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Nicholas J White

Publications and source records attributed to Nicholas J White.

At least 73 records · Page 4Linked to original sources
PubMed2005

Trimethoprim/sulfamethoxazole resistance in clinical isolates of Burkholderia pseudomallei.

OBJECTIVES: Trimethoprim/sulfamethoxazole is commonly used to treat melioidosis. Antimicrobial susceptibility testing using the disc diffusion method is commonly used in melioidosis-endemic areas, but may overestimate resistance to trimethoprim/sulfamethoxazole. PATIENTS AND METHODS: We performed disc diffusion and Etest on isolates from the first positive culture for all patients presenting to Sappasithiprasong Hospital, Ubon Ratchathani, Thailand, with culture-confirmed melioidosis between 1992 and 2003. RESULTS: The estimated resistance rate for 1976 clinical Burkholderia pseudomallei isolates was 13% by Etest and 71% by disc diffusion. All isolates classed as either susceptible (n=358) or as having intermediate resistance (n=218) on disc diffusion were susceptible by Etest. Only 258 of the 1400 (18%) isolates classed as resistant on disc diffusion were resistant by Etest. CONCLUSIONS: Disc diffusion testing of B. pseudomallei may be useful as a limited screening tool in resource poor settings. Isolates assigned as 'susceptible' or 'intermediate' by disc diffusion may be viewed as 'susceptible'; those assigned as 'resistant' require further evaluation by MIC methodology.

Anti-Infective Agents↗
PubMed2005

Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1.

BACKGROUND: Plasmodium vivax is the second most prevalent malaria parasite affecting more than 75 million people each year, mostly in South America and Asia. In addition to major morbidity this parasite is associated with relapses and a reduction in birthweight. The emergence and spread of drug resistance in Plasmodium falciparum is a major factor in the resurgence of this parasite. P. vivax resistance to drugs has more recently emerged and monitoring the situation would be helped, as for P. falciparum, by molecular methods that can be used to characterize parasites in field studies and drug efficacy trials. METHODS: Practical PCR genotyping protocols based on polymorphic loci present in two P. vivax genetic markers, Pvcs and Pvmsp1, were developed. The methodology was evaluated using 100 P. vivax isolates collected in Thailand. RESULTS AND DISCUSSION: Analysis revealed that P. vivax populations in Thailand are highly diverse genetically, with mixed genotype infections found in 26 % of the samples (average multiplicity of infection = 1.29). A large number of distinguishable alleles were found for the two markers, 23 for Pvcs and 36 for Pvmsp1. These were generally randomly distributed amongst the isolates. A total of 68 distinct genotypes could be enumerated in the 74 isolates with a multiplicity of infection of 1. CONCLUSION: These results indicate that the genotyping protocols presented can be useful in the assessment of in vivo drug efficacy clinical trials conducted in endemic areas and for epidemiological studies of P. vivax infections.

Alleles↗
PubMed2005

IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis.

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.

Cryptococcus neoformans↗
PubMed2005

Population biology and antimalarial resistance: The transmission of antimalarial drug resistance in Plasmodium falciparum.

Malaria morbidity and mortality continue to increase across sub-Saharan Africa. This is largely as a result of the continued use of chloroquine and sulfadoxine-pyrimethamine, despite widespread resistance. Although eliminating the asexual stages of Plasmodium falciparum is the focus of treatment of individual symptomatic patients, at a population level, reducing the carriage of gametocytes - the sexual stage responsible for infection of the mosquito vector - is necessary to limit the transmission of malaria parasites and the spread of antimalarial resistance. The probability of a mosquito being infected depends on the prevalence, duration and density of viable gametocyte carriage in the human host, although additional humoral and leukocyte factors also affect transmissibility. There is a log-sigmoid relationship between gametocyte density in the patients' blood and infectivity to the mosquito. The infectivity and thus transmission potential associated with a particular antimalarial treatment can be characterised as a function of blood gametocyte density and time, summing these over the acute and all subsequent recrudescences of that infection. Gametocyte carriage and infectivity to mosquitoes is consistently higher in patients infected with drug resistant compared with drug sensitive malaria parasites. It is the ratio of transmission potential in drug resistant versus sensitive infections that drives the spread of resistance. Early access to highly effective antimalarial treatment reduces the risk of disease progression and limits gametocyte carriage. The remarkable spread of sulfadoxine-pyrimethamine (SP) resistance across vast regions results from the very high post-treatment prevalence and density of gametocyte carriage following SP treatment. In areas of low intensity malaria transmission, the gametocyte-reducing effect of widespread use of artemisinin-based combination therapy has resulted in a sustained decrease in malaria transmission and a decrease in the spread of resistance. Malaria treatment policy should be based primarily on therapeutic efficacy against asexual stages, but should also consider transmission reduction potential. Artemisinin-based combination therapies are the only antimalarials currently available which rapidly reduce both asexual and gametocyte stages of the P. falciparum lifecycle.

