Longitudinal analysis of patterns and predictors of changes in self-reported adherence to antiretroviral therapy: Swiss HIV Cohort Study.

BACKGROUND: Adherence to combination antiretroviral therapy (cART) is a dynamic process, however, changes in adherence behavior over time are insufficiently understood. METHODS: Data on self-reported missed doses of cART was collected every 6 months in Swiss HIV Cohort Study participants. We identified behavioral groups associated with specific cART adherence patterns using trajectory analyses. Repeated measures logistic regression identified predictors of changes in adherence between consecutive visits. RESULTS: Six thousand seven hundred nine individuals completed 49,071 adherence questionnaires [median 8 (interquartile range: 5-10)] during a median follow-up time of 4.5 years (interquartile range: 2.4-5.1). Individuals were clustered into 4 adherence groups: good (51.8%), worsening (17.4%), improving (17.6%), and poor adherence (13.2%). Independent predictors of worsening adherence were younger age, basic education, loss of a roommate, starting intravenous drug use, increasing alcohol intake, depression, longer time with HIV, onset of lipodystrophy, and changing care provider. Independent predictors of improvements in adherence were regimen simplification, changing class of cART, less time on cART, and starting comedications. CONCLUSIONS: Treatment, behavioral changes, and life events influence patterns of drug intake in HIV patients. Clinical care providers should routinely monitor factors related to worsening adherence and intervene early to reduce the risk of treatment failure and drug resistance.

Complicated intra-abdominal infections in a worldwide context: an observational prospective study (CIAOW Study).

Despite advances in diagnosis, surgery, and antimicrobial therapy, mortality rates associated with complicated intra-abdominal infections remain exceedingly high. The World Society of Emergency Surgery (WSES) has designed the CIAOW study in order to describe the clinical, microbiological, and management-related profiles of both community- and healthcare-acquired complicated intra-abdominal infections in a worldwide context. The CIAOW study (Complicated Intra-Abdominal infection Observational Worldwide Study) is a multicenter observational study currently underway in 57 medical institutions worldwide. The study includes patients undergoing surgery or interventional drainage to address complicated intra-abdominal infections. This preliminary report includes all data from almost the first two months of the six-month study period. Patients who met inclusion criteria with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study. 702 patients with a mean age of 49.2 years (range 18-98) were enrolled in the study. 272 patients (38.7%) were women and 430 (62.3%) were men. Among these patients, 615 (87.6%) were affected by community-acquired IAIs while the remaining 87 (12.4%) suffered from healthcare-associated infections. Generalized peritonitis was observed in 304 patients (43.3%), whereas localized peritonitis or abscesses was registered in 398 (57.7%) patients.The overall mortality rate was 10.1% (71/702). The final results of the CIAOW Study will be published following the conclusion of the study period in March 2013.

Role of amoxicillin serum levels for successful prophylaxis of experimental endocarditis due to tolerant streptococci.

The importance of amoxicillin serum profiles for successful prophylaxis of experimental endocarditis in rats was assessed. Animals with catheter-induced vegetations were challenged intravenously with large inocula of Streptococcus sanguis and received one of the following amoxicillin dosages: single or multiple bolus injection of 40 mg/kg; 40 mg/kg administered as a continuous infusion over 12 h; or either 9 or 18 mg/kg administered over 12 or 24 h, respectively. The regimen producing a single transient high peak serum level failed to prevent experimental endocarditis; in contrast, a second injection 6 h after the first resulted in successful prophylaxis. Likewise, the three regimens of continuous, relatively low-dose regimens prevented infections. Thus, the most important parameter for successful prophylaxis was the duration of inhibitory concentration of the drug in the serum. The total dose of antibiotic, the peak serum levels, or the area-under-the-curve values were not predictive of successful prophylaxis.

