Jennifer E. Layden

Timing of susceptibility-based antifungal drug administration in patients with Candida bloodstream infection: correlation with outcomes

OBJECTIVES We sought to determine the impact of timing of appropriate antifungal therapy, as assessed by susceptibility results, on patient survival. METHODS Patients ≥16 years of age with first episodes of candidaemia during 2001-09 were included. Clinical data were collected retrospectively, including time to appropriate antifungal therapy and patient survival. RESULTS The study population included 446 patients [243 (54%) female, mean age 53 years] with candidaemia, 380 (85%) of whom had antifungal susceptibility data. Candida albicans was the most common pathogen (221, 50%) followed by Candida glabrata (99, 22%), Candida parapsilosis (59, 13%), Candida tropicalis (48, 11%) and Candida krusei (6, 1%). Appropriate antifungal therapy consisted of fluconazole (177, 40%), an echinocandin (125, 28%), amphotericin B (41, 9%) and voriconazole (6, 1%); 97 (22%) failed to receive appropriate antifungal therapy. The 30 day mortality was 34% (151/446) and there was no clear relationship between time from positive culture to receipt of appropriate antifungal therapy and 30 day survival. On multivariable Cox regression, increased APACHE II score [hazard ratio (HR) 1.11, 95% CI 1.09-1.13, P<0.001], cirrhosis (HR 2.15, 95% CI 1.48-3.13, P<0.001) and HIV infection (HR 2.03, 95% CI 1.11-3.72, P=0.02) were independent predictors of mortality. A secondary analysis requiring patients in the early treatment group to have received ≥24 h of effective antifungal therapy did show a significant mortality benefit to receiving antifungal treatment within 72 h of a positive blood culture being drawn (30 day mortality for early treatment: 27% versus 40%, P=0.004; HR for mortality with delayed treatment on multivariable analysis: 1.41, 95% CI 1.01-1.98, P=0.045). CONCLUSIONS Candida bloodstream infection is associated with high mortality, despite timely receipt of appropriate antifungal therapy.

Mathematical modeling of viral kinetics: ☆: a tool to understand and optimize therapy

One theme that continues to emerge from these studies is the relevance and need for a strong IFN effectiveness. In the prediction studies, the importance of IFN effectiveness for eventual clearance of the virus is present. In the study by Layden et al, the relevance of the viral load at the end of the first phase and IFN effectiveness, to the subsequent second-phase viral decline, is discussed. In the recently developed triphasic model by Bergmann et al, it is illustrated how, theoretically, the viral load at the end of the first phase could impact the second-phase viral decline and eventual clearance of the virus. And, in the investigation into the difference in viral dynamics between African Americans and Caucasians, it appears that a strong effectiveness and first-phase log drop is crucial for virus eradication. More work needs to be completed to understand better why the effectiveness is so crucial for elimination of the virus, and why the effectiveness varies so significantly from one person to another, or from one genotype to another. In a rather short time, the study of viral kinetics has improved our understanding of HCV infection, especially in relation to treatment response. Information has been gleaned on the rapid turnover and clearance rate of the virus, the mode of action of IFN, and the dose-dependence of IFN in inhibiting viral production. Such information has been used to challenge the way we treat patients, understand the difference between nonresponders and responders, gain insight into possible mechanisms of treatment resistance, and predict treatment response. As newer drugs emerge, viral kinetic studies should be able to shed light on the dose-dependent efficacy and mode of action of these newer forms of therapy. The use of kinetics needs to be extended to other areas, such as the study and treatment of acute HCV infection as well as following liver transplantation (see article by Drs. Pawlotsky and Rosen). If the past is any indication of the usefulness of mathematical modeling and kinetics in the study of viruses, continued employment of these tools will only prove beneficial.

High Frequency of Active HCV Infection Among Seropositive Cases in West Africa and Evidence for Multiple Transmission Pathways

