L.A. Nicolini

Incidence of candidaemia and relationship with fluconazole use in an intensive care unit

OBJECTIVES Candida spp. are the most important non-bacterial pathogens in critically ill patients. The aim of this study was to evaluate trends in the incidence of candidaemia and the distribution of Candida albicans and non-albicans over a 9 year period (1999-2007), and to assess their relationship with fluconazole use. METHODS This was an interventional cross-over study. Patients admitted to the intensive care unit (ICU) who developed a clinically and microbiologically documented candidaemia were analysed. Fluconazole was used as prophylaxis in critically ill patients until 2002; from January 2003 infectious disease consultants strongly discouraged its use. Fluconazole use, measured as defined daily dose per 1000 patient-days, was calculated. The main outcome of the study is the evaluation of the restriction policy in terms of change in fluconazole use and in incidence of candidaemia. RESULTS During the 108 month period (January 1999-December 2007), a total of 213 episodes of candidaemia (average incidence 1.42 episodes/10 000 patient-days/year, range 0.36-3.02 episodes) were recorded in a mixed medical and surgical ICU in Italy. C. albicans was the most prevalent isolated species (n = 98, 46%); non-albicans (n = 115, 54%) were mainly represented by Candida parapsilosis (n = 46, 22%) and by Candida glabrata (n = 28, 13%). Segmented regression analysis of the interrupted time series showed that a change in the fluconazole prophylactic strategy resulted in a significant reduction in fluconazole use from the second semester of 2002. A dramatic decrease in the incidence of fungaemia due to C. non-albicans was observed from the second semester of 2003 (intervention effect in the second semester of 2007: -2.31/10 000 patient-days); minor changes in the incidence of C. albicans fungaemia emerged (intervention effect in the second semester of 2007: -0.23/10 000 patient-days). CONCLUSIONS The study showed a clear correlation between fluconazole use control and decreasing incidence of non-albicans candidaemia. Even if fluconazole remains a first-line treatment option in several cases of invasive candidiasis, its prophylactic use should be carefully evaluated.

Drug treatment for multidrug-resistant Acinetobacter baumannii infections

Acinetobacter baumannii has emerged in the last decades as a major cause of healthcare-associated infections and nosocomial outbreaks. Multidrug-resistant (MDR) A. baumannii is a rapidly emerging pathogen in healthcare settings, where it causes infections that include bacteremia, pneumonia, meningitis, and urinary tract and wound infections. Antimicrobial resistance poses great limits for therapeutic options in infected patients, especially if the isolates are resistant to the carbapenems. Other therapeutic options include sulbactam, aminoglycosides, polymixyns and tigecycline. The discovery of new therapies coupled with the development of controlled clinical trial antibiotic testing combinations and the prevention of transmission of MDR Acinetobacter infection are essential to face this important hospital problem.

Tigecycline use in serious nosocomial infections: a drug use evaluation

BackgroundTigecycline is a novel antibiotic with activity against multidrug resistant bacteria. The aim of this study was to assess the efficacy of tigecycline use in serious hospital-acquired infections (HAI)Case presentationProspective observational study of tigecycline use was conducted in a 1500 beds university hospital. From January 1, 2007 and January 31, 2010, 207 pts were treated with tigecycline for the following indications: intra-abdominal, pneumonia, bloodstream and complicated skin and soft tissue infections and febrile neutropenia. The therapy was targeted in 130/207 (63%) and empirical in 77/207 (37%) patients. All bacteria treated were susceptible to tigecycline. Median duration of tigecycline therapy was 13 days (range, 6-28). Clinical success was obtained in 151/207 (73%) cases, with the highest success rate recorded in intra-abdominal infections [81/99 (82%)]. Microbiological success was achieved in 100/129 (78%) treated patients. Adverse clinical events were seen in 16/207 patients (7.7%):ConclusionsConsidering the lack of data on tigecycline for critically ill patients, we think that the reported data of our clinical experience despite some limitations can be useful for clinicians.

