A Look Back at an Ongoing Problem: Shigella dysenteriae Type 1 Epidemics in Refugee Settings in Central Africa (1993–1995)

BACKGROUND: Shigella dysenteriae type 1 (Sd1) is a cause of major dysentery outbreaks, particularly among children and displaced populations in tropical countries. Although outbreaks continue, the characteristics of such outbreaks have rarely been documented. Here, we describe the Sd1 outbreaks occurring between 1993 and 1995 in 11 refugee settlements in Rwanda, Tanzania and Democratic Republic of the Congo (DRC). We also explored the links between the different types of the camps and the magnitude of the outbreaks. METHODOLOGY/PRINCIPAL FINDINGS: Number of cases of bloody diarrhea and deaths were collected on a weekly basis in 11 refugee camps, and analyzed retrospectively. Between November 1993 and February 1995, 181,921 cases of bloody diarrhea were reported. Attack rates ranged from 6.3% to 39.1% and case fatality ratios (CFRs) from 1.5% to 9.0% (available for 5 camps). The CFRs were higher in children under age 5. In Tanzania where the response was rapidly deployed, the mean attack rate was lower than in camps in the region of Goma without an immediate response (13.3% versus 32.1% respectively). CONCLUSIONS/SIGNIFICANCE: This description, and the areas where data is missing, highlight both the importance of collecting data in future epidemics, difficulties in documenting outbreaks occurring in complex emergencies and most importantly, the need to assure that minimal requirements are met

Evaluating drug resistance in visceral leishmaniasis: the challenges.

For decades antimonials were the drugs of choice for the treatment of visceral leishmaniasis (VL), but the recent emergence of resistance has made them redundant as first-line therapy in the endemic VL region in the Indian subcontinent. The application of other drugs has been limited due to adverse effects, perceived high cost, need for parenteral administration and increasing rate of treatment failures. Liposomal amphotericin B (AmB) and miltefosine (MIL) have been positioned as the effective first-line treatments; however, the number of monotherapy MIL-failures has increased after a decade of use. Since no validated molecular resistance markers are yet available, monitoring and surveillance of changes in drug sensitivity and resistance still depends on standard phenotypic in vitro promastigote or amastigote susceptibility assays. Clinical isolates displaying defined MIL- or AmB-resistance are still fairly scarce and fundamental and applied research on resistance mechanisms and dynamics remains largely dependent on laboratory-generated drug resistant strains. This review addresses the various challenges associated with drug susceptibility and -resistance monitoring in VL, with particular emphasis on the choice of strains, susceptibility model selection and standardization of procedures with specific read-out parameters and well-defined threshold criteria. The latter are essential to support surveillance systems and safeguard the limited number of currently available antileishmanial drugs

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in bihar, India:a retrospective cohort study

Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Learning object relationships which determine the outcome of actions

Peer reviewedPublisher PD

The Suppressor of AAC2 Lethality SAL1 Modulates Sensitivity of Heterologously Expressed Artemia ADP/ATP Carrier to Bongkrekate in Yeast

The ADP/ATP carrier protein (AAC) expressed in Artemia franciscana is refractory to bongkrekate. We generated two strains of Saccharomyces cerevisiae where AAC1 and AAC3 were inactivated and the AAC2 isoform was replaced with Artemia AAC containing a hemagglutinin tag (ArAAC-HA). In one of the strains the suppressor of ΔAAC2 lethality, SAL1, was also inactivated but a plasmid coding for yeast AAC2 was included, because the ArAACΔsal1Δ strain was lethal. In both strains ArAAC-HA was expressed and correctly localized to the mitochondria. Peptide sequencing of ArAAC expressed in Artemia and that expressed in the modified yeasts revealed identical amino acid sequences. The isolated mitochondria from both modified strains developed 85% of the membrane potential attained by mitochondria of control strains, and addition of ADP yielded bongkrekate-sensitive depolarizations implying acquired sensitivity of ArAAC-mediated adenine nucleotide exchange to this poison, independent from SAL1. However, growth of ArAAC-expressing yeasts in glycerol-containing media was arrested by bongkrekate only in the presence of SAL1. We conclude that the mitochondrial environment of yeasts relying on respiratory growth conferred sensitivity of ArAAC to bongkrekate in a SAL1-dependent manner. © 2013 Wysocka-Kapcinska et al

In vitro and in vivo antileishmanial efficacy of a combination therapy of diminazene and artesunate against Leishmania donovani in BALB /c mice

The in vitro and in vivo activity of diminazene (Dim), artesunate (Art) and combination of Dim and Art (Dim-Art) against Leishmania donovani was compared to reference drug; amphotericin B. IC50 of Dim-Art was found to be $2.28 \pm 0.24 \mu$ g/mL while those of Dim and Art were $9.16 \pm 0.3 \mu$ g/mL and $4.64 \pm 0.48 \mu$ g/mL respectively. The IC50 for Amphot B was $0.16 \pm 0.32 \mu$ g/mL against stationary-phase promastigotes. In vivo evaluation in the L. donovani BALB/c mice model indicated that treatments with the combined drug therapy at doses of 12.5 mg/kg for 28 consecutive days significantly ($p < 0.001$) reduced parasite burden in the spleen as compared to the single drug treatments given at the same dosages. Although parasite burden was slightly lower ($p < 0.05$) in the Amphot B group than in the Dim-Art treatment group, the present study demonstrates the positive advantage and the potential use of the combined therapy of Dim-Art over the constituent drugs, Dim or Art when used alone. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.Comment: 4 Pages, 3 Figure