Molecular markers and genetic diversity of Plasmodium vivax

Enhanced understanding of the transmission dynamics and population genetics for Plasmodium vivax is crucial in predicting the emergence and spread of novel parasite phenotypes with major public health implications, such as new relapsing patterns, drug resistance and increased virulence. Suitable molecular markers are required for these population genetic studies. Here, we focus on two groups of molecular markers that are commonly used to analyse natural populations of P. vivax. We use markers under selective pressure, for instance, antigen-coding polymorphic genes, and markers that are not under strong natural selection, such as most minisatellite and microsatellite loci. First, we review data obtained using genes encoding for P. vivax antigens: circumsporozoite protein, merozoite surface proteins 1 and 3α, apical membrane antigen 1 and Duffy binding antigen. We next address neutral or nearly neutral molecular markers, especially microsatellite loci, providing a complete list of markers that have already been used in P. vivax populations studies. We also analyse the microsatellite loci identified in the P. vivax genome project. Finally, we discuss some practical uses for P. vivax genotyping, for example, detecting multiple-clone infections and tracking the geographic origin of isolates.

Sentinel network for monitoring in vitro susceptibility of Plasmodium falciparum to antimalarial drugs in Colombia: a proof of concept

Drug resistance is one of the principal obstacles blocking worldwide malaria control. In Colombia, malaria remains a major public health concern and drug-resistant parasites have been reported. In vitro drug susceptibility assays are a useful tool for monitoring the emergence and spread of drug-resistant Plasmodium falciparum. The present study was conducted as a proof of concept for an antimalarial drug resistance surveillance network based on in vitro susceptibility testing in Colombia. Sentinel laboratories were set up in three malaria endemic areas. The enzyme linked immunosorbent assay-histidine rich protein 2 and schizont maturation methods were used to assess the susceptibility of fresh P. falciparum isolates to six antimalarial drugs. This study demonstrates that an antimalarial drug resistance surveillance network based on in vitro methods is feasible in the field with the participation of a research institute, local health institutions and universities. It could also serve as a model for a regional surveillance network. Preliminary susceptibility results showed widespread chloroquine resistance, which was consistent with previous reports for the Pacific region. However, high susceptibility to dihydroartemisinin and lumefantrine compounds, currently used for treatment in the country, was also reported. The implementation process identified critical points and opportunities for the improvement of network sustainability strategies.

Complicated intra-abdominal infections in Europe: a comprehensive review of the CIAO study.

The CIAO Study ("Complicated Intra-Abdominal infection Observational" Study) is a multicenter investigation performed in 68 medical institutions throughout Europe over the course of a 6-month observational period (January-June 2012).Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study.2,152 patients with a mean age of 53.8 years (range: 4-98 years) were enrolled in the study. 46.3% of the patients were women and 53.7% were men. Intraperitoneal specimens were collected from 62.2% of the enrolled patients, and from these samples, a variety of microorganisms were collectively identified.The overall mortality rate was 7.5% (163/2.152).According to multivariate analysis of the compiled data, several criteria were found to be independent variables predictive of patient mortality, including patient age, the presence of an intestinal non-appendicular source of infection (colonic non-diverticular perforation, complicated diverticulitis, small bowel perforation), a delayed initial intervention (a delay exceeding 24 hours), sepsis and septic shock in the immediate post-operative period, and ICU admission.Given the sweeping geographical distribution of the participating medical centers, the CIAO Study gives an accurate description of the epidemiological, clinical, microbiological, and treatment profiles of complicated intra-abdominal infections (IAIs) throughout Europe.

HIV-1 tropism and CD4 T lymphocyte recovery in a prospective cohort of patients initiating HAART in Ribeirão Preto, Brazil

