with 19 % of those without complications (p<0.02). Of the three patients with complications who were treated for 14 days with intravenous antistaphylococcal antibiotics, two relapsed; in contrast, all of the nine patients with complications who were treated for more than 14 days (mean 4 weeks) were cured, and none relapsed (p<0.05). Of the nine patients with complications who were treated with a long course of therapy, only one required surgery. The possibility of septic thrombosis and/or deep-seated infections should be considered in all cancer patients with catheter-relatedStaphylococcus aureus bacteremia, and if present, the condition should be treated with appropriate intravenous antibiotics for at least four weeks.