Using European travellers as an early alert to detect emerging pathogens in countries with limited laboratory resources

BACKGROUND: The volume, extent and speed of travel have dramatically increased in the past decades, providing the potential for an infectious disease to spread through the transportation network. By collecting information on the suspected place of infection, existing surveillance systems in industrialized countries may provide timely information for areas of the world without adequate surveillance currently in place. We present the results of a case study using reported cases of Shigella dysenteriae serotype 1 (Sd1) in European travellers to detect "events" of Sd1, related to either epidemic cases or endemic cases in developing countries. METHODS: We identified papers from a Medline search for reported events of Sd1 from 1940 to 2002. We requested data on shigella infections reported to the responsible surveillance entities in 17 European countries. Reports of Sd1 from the published literature were then compared with Sd1 notified cases among European travellers from 1990 to 2002. RESULTS: Prior to a large epidemic in 1999–2000, no cases of Sd1 had been identified in West Africa. However, if travellers had been used as an early warning, Sd1 could have been identified in this region as earlier as 1992. CONCLUSION: This project demonstrates that tracking diseases in European travellers could be used to detect emerging disease in developing countries. This approach should be further tested with a view to the continuous improvement of national health surveillance systems and existing European networks, and may play a significant role in aiding the international public health community to improve infectious disease control

A comparative, randomized clinical trial of artemisinin/naphtoquine twice daily one day versus artemether/lumefantrine six doses regimen in children and adults with uncomplicated falciparum malaria in Côte d'Ivoire

<p>Abstract</p> <p>Background</p> <p>Drug resistance in <it>Plasmodium falciparum </it>poses a major threat to malaria control. Combination anti-malarial therapy, including artemisinins, has been advocated to improve efficacy and limit the spread of resistance. The fixed combination of oral artemether-lumefantrine (AL) is highly effective and well-tolerated. Artemisinin/naphtoquine (AN) is a fixed-dose ACT that has recently become available in Africa.</p> <p>The objectives of the study were to compare the efficacy and safety of AN and AL for the treatment of uncomplicated <it>falciparum </it>malaria in a high transmission-intensity site in Ivory Coast.</p> <p>Methods</p> <p>We enrolled 122 participants aged 6 months or more with uncomplicated <it>falciparum </it>malaria. Participants were randomized to receive either artemisinin/naphtoquine or artemether/lumefantrine with variable dose according to their weight. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection.</p> <p>Results</p> <p>Among 125 participants enrolled, 123 (98.4%) completed follow-up. Clinical evaluation of the 123 participants showed that cumulative PCR-uncorrected cure rate on day 28 was 100% for artemisinin/naphtoquine and 98.4% for artemether/lumefantrine. Both artemisinin-based combinations effected rapid fever and parasite clearance.</p> <p>Interpretation</p> <p>These data suggest that Arco^®could prove to be suitable for use as combination antimalarial therapy. Meanwhile, pharmacokinetic studies and further efficacy assessment should be conducted before its widespread use can be supported.</p

Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.

BACKGROUND: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine. METHODS AND FINDINGS: Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers' currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3-44.3) ng/ml in small children compared to 38.1 (25.8-56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers' recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals. CONCLUSIONS: The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015)

Dipstick Test for Rapid Diagnosis of Shigella dysenteriae 1 in Bacterial Cultures and Its Potential Use on Stool Samples

International audienceBACKGROUND: We describe a test for rapid detection of S. dysenteriae 1 in bacterial cultures and in stools, at the bedside of patients. METHODOLOGY/PRINCIPAL FINDINGS: The test is based on the detection of S. dysenteriae 1 lipopolysaccharide (LPS) using serotype 1-specific monoclonal antibodies coupled to gold particles and displayed on a one-step immunochromatographic dipstick. A concentration as low as 15 ng/ml of LPS was detected in distilled water and in reconstituted stools in 10 minutes. In distilled water and in reconstituted stools, an unequivocal positive reaction was obtained with 1.6×10⁶ CFU/ml and 4.9×10⁶ CFU/ml of S. dysenteriae 1, respectively. Optimal conditions to read the test have been determined to limit the risk of ambiguous results due to appearance of a faint yellow test band in some negative samples. The specificity was 100% when tested with a battery of Shigella and unrelated strains in culture. When tested on 328 clinical samples in India, Vietnam, Senegal and France by laboratory technicians and in Democratic Republic of Congo by a field technician, the specificity (312/316) was 98.7% (95% CI:96.6-99.6%) and the sensitivity (11/12) was 91.7% (95% CI:59.8-99.6%). Stool cultures and the immunochromatographic test showed concordant results in 98.4 % of cases (323/328) in comparative studies. Positive and negative predictive values were 73.3% (95% CI:44.8-91.1%) and 99.7% (95% CI:98-100%). CONCLUSION: The initial findings presented here for a simple dipstick-based test to diagnose S. dysenteriae 1 demonstrates its promising potential to become a powerful tool for case management and epidemiological surveys