While human immunodeficiency virus (HIV)-1 chemokine co-receptors 5 tropism and the GWGR motif in the envelope third variable region (V3 loop) have been associated with a slower disease progression, their influence on antiretroviral response remains unclear. The impact of baseline V3 characteristics on treatment response was evaluated in a randomised, double blind, prospective cohort study with patients initiating highly active antiretroviral therapy with lopinavir or efavirenz plus azithothymidine/3TC (1:1) over 48 weeks. Similar virological and immunological responses were observed for both treatment regimens. The 43 individuals had a mean baseline CD4 T cell count of 119 cells/mm³ [standard deviation (SD) = 99] and a mean viral load of 5.09 log10 copies/mL (SD = 0.49). The GWGR motif was not associated with a CD4 T cell response, but predicted R5 tropism by the geno2pheno[clinical20%] algorithm correlated with higher CD4 T cell levels at all monitoring points (p < 0.05). Moreover, higher false-positive rates (FPR) values from this analysis revealed a strong correlation with CD4 T cell recovery (p < 0.0001). Transmitted drug resistance mutations, documented in 3/41 (7.3%) cases, were unrelated to the assigned antiretroviral regimen and had no impact on patient outcomes. In conclusion, naÏve HIV-1 R5 infected patients exhibited higher CD4 T cell counts at baseline; this difference was sustained throughout therapy. The geno2pheno[clinical] option FPR positively correlated with CD4 T cell gain and may be useful in predicting CD4 T cell recovery.

Combatir la resistencia a los antimicrobianos, lema del día mundial de la salud 2011

Boletín semanal para profesionales sanitarios de la Secretaría General de Salud Pública y Participación Social de la Consejería de Salud

Maladies infectieuses [Infectious diseases].

The recommendations for the treatment of gonorrhea have been changed: ceftriaxone 500 mg IM plus azithromycin 1 g PO is recommended. Prophylaxis of recurrent cellulitis with penicillin 250 mg 2 x/d PO may be considered. E. coli ESBL does not require contact isolation anymore. Fecal transplantation seems so far to be the most effective treatment of recurrent C. dificile. Two new respiratory viruses, Middle East Coronavirus (MERS-CoV) and avian-origin Influenza A (H7N9) have been reported. Oral valganciclovir treatment reduces the risk of hearing loss in congenital CMV infection. An outbreak of mould infections of the central nervous system has been described in the United States following injection of contaminated steroids.

The activity of echinocandins, amphotericin B and voriconazole against fluconazole-susceptible and fluconazole-resistant Brazilian Candida glabrata isolates

The extensive use of azole antifungal agents has promoted the resistance of Candida spp to these drugs. Candida glabrata is a problematic yeast because it presents a high degree of primary or secondary resistance to fluconazole. In Brazil, C. glabrata has been less studied than other species. In this paper, we compared the activity of three major classes of antifungal agents (azoles, echinocandins and polyenes) against fluconazole-susceptible (FS) and fluconazole-resistant (FR) C. glabrata strains. Cross-resistance between fluconazole and voriconazole was remarkable. Among the antifungal agents, the echinocandins were the most effective against FS and FR C. glabrata and micafungin showed the lowest minimal inhibitory concentrations.

The level of ascorbate peroxidase is enhanced in benznidazole-resistant populations of Trypanosoma cruzi and its expression is modulated by stress generated by hydrogen peroxide

Ascorbate peroxidases (APX) are class I heme-containing enzymes that convert hydrogen peroxide into water molecules. The gene encoding APX has been characterized in 11 strains of Trypanosoma cruzi that are sensitive or resistant to benznidazole (BZ). Bioinformatic analysis revealed the presence of two complete copies of the T. cruzi APX (TcAPX) gene in the genome of the parasite, while karyotype analysis showed that the gene was present in the 2.000-kb chromosome of all of the strains analyzed. The sequence of TcAPX exhibited greater levels of similarity to those of orthologous enzymes from Leishmania spp than to APXs from the higher plant Arabidopsis thaliana. Northern blot and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed no significant differences in TcAPX mRNA levels between the T. cruzi strains analyzed. On the other hand, Western blots showed that the expression levels of TcAPX protein were, respectively, two and three-fold higher in T. cruzi populations with in vitro induced (17 LER) and in vivo selected (BZR) resistance to BZ, in comparison with their corresponding susceptible counterparts. Moreover, the two BZ-resistant populations exhibited higher tolerances to exogenous hydrogen peroxide than their susceptible counterparts and showed TcAPX levels that increased in a dose-dependent manner following exposure to 100 and 200 µM hydrogen peroxide.

Munc18c in adipose tissue is downregulated in obesity and is associated with insulin.