BACKGROUND Sub-Saharan Africa (SSA) has one of the highest global hepatitis C virus (HCV) prevalence estimates. However, reports that suggest high rates of serologic false positives and low levels of viremia have led to uncertainty regarding the burden of active infection in this region. Additionally, little is known about the predominant transmission risk factors in SSA. METHODS We prospectively recalled 363 past blood donors (180 who were rapid screen assay [RSA] positive and 183 who were RSA negative at time of donation) to identify the level of active infection and risk factors for infection at a teaching hospital in Kumasi, Ghana. Participants had repeat blood testing and were administered a questionnaire on risk factors. RESULTS The frequency of HCV active infection ranged from 74.4% to 88% depending on the criteria used to define serologically positive cases. Individuals with active disease had biochemical evidence of liver inflammation and median viral loads of 5.7 log copies/mL. Individuals from the northern and upper regions of Ghana had greater risks of infection compared with participants from other areas. Additional risk factors included traditional circumcision, home birth, tribal scarring, and hepatitis B virus coinfection. CONCLUSIONS Viremic infection was common among serologically confirmed cases. Attention to testing algorithms is needed in order to define the true HCV burden in SSA. These data also suggest that several transmission modes are likely contributing to the current HCV epidemic in Ghana and that the distribution of these practices may result in substantial regional variation in prevalence.

Hepatitis C in sub-saharan Africa: urgent need for attention.

The hepatitis C virus (HCV), which was not recognized as an infectious agent until the 1980s, is responsible for a worldwide epidemic. The World Health Organization estimates global prevalence at 2.8%, with 185 million persons infected. In contrast to hepatitis B, where successful vaccine campaigns have reduced the disease burden, much less progress has been made toward the control of HCV. Phylogenetic studies suggest that HCV originated in Africa and has been endemic in some regions for at least 500–600 years. However, little is known about the epidemiology, transmission, and clinical course of HCV in Africa. With the advent of highly effective anti-HCV agents, there exists great potential to at least curb the global epidemic. For regions such as sub-Saharan Africa, however, this will require a thorough understanding of the regional population-level epidemiology, risk factors, and transmission mechanisms. Only then can effective treatment and prevention strategies be introduced.

Risk factors and outcomes associated with vancomycin-resistant Enterococcus infections with reduced susceptibilities to linezolid.

A retrospective matched case-control study of hospitalized patients with vancomycin-resistant Enterococcus (VRE) infection with reduced susceptibility to linezolid was performed in order to identify risk factors for this infection and describe patient outcomes. Forty-eight linezolid nonsusceptible VRE cases were identified between January 1, 2000, and September 30, 2008, and compared to 96 controls with linezolid-susceptible VRE, matched based on culture date and anatomic site of infection. Demographic, clinical and microbiological data were collected. On univariable analysis, risk factors for reduced linezolid susceptibility included allogeneic hematopoietic stem cell transplant and/or solid organ transplant (odds ratio [OR]: 2.63; 95% confidence interval [CI]: 1.13-6.15; P = 0.025), receipt of immunosuppressive medications (OR: 2.39; 95% CI: 1.08-5.29; P = 0.032) including corticosteroids (OR: 2.40; 95% CI: 1.03-5.58; P = 0.042) and noncorticosteroid immunosuppressives (OR: 2.31; 95% CI: 1.00-5.30; P = 0.049), and receipt of linezolid within 1 year prior to infection (OR: 34.50, 95% CI: 4.60-259.02; P < 0.001). On multivariable analysis, only receipt of linezolid within 1 year remained an independent risk factor for reduced linezolid susceptibility (OR: 31.84; 95% CI: 4.20-241.39; P < 0.001), although most patients with VRE with reduced linezolid susceptibility had not received linezolid in the year prior. Reduced linezolid susceptibility did not impact patient outcomes including clinical or microbiological cure, hospital length of stay, or all-cause mortality.

Impact of donor and recipient race on survival after hepatitis C-related liver transplantation.

Background. Both donor and recipient race impact outcomes after liver transplantation (LT), especially for hepatitis C virus (HCV). The interaction and simultaneous impact of both on patient survival is not clearly defined. The purpose of this study was to examine the impact of donor and recipient race on recipient and graft survival after HCV-related LT using the United Network for Organ Sharing database. Methods. A total of 16,053 recipients (75.5% white, 9.3% black, and 15.2% Hispanic) who underwent primary LT for HCV between 1998 and 2008 were included. Cox regression models were used to assess the association between recipient/donor race and patient survival. Results. A significant interaction between donor and recipient race was noted (P=0.01). Black recipients with white donors had a higher risk of patient mortality (adjusted hazard ratio, 1.66; 95% confidence interval, 1.47–1.87) compared with that of white recipients with white donors. In contrast, the pairing of Hispanic recipients with black donors was associated with a lower risk of recipient mortality compared with that of white recipients with white donors (adjusted hazard ratio, 0.64; 95% confidence interval, 0.46–0.87). Similar results were noted for graft failure. Conclusion. In conclusion, the impact of donor and recipient race on patient survival varies substantially by the matching of recipient/donor race.