Animals↗
PubMed2005

Artesunate-dapsone-proguanil treatment of falciparum malaria: genotypic determinants of therapeutic response.

The combination of chlorproguanil and dapsone is being considered as an alternative antimalarial to sulfadoxine-pyrimethamine in Africa, because of its greater efficacy against resistant parasites, and its shorter half-lives, which exert less selective pressure for the emergence of resistance. A triple artesunate-chlorproguanil-dapsone combination is under development. In a previous study of relatively low-dose chlorproguanil-dapsone in multidrug-resistant falciparum malaria in Thailand failure rates were high. Proguanil is inexpensive, widely available and very similar to chlorproguanil. The safety and efficacy of artesunate-dapsone-proguanil (artesunate 4 mg/kg, dapsone 2.5mg/kg, proguanil 8 mg/kg daily for three days), was studied prospectively in 48 Thai adult patients with acute falciparum malaria followed daily for 28 days. Eleven of these had a recrudescence of their infection. Genotyping of Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) indicated that the Pfdhfr I164L mutation was the main determinant of therapeutic outcome; all 11 failures carried this mutation (failure rate 11/37; 30%) whereas none of the 11 infections with 'wild type' 164 genotypes failed. The addition of artesunate considerably augments the antimalarial activity of the biguanide-dapsone combination, but this is insufficient for infections with parasites carrying the highly antifol-resistant Pfdhfr I164L mutation.

Adolescent↗
PubMed2005

A randomized comparison of oral chloramphenicol versus ofloxacin in the treatment of uncomplicated typhoid fever in Laos.

We conducted a randomized open trial of oral chloramphenicol (50mg/kg/day in four divided doses for 14 days) versus ofloxacin (15 mg/kg/day in two divided doses for 3 days) in 50 adults with culture-confirmed uncomplicated typhoid fever in Vientiane, Laos. Patients had been ill for a median (range) of 8 (2-30) days. All Salmonella enterica serotype typhi isolates were nalidixic acid-sensitive, four (8%) were chloramphenicol-resistant and three (6%) were multidrug-resistant. Median (range) fever clearance times were 90 (24-224) hours in the chloramphenicol group and 54 (6-93) hours in the ofloxacin group (P<0.001). One patient in the chloramphenicol group developed an ileal perforation. Three days ofloxacin was more effective than 14 days chloramphenicol for the in-patient treatment of typhoid fever, irrespective of antibiotic susceptibility, and was of similar cost.

Administration, Oral↗
PubMed2005

Stage-dependent production and release of histidine-rich protein 2 by Plasmodium falciparum.

Because of their sequestration in the microcirculation, the pathogenic late stages of Plasmodium falciparum are under-represented in peripheral blood samples from patients with falciparum malaria. Excreted products of the parasite might help to estimate this sequestered biomass. We quantified the stage-dependent production and release per parasite of P. falciparum histidine-rich protein 2 (PfHRP2) with the objective of measuring the sequestered biomass. A simple method to relate parasite stage to parasite age was developed to facilitate this. In four isolates of P. falciparum, the median (range) PfHRP2 content was 2.0fg (0.5-4.3fg) for a young ring stage infected erythrocyte, and 5.4fg (2.1-10.2fg) for the schizont stage. The amount of PfHRP2 in the parasitized erythrocyte increased most during development to the mature trophozoite stage. The median (range) amount of PfHRP2 secreted per parasite per entire erythrocytic cycle was 5.2fg (1.1-13.0fg). A median of 89% of the total PfHRP2 was excreted at the moment of schizont rupture. This assessment of the stage-dependent release of PfHRP2 is an essential prerequisite for future studies aimed at estimating the total patient parasite mass from the peripheral blood PfHRP2 concentration.