OBJECTIVE Munc18c is associated with glucose metabolism and could play a relevant role in obesity. However, little is known about the regulation of Munc18c expression. We analyzed Munc18c gene expression in human visceral (VAT) and subcutaneous (SAT) adipose tissue and its relationship with obesity and insulin. MATERIALS AND METHODS We evaluated 70 subjects distributed in 12 non-obese lean subjects, 23 overweight subjects, 12 obese subjects and 23 nondiabetic morbidly obese patients (11 with low insulin resistance and 12 with high insulin resistance). RESULTS The lean, overweight and obese persons had a greater Munc18c gene expression in adipose tissue than the morbidly obese patients (p<0.001). VAT Munc18c gene expression was predicted by the body mass index (B = -0.001, p = 0.009). In SAT, no associations were found by different multiple regression analysis models. SAT Munc18c gene expression was the main determinant of the improvement in the HOMA-IR index 15 days after bariatric surgery (B = -2148.4, p = 0.038). SAT explant cultures showed that insulin produced a significant down-regulation of Munc18c gene expression (p = 0.048). This decrease was also obtained when explants were incubated with liver X receptor alpha (LXRα) agonist, either without (p = 0.038) or with insulin (p = 0.050). However, Munc18c gene expression was not affected when explants were incubated with insulin plus a sterol regulatory element-binding protein-1c (SREBP-1c) inhibitor (p = 0.504). CONCLUSIONS Munc18c gene expression in human adipose tissue is down-regulated in morbid obesity. Insulin may have an effect on the Munc18c expression, probably through LXRα and SREBP-1c.

A study of multidrug-resistant tuberculosis in risk groups in the city of Santos, São Paulo, Brazil

Monitoring the extent of and trends in multidrug-resistant tuberculosis (MDR-TB) is a priority of the Brazilian National Tuberculosis Control Programme. The current study aimed to estimate the incidence of MDR-TB, describe the profile of TB drug resistance in risk groups and examine whether screening for MDR-TB adhered to the recommended guidelines. A descriptive study that examined diagnosed cases of pulmonary TB was conducted in the city of Santos, Brazil, between 2000-2004. Of the 2,176 pulmonary TB cases studied, 671 (30.8%) met the criteria for drug sensitivity testing and, of these cases, 31.7% (213/671) were tested. Among the tested cases, 9.4% were resistant to one anti-TB drug and 15% were MDR. MDR was observed in 11.6% of 86 new TB cases and 17.3% of 127 previously treated cases. The average annual incidence of MDR-TB was 1.9 per 100,000 inhabitants-years. The extent of known MDR-TB in the city of Santos is high, though likely to be underestimated. Our study therefore indicates an inadequate adherence to the guidelines for MDR-TB screening and suggests the necessity of alternative strategies of MDR-TB surveillance.

MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations.

The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML.

Fast test for assessing the susceptibility of Mycobacterium tuberculosis to isoniazid and rifampin by real-time PCR

Mycobacterium tuberculosis is the bacterium that causes tuberculosis (TB), a leading cause of death from infectious disease worldwide. Rapid diagnosis of resistant strains is important for the control of TB. Real-time polymerase chain reaction (RT-PCR) assays may detect all of the mutations that occur in the M. tuberculosis 81-bp core region of the rpoB gene, which is responsible for resistance to rifampin (RIF) and codon 315 of the katG gene and the inhA ribosomal binding site, which are responsible for isoniazid (INH). The goal of this study was to assess the performance of RT-PCR compared to traditional culture-based methods for determining the drug susceptibility of M. tuberculosis. BACTEC TM MGIT TM 960 was used as the gold standard method for phenotypic drug susceptibility testing. Susceptibilities to INH and RIF were also determined by genotyping of katG, inhA and rpoB genes. RT-PCR based on molecular beacons probes was used to detect specific point mutations associated with resistance. The sensitivities of RT-PCR in detecting INH resistance using katG and inhA targets individually were 55% and 25%, respectively and 73% when combined. The sensitivity of the RT-PCR assay in detecting RIF resistance was 99%. The median time to complete the RT-PCR assay was three-four hours. The specificities for tests were both 100%. Our results confirm that RT-PCR can detect INH and RIF resistance in less than four hours with high sensitivity.