Publications

BACKGROUND

Artemisinin combination therapy has become the standard of care for uncomplicated malaria in most of Africa. However, there is limited data on the safety and tolerability of these drugs, especially in young children and patients co-infected with HIV.

METHODS

A longitudinal, randomized controlled trial was conducted in a cohort of HIV-infected and uninfected children aged 4-22 months in Tororo, Uganda. Participants were randomized to treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) upon diagnosis of their first episode of uncomplicated malaria and received the same regimen for all subsequent episodes. Participants were actively monitored for adverse events for 28 days and then passively for up to 63 days after treatment. This study was registered in ClinicalTrials.gov (registration # NCT00527800).

RESULTS

A total of 122 children were randomized to AL and 124 to DP, resulting in 412 and 425 treatments, respectively. Most adverse events were rare, with only cough, diarrhoea, vomiting, and anaemia occurring in more than 1% of treatments. There were no differences in the risk of these events between treatment groups. Younger age was associated with an increased risk of diarrhoea in both the AL and DP treatment arms. Retreatment for malaria within 17-28 days was associated with an increased risk of vomiting in the DP treatment arm (HR = 6.47, 95% CI 2.31-18.1, p < 0.001). There was no increase in the risk of diarrhoea or vomiting for children who were HIV-infected or on concomitant therapy with antiretrovirals or trimethoprim-sulphamethoxazole prophylaxis.

CONCLUSION

Both AL and DP were safe and well tolerated for the treatment of uncomplicated malaria in young HIV-infected and uninfected children.

TRIAL REGISTRATION

ClinicalTrials.gov: NCT00527800; http://clinicaltrials.gov/ct2/show/NCT00527800.

Since the cloning of the first membrane transporter, our understanding of the role of transporters in clinical drug disposition and response has grown enormously. In parallel, large-scale genome-wide variation studies and the emerging field of pharmacogenomics have ushered in a new understanding of variations in drug response. At the crossroads of pharmacogenomics and transporter biology is the National Institutes of Health-funded Pharmacogenomics of Membrane Transporters (PMT) project, centered at the University of California, San Francisco.

OBJECTIVE

To determine the demographic and clinical predictors of in-hospital mortality among hospitalized nursing home (NH) residents.

DESIGN

Retrospective analysis of the public-use copies of the 2005-2006 National Hospital Discharge Survey (NHDS) datasets.

SETTING

Non-federal acute-care, short-stay hospitals in all 50 states and the District of Columbia.

PARTICIPANTS

Participants were 1904 and 1752 NH residents, 45 years or older, hospitalized in 2005 and 2006, respectively.

MEASUREMENTS

In-hospital mortality.

METHODS

A multivariable logistic regression model was developed to determine independent predictors of in-hospital mortality using the 2005 dataset. The model was then applied to the 2006 dataset to determine the generalizability of the predictors.

RESULTS

Significant independent predictors of in-hospital mortality in 2005 included age 85 years or older (adjusted odds ratio [OR], 2.53; 95% confidence interval [CI], 1.21-5.30; P=.013), acute respiratory failure (adjusted OR, 5.67; 95% CI, 3.51-9.17; P < .0001), septicemia (adjusted OR, 4.63; 95% CI, 3.08-6.96; P < .0001), and acute renal failure (adjusted OR, 2.11; 95% CI, 1.30-3.41; P=.002). The following baseline characteristics also predicted in-hospital mortality in 2006: age 85 years or older (adjusted OR, 2.45; 95% CI, 1.31-4.59; P=.005), acute respiratory failure (adjusted OR, 7.11; 95% CI, 4.46-11.33; P < .0001), septicemia (adjusted OR, 3.91; 95% CI, 2.64-5.80; P < .0001), and acute renal failure (adjusted OR, 2.75; 95% CI, 1.82-4.15; P < .0001). Chronic morbidities were not associated with in-hospital mortality.

CONCLUSION

Among hospitalized NH residents, age 85 years or older and several acute conditions, but not chronic morbidities, predicted in-hospital mortality. Elderly NH residents at risk of developing these acute conditions may benefit from palliative care.

A total of 565 methicillin-resistant Staphylococcus aureus (MRSA) isolates were collected mostly from Europe and the Americas (2004 to 2007) during a phase IV clinical trial comparing linezolid with vancomycin for the treatment of complicated skin and skin structure infections proven to be due to MRSA. The isolates were tested for their susceptibilities by the broth microdilution method, they were tested for inducible clindamycin resistance by the D-test, and they were screened for heterogeneous resistance to vancomycin (heterogeneously vancomycin-intermediate S. aureus [hVISA]) by the Etest macromethod. The isolates were evaluated for the MRSA genotype by pulsed-field gel electrophoresis, staphylococcal protein A (spa) typing, multilocus sequence typing (MLST), and staphylococcal cassette chromosome mec (SCCmec) typing. All isolates were inhibited by 4 microg/ml of linezolid (MIC(50) and MIC(90), 2 and 4 microg/ml, respectively). The vast majority of isolates (92.4%) were resistant to erythromycin, and high clindamycin resistance rates were observed (28.5% constitutive and 16.3% inducible). Only 1.0% of the isolates were hVISA. Isolates from the United States were predominantly USA300 sequence type 8 (ST8)-SCCmec type IV (78.5%), followed by a lower prevalence of USA100 ST5-SCCmec type II isolates (14.2%). Strains belonging to the ST5 lineage were widely distributed in Portugal, South American countries, and Mexico. MRSA strains belonging to ST8-SCCmec type IV predominated in Russia (80.0%) and also emerged in Venezuela and Colombia. The epidemic MRSA type 15 clone predominated in the United Kingdom (55.6%) and Spain (100%). In addition, a new MLST profile (ST1071) was observed in South Africa. This study demonstrated the presence of major clones in particular regions (ST8 in the United States, ST5 in Latin America and Portugal, ST22 in Spain and the United Kingdom); however, emerging clones were identified, suggesting that the epidemiology of MRSA continues to evolve.