Animals↗
PubMed2005

Cerebrospinal fluid levels of markers of brain parenchymal damage in Vietnamese adults with severe malaria.

A retrospective study of cerebrospinal fluid (CSF) markers of brain parenchymal damage was conducted in Vietnamese adults with severe malaria. Three markers were analysed by immunoassays: the microtubule-associated protein tau, for degenerated axons; neuron-specific enolase (NSE), for neurons; and S100B for astrocytes. The mean concentration of tau proteins in the CSF was significantly raised in patients with severe malaria compared with controls (P=0.0003) as reported for other central nervous system diseases. By contrast, the mean concentration of NSE and S100B remained within the normal range. Tau levels were associated with duration of coma (P=0.004) and S100B was associated with convulsions (P=0.006). Concentrations of axonal and astrocyte degeneration markers also were associated with vital organ dysfunction. No association was found between the level of markers of brain parenchymal damage on admission and a fatal outcome. On admission to hospital, patients with severe malaria had biochemical evidence of brain parenchymal damage predominantly affecting axons.

Adult↗
PubMed2005

Artemisinin-based combinations.

PURPOSE OF REVIEW: Artemisinin-based combination treatments have been the mainstay of treatment for falciparum malaria in Southeast Asia for more than 10 years and are now increasingly recommended as first-line treatment throughout the rest of the world. RECENT FINDINGS: A large multicentre randomised trial conducted in East Asia has shown a 35% reduction in mortality from severe malaria following treatment with parenteral artesunate compared with quinine. There is increasing evidence that artemisinin-based combination treatments are safe and rapidly effective. Artemether-lumefantrine (six doses) has been shown to be very effective in large trials reported from Uganda and Tanzania. A once daily three-dose treatment of dihydroartemisinin piperaquine, a newer fixed combination, was a highly efficacious and well tolerated treatment for multi-drug resistant falciparum malaria in Southeast Asia. SUMMARY: Early diagnosis and treatment of uncomplicated malaria with effective drugs remains a priority as part of a comprehensive malaria control strategy. Artemisinin-based combination treatments have consistently been shown to be highly effective and safe. The challenge is to make them accessible in tropical countries.

Adult↗
PubMed2005

How do patients use antimalarial drugs? A review of the evidence.

Patient adherence is a major determinant of the therapeutic response to antimalarial drugs, as most treatments are taken at home without medical supervision. With the introduction of new, effective, but more expensive antimalarials, there is concern that the high levels of efficacy observed in clinical trials may not be translated into effectiveness in the normal context of use. We reviewed available published evidence on adherence to antimalarial drugs and community drug usage; 24 studies were identified of which nine were 'intervention' studies, seven were classified as 'outcome studies', and the remainder were purely descriptive studies of antimalarial adherence. Definitions, methods, and results varied widely. Adherence was generally better when treatments were effective, and was improved by interventions focusing on provider knowledge and behaviour, packaging, and provision of correct dosages. There is insufficient information on this important subject, and current data certainly do not justify extrapolation from results with ineffective drugs to new effective treatments. Research in this area would benefit from of standardization of methodologies and the application of pharmacokinetic modelling.

Antimalarials↗
PubMed2005

Destabilisation and subsequent lysis of human erythrocytes induced by Plasmodium falciparum haem products.

In falciparum malaria, both infected and uninfected red cells have structural and functional alterations. To investigate the mechanisms of these modifications, we studied the effects of two Plasmodium falciparum haem products (haematin and malaria pigment in the synthetic form beta-haematin) on isolated human red blood cells (RBCs) and purified RBC ghosts. A dose- and time-dependent incorporation of haematin into RBC ghosts and intact cells was observed, which was in proportion to the extent of haematin- induced haemolysis. RBCs pre-incubated with haematin were more sensitive to haemolysis induced by hypotonic shock, low pH, H2O2 or haematin itself. Haemolysis was not related to membrane lipid peroxidation and only partially to oxidation of protein sulphydryl groups and it could not be prevented by scavengers of lipid peroxidation or hydroperoxide groups. N-acetylcysteine partly protected the oxidation of SH groups and significantly reduced haemolysis. In contrast, beta-haematin was neither haemolytic nor oxidative towards protein sulphydryl groups. Beta-haematin did destabilise the RBC membrane, but to a lesser extent than haematin, inducing increased susceptibility to lysis caused by hypotonic medium, H2O2 or haematin. This study suggests that the destabilising effect of haematin and, to a much less extent, beta-haematin on the RBC membrane does not result from oxidative damage of membrane lipids but from direct binding or incorporation which may affect the reciprocal interactions between the membrane and cytoskeleton proteins. These changes could contribute to the reduced red cell deformability associated with severe malaria.