Hepatitis B reactivation in HBsAg-negative/HBcAb-positive allogeneic haematopoietic stem cell transplant recipients: risk factors and outcome

HBsAg-negative/HBcAb-positive haematopoietic stem cell transplant (HSCT) recipients are at high risk of hepatitis B virus (HBV) reactivation. Allogeneic HSCT recipients from years 2000 to 2010 were evaluated in order to study the impact of being HBsAg-negative/HBcAb-positive in this population. Overall, 137 of 764 patients (18%) were HBsAg-negative/HBcAb-positive before HSCT. Overall survival, non-relapse mortality (NRM), acute and chronic graft-vs.-host disease were similar in HBcAb-positive and HBcAb-negative patients. Reactivation occurred in 14 patients (10%) within a median of 19 months after HSCT (range 9-77). Cause-specific hazard for reactivation was decreased in the case of an HBV-immune/exposed donor (HRadjusted = 0.12; 95% CI, 0.02-0.96; p 0.045) and increased in patients who received rituximab treatment (HRadjusted = 2.91; 95%CI, 0.77-10.97; p 0.11). Competing risk analyses documented a protective role of an HBV-immune/exposed donor (p 0.041) and an increased probability associated with the length of treatment with cyclosporine (p <0.001) and treatment with rituximab (but not with low-dose rituximab prophylaxis, p <0.001 at each landmark point). No differences in overall survival and NRM were found between patients with and without HBV reactivation. The donors immunity was independently and consistently associated with a decreased risk of HBV reactivation, while rituximab and cyclosporine treatments increased the probability.

Current Status of Newer Carbapenems

OBJECTIVES Beta-lactam antibiotics represent the most commonly prescribed antibacterial agents. Since many bacteria have developed resistance to older agents, new beta-lactams have been introduced constantly. In the late 1970s, a new class of exceptionally broad-spectrum beta-lactams, the carbapenems, was identified. The carbapenems, such as the most popular imipenem and meropenem, have the widest spectra of antibacterial activity of all the beta-lactams and provide excellent coverage of many gram-negative and gram-positive aerobic and anaerobic bacteria. Despite the wide antibacterial spectrum, the carbapenems globally lack activity against Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA) and Stenotrophomonas maltophilia. METHODS We reviewed the principal characteristics of the novel carbapenems and their clinical implications. RESULTS AND CONCLUSIONS We included in our review: ertapenem, biapenem, panipenem, doripenem, tebipenem pivoxil and tomopenem.

Evaluation of insulin resistance in a cohort of HIV-infected youth

OBJECTIVE Metabolic abnormalities, including impairment of glucose homeostasis, have been well characterized in HIV-infected patients. In contrast to adults, insulin resistance and diabetes mellitus appear to be relatively uncommon finding in youth. DESIGN We assessed insulin resistance, and associated risk factors, in a population of vertically HIV-infected children and young adults, when compared with a control population of healthy children. METHODS At the time of enrolment, weeks of pregnancy, birth weight, sex, age, weight, height, body mass index (BMI), pubertal stages, CDC classification, blood pressure, clinical lipodystrophy, hepatitis B or C co-infection, antiretroviral therapy, CD4 T lymphocyte counts, and HIV-RNA levels were recorded. Fasting plasma glucose and insulin levels and homeostatic model assessment-insulin resistance (HOMA-IR) were determined. These parameters were compared between HIV patients and healthy controls with multivariate analyses. RESULTS Fasting insulin levels (OR=1.21, P<0.001) and glycemia (OR=0.89, P<0.001) were significantly different between HIV-infected patients and controls. Antiretroviral therapy duration (r=0.281, P<0.05), triglyceride levels (r=0.286, P<0.05), age (r=0.299, P<0.05), and BMI SDS (r=0.485, P<0.001) were significant predictor variables of insulin resistance, expressed as HOMA-IR. Moreover, clinical lipodystrophy seems to be strongly correlated to glycemia (P<0.05), triglyceride levels (P<0.05), serum insulin levels (P<0.001), HOMA-IR (P<0.05), and also with therapy duration (P<0.05). CONCLUSIONS Both HIV infection and antiretroviral therapy demonstrate differential effects on glucose metabolism in HIV-infected children. Targeted prevention of insulin resistance and diabetes mellitus in HIV-infected children and young adults is needed in order to avoid the associated long-term complications that would otherwise occur, given the improvement in life expectancy of HIV-infected individuals.

