Francesca Ginocchio

Predictors of Mortality in Bloodstream Infections Caused by Klebsiella pneumoniae Carbapenemase–Producing K. pneumoniae: Importance of Combination Therapy

BACKGROUND The spread of Klebsiella pneumoniae (Kp) strains that produce K. pneumoniae carbapenemases (KPCs) has become a significant problem, and treatment of infections caused by these pathogens is a major challenge for clinicians. METHODS In this multicenter retrospective cohort study, conducted in 3 large Italian teaching hospitals, we examined 125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates (KPC-Kp) diagnosed between 1 January 2010 and 30 June 2011. The outcome measured was death within 30 days of the first positive blood culture. Survivor and nonsurvivor subgroups were compared to identify predictors of mortality. RESULTS The overall 30-day mortality rate was 41.6%. A significantly higher rate was observed among patients treated with monotherapy (54.3% vs 34.1% in those who received combined drug therapy; P = .02). In logistic regression analysis, 30-day mortality was independently associated with septic shock at BSI onset (odds ratio [OR]: 7.17; 95% confidence interval [CI]: 1.65-31.03; P = .008); inadequate initial antimicrobial therapy (OR: 4.17; 95% CI: 1.61-10.76; P = .003); and high APACHE III scores (OR: 1.04; 95% CI: 1.02-1.07; P < .001). Postantibiogram therapy with a combination of tigecycline, colistin, and meropenem was associated with lower mortality (OR: 0.11; 95% CI: .02-.69; P = .01). CONCLUSIONS KPC-Kp BSIs are associated with high mortality. To improve survival, combined treatment with 2 or more drugs with in vitro activity against the isolate, especially those also including a carbapenem, may be more effective than active monotherapy.

High-dose daptomycin in documented Staphylococcus aureus infections

Daptomycin is approved at a dose of 4-6 mg/kg/day for the treatment of complicated skin and soft-tissue infection and Staphylococcus aureus bloodstream infection. Clinical experience with doses >6 mg/kg/day is limited, but data reported to date suggest that daptomycin can be safe and effective at higher doses. We describe our experience with daptomycin at doses >6 mg/kg/day and ≤6 mg/kg/day for S. aureus infections. A retrospective chart review of all patients treated with daptomycin from January 2008 to 28 February 2010 was performed. During the study period, 53 patients received daptomycin, including 22 patients receiving daptomycin at a standard dose (SD) (mean 5 mg/kg/day, range 4-6 mg/kg/day) and 31 patients receiving a higher dose (HD) (mean 8 mg/kg/day, range 7-9 mg/kg). The median treatment duration was 13.5 days and 19 days for the SD and HD groups, respectively. Clinical success was observed in 16/22 patients (73%) in the SD group and 29/31 patients (94%) in the HD group (P=0.05). Microbiological success was observed in 13/19 patients (68%) and 27/29 patients (93%) in the SD and HD groups, respectively (P<0.05). Of the 53 patients, 2/22 treated with SD daptomycin and 3/31 treated with HD daptomycin experienced a grade 1 adverse event while receiving therapy (i.e. anaemia, diarrhoea, nausea, hypokalaemia and arthralgia) but did not require discontinuation of daptomycin treatment. These results suggest that daptomycin may be used at doses higher than 6 mg/kg/day without toxicity and possibly with better outcome than conventional doses. We recommend further randomised controlled prospective studies with higher doses of daptomycin.

Primary varicella zoster infection associated with fingolimod treatment

The therapy of relapsing-remitting multiple sclerosis (MS) has been revolutionized since the appearance of first-line disease-modifying drugs such as interferon-β and glatiramer acetate. These drugs are associated with moderate efficacy but no life-threatening risks. In contrast, new treatments, which have recently entered the MS scene, have been reported to display a superior efficacy with respect to relapse rate and progression of disability but also an unexpected risk of fatal adverse events.1,2 The oral drug sphingosine-1-phosphate-receptor modulator, fingolimod (FTY720), has been recently shown to have superior efficacy vs IM interferon-β 1a on clinical and MRI outcomes (TRANSFORMS study).3 However, 2 fatal viral infections occurred in patients who received fingolimod, including one case of primary varicella zoster (VZ). Recently, other adverse effects have been reported, mainly affecting the vascular system, such as a case of hemorrhagic focal …

Will new antimicrobials overcome resistance among Gram-negatives?

The spread of resistance among Gram-positive and Gram-negative bacteria represents a growing challenge for the development of new antimicrobials. The pace of antibiotic drug development has slowed during the last decade and, especially for Gram-negatives, clinicians are facing a dramatic shortage in the availability of therapeutic options to face the emergency of the resistance problem throughout the world. In this alarming scenario, although there is a shortage of compounds reaching the market in the near future, antibiotic discovery remains one of the keys to successfully stem and maybe overcome the tide of resistance. Analogs of already known compounds and new agents belonging to completely new classes of antimicrobials are in early stages of development. Novel and promising anti-Gram-negative antimicrobials belong both to old (cephalosporins, carbapenems, β-lactamase inhibitors, monobactams, aminoglycosides, polymyxin analogues and tetracycline) and completely new antibacterial classes (boron-containing antibacterial protein synthesis inhibitors, bis-indoles, outer membrane synthesis inhibitors, antibiotics targeting novel sites of the 50S ribosomal subunit and antimicrobial peptides). However, all of these compounds are still far from being introduced into clinical practice. Therefore, infection control policies and optimization in the use of already existing molecules are still the most effective approaches to reduce the spread of resistance and preserve the activity of antimicrobials.

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.

Impact on bone mineral density of tenofovir-containing HAART in HIV-1 infected children and adolescents: a report from 5 years of clinical experience

Purpose of the study Tenofovir disoproxil fumarate (TDF) is not approved for use in HIV-infected children (<18 years). In clinical practice a TAMs-sparing regimen may be needed. Use of TDF in children seems to be associated with decrease in bone mineral density that sometimes can stabilize after 24 weeks. The primary purpose was to characterized the change in bone mineral density (BMD), as measured by osteosonography (QUS), during and after treatment with tenofovir-containing HAART.