Animals↗
PubMed2005

Open-label randomized trial of oral trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol compared with trimethoprim-sulfamethoxazole and doxycycline for maintenance therapy of melioidosis.

Melioidosis (infection caused by Burkholderia pseudomallei) requires a prolonged course of oral antibiotics following initial intravenous therapy to reduce the risk of relapse after cessation of treatment. The current recommendation is a four-drug regimen (trimethoprim [TMP], sulfamethoxazole [SMX], doxycycline, and chloramphenicol) and a total treatment time of 12 to 20 weeks. Drug side effects are common; the aim of this study was to compare the efficacy and tolerance of the four-drug regimen with a three-drug regimen (TMP-SMX and doxycycline). An open-label, randomized trial was conducted in northeast Thailand. A total of 180 adult Thai patients were enrolled, of which 91 were allocated to the four-drug regimen and 89 to the three-drug regimen. The trial was terminated early due to poor drug tolerance, particularly of the four-drug regimen. The culture-confirmed relapse rates at 1 year were 6.6% and 5.6% for the four- and three-drug regimens, respectively (P = 0.79). The three-drug regimen was better tolerated than the four-drug regimen; 36% of patients receiving four drugs and 19% of patients receiving three drugs required a switch in therapy due to side effects (P = 0.01). The duration of oral therapy was significantly associated with relapse; after adjustment for confounders, patients receiving less than 12 weeks of oral therapy had a 5.7-fold increase of relapse or death. A combination of TMP-SMX and doxycycline is as effective as and better tolerated than the conventional four-drug regimen for the oral treatment phase of melioidosis.

Adolescent↗
PubMed2005

Pitfalls in estimating piperaquine elimination.

By using a sensitive new assay, the terminal elimination half-life of the antimalarial piperaquine in a healthy volunteer was estimated to be 33 days, which is longer than estimated previously. This result illustrates the importance of extended sampling duration and sensitive assay methodologies in characterizing the disposition of slowly eliminated antimalarial drugs.

Animals↗
PubMed2005

Rapid immunofluorescence microscopy for diagnosis of melioidosis.

An immunofluorescent (IF) method that detects Burkholderia pseudomallei in clinical specimens within 10 min was devised. The results of this rapid method and those of an existing IF method were prospectively compared with the culture results for 776 specimens from patients with suspected melioidosis. The sensitivities of both IF tests were 66%, and the specificities were 99.5 and 99.4%, respectively.

Antigens, Bacterial↗
PubMed2005

Fatal Plasmodium falciparum malaria causes specific patterns of splenic architectural disorganization.

The spleen is critical for host defense against pathogens, including Plasmodium falciparum. It has a dual role, not only removing aged or antigenically altered erythrocytes from the blood but also as the major lymphoid organ for blood-borne or systemic infections. The human malaria parasite P. falciparum replicates within erythrocytes during asexual blood stages and causes repeated infections that can be associated with severe disease. In spite of the crucial role of the spleen in the innate and acquired immune response to malaria, there is little information on the pathology of the spleen in human malaria. We performed a histological and quantitative immunohistochemical study of spleen sections from Vietnamese adults dying from severe falciparum malaria and compared the findings with the findings for spleen sections from control patients and patients dying from systemic bacterial sepsis. Here we report that the white pulp in the spleens of patients dying from malaria showed a marked architectural disorganization. We observed a marked dissolution of the marginal zones with relative loss of B cells. Furthermore, we found strong HLA-DR expression on sinusoidal lining cells but downregulation on cordal macrophages. P. falciparum infection results in alterations in splenic leukocytes, many of which are not seen in sepsis.

Adult↗