An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: study protocol for a randomized controlled trial.

BACKGROUND: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined. METHODS/DESIGN: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient's Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen. DISCUSSION: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01918397 . Registered on 5 August 2013.

Substance Use and Adherence Among People Living with HIV/AIDS Receiving cART in Latin America.

This cross-sectional study describes substance use prevalence and its association with combination antiretroviral therapy (cART) adherence among 3343 individuals receiving care at HIV clinics in Argentina, Brazil, Chile, Honduras, Mexico, and Peru. A rapid screening tool evaluated self-reported 7-day recall of alcohol, marijuana, cocaine, heroin, and methamphetamine use, and missed cART doses. Overall, 29.3 % individuals reported having ≥1 alcoholic drinks, 5.0 % reported any illicit drug use and 17.0 % reported missed cART doses. In the logistic regression model, compared to no substance use, alcohol use [adjusted odds ratio (AOR) = 2.46, 95 % confidence interval (CI): 1.99-3.05], illicit drug use (AOR = 3.57, 95 % CI: 2.02-6.30), and using both alcohol and illicit drugs (AOR = 4.98, 95 % CI: 3.19-7.79) were associated with missed cART doses. The associations between substance use and likelihood of missing cART doses point to the need of targeting alcohol and illicit drug use to improve adherence among people living with HIV in Latin America.

Ascorbic acid has superior ex vivo antiproliferative, cell death-inducing and immunomodulatory effects over IFN-α in HTLV-1-associated myelopathy.

BACKGROUND: Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP. PRINCIPAL FINDINGS: Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes. CONCLUSIONS: In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.

Self-reported risks for multiple-drug resistance among new tuberculosis cases: implications for drug susceptibility screening and treatment.

BACKGROUND: Multiple drug-resistance in new tuberculosis (TB) cases accounts for the majority of all multiple drug-resistant TB (MDR-TB) worldwide. Effective control requires determining which new TB patients should be tested for MDR disease, yet the effectiveness of global screening recommendations of high-risk groups is unknown. METHODS: Sixty MDR-TB cases with no history of previous TB treatment, 80 drug-sensitive TB and 80 community-based controls were recruited in Lima, Peru between August and December, 2008 to investigate whether recommended screening practices identify individuals presenting with MDR-TB. Odd ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression to study the association of potential risk factors with case/control variables. RESULTS: MDR-TB cases did not differ from drug-sensitive TB and community controls in rates of human immunodeficiency virus infection, reported hospital or prison visits in the 3 years prior to diagnosis. MDR-TB cases were more likely than drug-sensitive TB controls to have had a recent MDR-TB household contact (OR 4.66, (95% CI 1.56-13.87)); however, only 15 cases (28.3%) reported this exposure. In multivariate modeling, recent TB household contact, but not contact with an MDR-TB case, remained predictive of MDR-TB, OR 7.47, (95% CI 1.91-29.3). Living with a partner rather than parents was associated with a lower risk of MDR-TB, OR 0.15, (95% CI 0.04-0.51). CONCLUSION: Targeted drug susceptibility testing (DST) linked to reported MDR-TB contact or other high-risk exposures does not identify the majority of new TB cases with MDR disease in Lima where it is endemic. All new TB cases should be screened with DST to identify MDR patients. These findings are likely applicable to other regions with endemic MDR-TB.

Outbreak of persistent cutaneous abscesses due to Mycobacterium chelonae after mesotherapy sessions, Lima, Peru

Outbreaks of rapidly growing mycobacteria have been occasionally described. The article reports an outbreak of cutaneous abscesses due to Mycobacterium chelonae following mesotherapy in Lima, Peru. From December 2004 through January 2005, 35 subjects who had participated in mesotherapy training sessions presented with persistent cutaneous abscesses. Thirteen (37 percent) of these suspected cases consented to underwent clinical examination. Skin punch-biopsies were collected from suspicious lesions and substances injected during mesotherapy were analyzed. Suspected cases were mainly young women and lesions included subcutaneous nodules, abscesses and ulcers. Mycobacterium chelonae was isolated from four patients and from a procaine vial. In conclusion, it is important to consider mesotherapy as a potential source of rapidly growing mycobacteria infections.