Effectiveness of a project to prevent HIV vertical transmission in the Republic of Congo

OBJECTIVES To evaluate the effectiveness of a prevention programme against the vertical transmission of HIV in a resource-limited setting and to investigate variables associated with compliance. PATIENTS AND METHODS The Kento-Mwana project (2005-2008) provided counselling, serological and biomolecular testing and prophylaxis/therapy to HIV-positive pregnant women and their children attending four antenatal clinics in Pointe Noire, Republic of Congo. Expected and actual rates of vertical transmission of HIV were compared. Univariate and multivariate analyses were performed in order to identify variables associated with non-compliance. RESULTS The observed transmission rate in the group who completed follow-up was 5/290 (1.7%, 95% CI 0.6%-4.1%). The overall estimated transmission rate in the target population, computed taking into account the expected vertical transmission of HIV among drop-outs, was 67-115/638 (10.5%-18.0%). A comparison between this rate and the expected transmission rate in the absence of intervention (25%-40%) showed that the programme was able to prevent approximately 50% of vertical transmissions. Older age (OR 0.33, 95% CI 0.16-0.66, P = 0.002), telephone availability (OR 0.42, 95% CI 0.24-0.72, P = 0.002) and occupation (OR 0.57, 95% CI 0.29-1.10, P = 0.092) were associated with better compliance. CONCLUSIONS Despite the vast majority of women accepting counselling and testing, many of them refused prophylaxis or dropped out, thus reducing the effectiveness of the intervention from an ideal 2% to a still important but less impressive median transmission rate of 15% (range 10.5%-18%). Promoting participation and compliance, rather than increasing the potency of antiretroviral regimens, is crucial for preventing the vertical transmission of HIV in Africa.

The role of telavancin in the treatment of MRSA infections in hospital

Background: Serious infections caused by Gram-positive bacteria, particularly multi-drug resistant, are an important cause of morbidity and mortality in patients admitted to intensive care units. Thus, new antibiotics covering these pathogens are urgently needed. Objective: To review characteristics of telavancin, a novel antibiotic intended to use for treating infections caused by difficult Gram-positive bacteria, such as Staphylococcus aureus, resistant to meticillin or vancomycin, multi-drug-resistant Streptococcus pneumoniae or glycopeptide-resistant enterococci. Methods: The studies on microbiological activity, clinical efficacy and safety of telavancin were reviewed. Results/conclusion: Telavancin is a lipoglycopeptide administered intravenously once-daily and excreted with urine. It proved to be microbiologically active against numerous Gram-positive pathogens including drug-resistant staphylococci, enterococci and pneumococci. Large randomized Phase II and III clinical trials on efficacy and safety of telavancin in treating complicated skin and skin structure infections reported telavancin to be non-inferior to standard treatment (mostly vancomycin). Preliminary data on telavancin in hospital-acquired pneumonia, including ventilator-associated pneumonia, documented that telavancin was efficacious for this indication. Overall incidence of adverse events was similar for telavancin and the comparator arms. Mild and transient disgeusia, nausea and vomiting resulted to be more frequent in telavancin group. Increase in creatinine values was also observed in telavancin arm.

Long course of daptomycin in the treatment of meticillin-resistant Staphylococcus epidermidis endocarditis and spondylodiscitis

Part of this study was presented in the DANMAP 2006 report. he technical staff at Statens Serum Institut and the National Food nstitute, Technical University of Denmark, are thanked for their ssistance. Funding: This study was supported by the Danish Ministry of amily and Consumer Affairs and the Danish Ministry of the Interior nd Health as part of the Danish Integrated Antimicrobial Resisance Monitoring and Research Programme (DANMAP). Competing interests: None declared. Ethical approval: The study protocol for healthy volunteers paricipating in this surveillance was approved by the Scientific Ethics ommittee for Copenhagen and Frederiksberg municipalities [(KF) 1-006/02].

CD8+CD28−CD127loCD39+ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection?

Background: HIV‐associated immunodeficiency is related to loss of CD4+ T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4+ T cells/&mgr;L. CD8+CD28−CD127loCD39+ T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV‐infected patients. Objectives: We sought to analyze the frequency of CD8+CD28−CD127loCD39+ Treg cells in the circulation of HIV‐infected patients. Methods: The frequency of circulating CD8+CD28−CD127loCD39+ Treg cells was analyzed and correlated with viral load and CD4+ T‐cell counts/percentages in 93 HIV‐1–infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long‐term nonprogressors (n = 7), and HIV‐infected patients affected by tumor (n = 4). The same analyses were performed in HIV‐negative patients with cancer (n = 53), hepatitis C virus–infected patients (n = 17), and healthy donors (n = 173). Results: HIV‐infected patients had increased circulating levels of functional CD8+CD28−CD127loCD39+ Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4+ T‐cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS‐ or non–AIDS‐related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant. Conclusion: HIV infection induces remarkable expansion of CD8+CD28−CD127loCD39+ Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met.