Racial differences in fibrosis progression after HCV-related liver transplantation

Background Black recipients undergoing liver transplantation (LT) for hepatitis C virus (HCV) have decreased patient and graft survival compared with white recipients, a finding that is primarily limited to black recipients of livers from white donors. The cause(s) for these discrepant outcomes are unclear but may be related to HCV disease recurrence. The rates of HCV-related disease recurrence and liver fibrosis progression among black and white liver transplant recipients have not been investigated. Methods In this study, we compared liver fibrosis progression between 105 black and 364 white recipients after HCV-related LT in a multisite cohort study and assessed the impact of donor race. Results At 6, 12, and 24 months after LT, there was a significantly higher percentage in the black recipient/white donor (B/W) group with severe fibrosis, defined as stage 3 or 4 (F3/F4), compared with all other recipient/donor race combinations. The adjusted odds ratio of developing F3/F4 for the B/W group was 2.54 (1.49–4.69; reference group, white recipient/white donor). Black recipients with black donors demonstrated a similar rate of progression to F3/F4 as white recipients. Patient survival was also decreased in the B/W group compared with other recipient/donor race combinations. Conclusion African American recipients with white donors have more severe fibrosis progression after HCV-related LT. The mechanisms responsible for accelerating fibrosis progression in this high-risk race-mismatched group need to be investigated.

Physical activity and pre-diabetes-an unacknowledged mid-life crisis: findings from NHANES 2003-2006.

The prevalence of pre-diabetes (PD) among US adults has increased substantially over the past two decades. By current estimates, over 34% of US adults fall in the PD category, 84% of whom meet the American Diabetes Association’s criteria for impaired fasting glucose (IFG). Low physical activity (PA) and/or sedentary behavior are key drivers of hyperglycemia. We examined the relationship between PD and objectively measured PA in NHANES 2003–2006 of 20,470 individuals, including 7,501 individuals between 20 and 65 yrs.We excluded all participants without IFG measures or adequate accelerometry data (final N = 1,317). Participants were identified as PD if FPG was 100–125 mg/dL (5.6–6.9 mmol/L). Moderate and vigorous PA in minutes/day individuals were summed to create the exposure variable “moderate-vigorous PA” (MVPA). The analysis sample included 884 normoglycemic persons and 433 with PD. There were significantly fewer PD subjects in the middle (30.3%) and highest (24.6%) tertiles of PA compared to the lowest tertile (35.5%). After adjusting for BMI, participants were 0.77 times as likely to be PD if they were in the highest tertile compared to the lowest PA tertile (p < 0.001). However, these results were no longer significant when age and BMI were held constant. Univariate analysis revealed that physical activity was associated with decreased fasting glucose of 0.5 mg/dL per minute of MVPA, but multivariate analysis adjusting for age and BMI was not significant. Overall, our data suggest a negative association between measures of PA and the prevalence of PD in middle-aged US adults independent of adiposity, but with significant confounding influence from measures of BMI and age.

Comparison of patients from Nigeria and the USA highlights modifiable risk factors for sickle cell anemia complications.

Abstract To identify factors that affect manifestations of sickle cell anemia we compared patients 11–30 years of age from University of Ibadan, Ibadan, Oyo, Nigeria (n = 214) and University of Illinois at Chicago, Chicago, IL, USA (n = 209). Paralleling findings in the general populations of the two countries, the Chicago patients were more often overweight or obese as defined by the Centers for Disease Control and Prevention (Atlanta, GA, USA) guidelines, and more often had elevated blood pressure (BP) as defined by the National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD, USA guidelines. The Ibadan patients did not receive the pneumococcal vaccine or hydroxyurea (HU) therapy as frequently as the Chicago patients. Consistent with lower rates of elevated BP and increased body mass index (BMI), stroke history was less frequent in the Ibadan patients ≥18 years old. Furthermore, in combined analyses, systolic and diastolic BP directly correlated with BMI, and elevated weight status independently associated with history of stroke. Our findings are consistent with the possibility that higher values for BMI and BP in Chicago sickle cell anemia patients may contribute to an increased risk of stroke and highlights the need for measures to reduce these risk factors. On the other hand, lower pneumococcal vaccination and HU therapy rates in Ibadan patients highlights the need for more improved vaccination coverage and for studies to define the role of HU therapy in Africa.

The use of fosfomycin to treat urinary tract infections in kidney transplant recipients.

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