Surtos de micobactérias de crescimento rápido têm sido relatados ocasionalmente. O estudo relata um surto de abscessos cutâneos por Mycobacterium chelonae após sessões de mesoterapia em Lima, Peru. De dezembro de 2004 a janeiro de 2005, 35 pessoas que haviam passado por sessões de mesoterapia apresentaram esses abscessos cutâneos. Treze (37 por cento) desses casos suspeitos concordaram em realizar exames clínicos. Foram realizadas biópsias de punção de pele de lesões suspeitas e examinadas substâncias injetadas durante a mesoterapia. Os casos suspeitos eram predominantemente mulheres jovens e as lesões incluíram nódulos subcutâneos, abscessos e úlceras. Mycobacterium chelonae foi isolada de quatro pacientes e de um frasco de procaína. Em conclusão, é importante considerar a mesoterapia como fonte potencial de infecções de micobactérias de crescimento rápido.

Outbreak of persistent cutaneous abscesses due to Mycobacterium chelonae after mesotherapy sessions, Lima, Peru.

Outbreaks of rapidly growing mycobacteria have been occasionally described. The article reports an outbreak of cutaneous abscesses due to Mycobacterium chelonae following mesotherapy in Lima, Peru. From December 2004 through January 2005, 35 subjects who had participated in mesotherapy training sessions presented with persistent cutaneous abscesses. Thirteen (37%) of these suspected cases consented to undergo clinical examination. Skin punch-biopsies were collected from suspicious lesions and substances injected during mesotherapy were analyzed. Suspected cases were mainly young women and lesions included subcutaneous nodules, abscesses and ulcers. Mycobacterium chelonae was isolated from four patients and from a procaine vial. In conclusion, it is important to consider mesotherapy as a potential source of rapidly growing mycobacteria infections.

A double-blind randomized controlled trial of antenatal mebendazole to reduce low birthweight in a hookworm-endemic area of Peru.

OBJECTIVE: To assess the effect on birthweight of antenatal mebendazole plus iron vs. placebo plus iron in a highly hookworm-endemic area. METHODS: Double-blind, randomized controlled trial set in rural and peri-urban communities in the Peruvian Amazon region. A total of 1042 second trimester pregnant women between the ages of 18 and 44 years were recruited from April to November 2003, and followed to July 2004. Women were randomly assigned to receive either mebendazole (500 mg single dose) plus iron supplements (60 mg elemental iron daily) or placebo plus iron supplements. The primary outcome was mean infant birthweight and secondary measures included proportion of low birthweight babies and maternal anaemia. RESULTS: The prevalence of hookworm infection was 47.5%. There were no differences between intervention groups in mean birthweight (3104 g vs. 3090 g, P = 0.629), proportion of low birthweight (<2500 g; 8.1%vs. 8.7%, P = 0.755) or maternal anaemia in the third trimester [33.0% (158/479) vs. 32.3% (152/471), P = 0.815]. However, the proportion of very low birthweight (<1500 g) was significantly lower in the mebendazole group [0% (0/479) vs. 1.5% (7/471), P = 0.007]. CONCLUSIONS: This trial provides additional evidence for the use of anthelmintics, over and above iron supplementation, within antenatal care programmes in hookworm-endemic areas. Benefits of de-worming may be higher in countries not having an antenatal iron supplementation programme or where intensity of hookworm infections is higher.

Lack of risk of adverse birth outcomes after deworming in pregnant women.

BACKGROUND: Pregnant women who live in hookworm-endemic areas may benefit from deworming during their pregnancy. The benefit derives from reducing anemia, primarily iron-deficiency anemia caused by hookworm infection-attributable blood loss. Where the prevalence of hookworm is more than 20% to 30%, the World Health Organization recommends that pregnant women receive anthelminthic treatment (mebendazole, albendazole, levamisole or pyrantel) after their first trimester. The objective of this study is to report, describe and compare the occurrence of adverse birth outcomes in a large randomized, controlled trial of antenatal mebendazole (500 mg single dose) plus iron supplements versus placebo plus iron supplements conducted between April 2003 and June 2004 in the Amazon region of Peru. METHODS: Physician-recorded data on adverse birth outcomes occurring during the trial (N = 1042) were obtained. Proportions were compared using chi analysis. RESULTS: No statistically significant difference (P = 0.664) was found between the mebendazole group and the placebo group in terms of numbers of miscarriages, malformations, stillbirths, early neonatal deaths and premature babies (28 versus 31, respectively). CONCLUSIONS: The evidence provided by this large randomized, controlled trial of mebendazole administered during pregnancy indicates that deworming with mebendazole can be safely included in antenatal care programs in hookworm-endemic areas.