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C Anthony Hart

Publications and source records attributed to C Anthony Hart.

At least 19 recordsLinked to original sources
PubMed2007

Chemokine responses are increased in HIV-infected Malawian children with invasive pneumococcal disease.

BACKGROUND: Chemokines play an important role in the recruitment and regulation of leukocyte traffic during bacterial infection. The aims of this study were to investigate the chemokine response to invasive pneumococcal disease (IPD) and to examine the influence of HIV infection on the chemokine response, pneumococcal bacterial loads, and outcome. METHODS: We prospectively studied 95 children with IPD, and blood and cerebrospinal fluid (CSF) samples were taken at admission for the determination of chemokines, interferon-gamma (IFNgamma), and pneumococcal bacterial loads. RESULTS: Plasma CXCL8 and CCL2, CSF CXCL8 and CCL4, and IFNgamma were significantly higher in HIV-infected children than in HIV-uninfected children. Blood and CSF pneumococcal bacterial loads correlated with plasma and CSF chemokines, respectively, and were higher in HIV-infected children compared with HIV-uninfected children. Among HIV-infected children, plasma concentrations of CXCL8 and CCL2 were significantly higher in nonsurvivors than in survivors, but CCL5 was significantly lower. HIV-infected and HIV-uninfected children with IPD had higher concentrations of chemokines (except CCL5) than acutely ill HIV-infected and HIV-uninfected children with no detectable bacterial infection. Male gender and low plasma CCL2 concentrations were shown to be independently associated with survival. CONCLUSIONS: Chemokines, in particular CCL2, are associated with survival in IPD and correlate with pneumococcal bacterial loads, disease presentation, and outcome.

Adolescent↗
PubMed2006

Decreasing prevalence of antimicrobial resistance in non-typhoidal Salmonella isolated from children with bacteraemia in a rural district hospital, Kenya.

We analysed 336 non-typhoidal Salmonella (NTS) isolated from children <13 years of age with bacteraemia admitted to a rural district hospital in Kenya from 1994 to 2005. Pulsed-field gel electrophoresis was used to determine genetic relatedness of strains, and antimicrobial susceptibility testing was also performed. Most NTS were either Salmonella enterica serovar Typhimurium (n=114; 33.9%) or S. enterica serovar Enteritidis (n=128; 38.1%), with minimal genotypic diversity over the study period. The NTS showed a remarkable decrease in levels of resistance especially to two commonly available antimicrobials (amoxicillin and co-trimoxazole), from high of 69.2% and 68.4% during 1994-1997 to 11% and 13%, respectively, in 2002-2005 (P<0.01). All NTS remained fully susceptible to cefotaxime and ciprofloxacin. Our findings show that commonly available drugs may still be useful for treatment of invasive NTS infections in this rural population.

Anti-Bacterial Agents↗
PubMed2006

Identification and characterization of ceftriaxone resistance and extended-spectrum beta-lactamases in Malawian bacteraemic Enterobacteriaceae.

OBJECTIVES: To enumerate and characterize extended-spectrum beta-lactamases (ESBLs) amongst ceftriaxone-resistant coliforms in Blantyre, Malawi, where third-generation cephalosporin use is currently highly restricted. METHODS: Over the period April 2004-March 2005 all ceftriaxone-resistant isolates from blood cultures were examined for the presence of ESBLs. Isoelectric focusing was performed on enzyme extracts. PCR and DNA sequencing of amplicons were used to identify the underlying genetic determinants responsible for the ESBL phenotypes. Transferability of the ESBL phenotypes was tested by conjugation to a susceptible Escherichia coli J53. RESULTS: Enterobacteriaceae were isolated from 1191 blood cultures, of which 19 (1.6%) were ceftriaxone resistant. Ten isolates (0.7% of all isolates) demonstrated an ESBL phenotype but only eight were characterized as three isolates were from the same patient. Genotypes SHV-11 (n = 1), SHV-12 (n = 3), SHV-27 (n = 1), TEM-63 (n = 2) and CTX-M-15 (n = 1) were detected. Plasmid transfer of the ESBL resistance phenotype was successful for all the isolates. CONCLUSIONS: In a clinical setting of minimal cephalosporin usage there is already a diversity of ESBL genotypes. Increased use of cephalosporins in this setting is likely to result in a rapid expansion of ESBLs and their prevalence will need to be carefully monitored.

Adult↗
PubMed2006

Invasive multidrug-resistant non-typhoidal Salmonella infections in Africa: zoonotic or anthroponotic transmission?

In Africa, multidrug-resistant non-typhoidal salmonellae (NTS) are one of the leading causes of morbidity and high mortality in children under 5 years of age, second in importance only to pneumococcal disease. The authors studied NTS isolates from paediatric admissions at two hospitals in Nairobi, Kenya, and followed the index cases to their homes, where rectal swabs and stools from parents and siblings, and from animals in close contact, were obtained. The majority of NTS obtained from cases were Salmonella enterica serotype Typhimurium (106 out of 193; 54.9%) and Salmonella enterica serotype Enteritidis (64; 33.2%), a significant proportion (34.2%) of which were multiply resistant to three or more antibiotics, including ampicillin, tetracycline, cotrimoxazole and chloramphenicol. Only 23.4% of NTS were fully susceptible to all 10 antibiotics tested. Of the 32 NTS obtained from contacts (nine adults and 23 children) at the homes of index cases, 21 (65.6%) isolates were similar by antibiotic-susceptibility profiles and plasmid content, and their XbaI- and SpeI-digested chromosomal DNA patterns were indistinguishable from those of the corresponding index cases. Only three out of 180 (1.7%) samples from environmental sources, including animals, soil, sewers and food, contained NTS matching those from corresponding index cases. The carriage of NTS in an asymptomatic population was represented by 6.9% of human contacts from 27 out of 127 homes sampled. This population of carriers may represent an important reservoir of NTS that would play a significant role in the epidemiology of community-acquired NTS bacteraemia in children.

Anti-Bacterial Agents↗
PubMed2006

Use of suppression subtractive hybridization to examine the accessory genome of the Liverpool cystic fibrosis epidemic strain of Pseudomonas aeruginosa.

The Liverpool epidemic strain (LES) of Pseudomonas aeruginosa has been highly successful at colonizing cystic fibrosis (CF) patients throughout the UK, has replaced previously established strains in CF patients, has caused infections of non-CF parents of CF patients, and can cause greater morbidity in CF than other strains of P. aeruginosa. Using suppression subtractive hybridization (SSH) to identify strain-specific sequences, a diagnostic test for the LES based on PCR amplification of SSH sequence PS21 had previously been developed. In this study, the SSH sequence database of LES was substantially increased, using both extension of previous sequences and new rounds of subtraction. Of 92 SSH sequences identified as present in the LES but absent from strain PAO1, 25 were assessed for prevalence amongst a strain panel consisting mainly of LES and non-LES CF isolates. Preliminary analysis of genome sequence data indicated that all SSH sequences that were LES specific or found only rarely in other strains of P. aeruginosa were present on one of three contigs. All of the SSH sequences screened were either unstable amongst LES isolates or were not completely LES specific. Rare false positives were found with the PS21 test. The authors suggest that a second PCR assay designed to detect SSH sequence LESF9 can be used to confirm the identity of the most prevalent CF epidemic lineage in the UK.

Base Sequence↗
PubMed2006

Development of a diagnostic test for the Midlands 1 cystic fibrosis epidemic strain of Pseudomonas aeruginosa.

In a previous study of isolates from cystic fibrosis (CF) patients in England and Wales, the Midlands 1 strain of Pseudomonas aeruginosa was identified as the second most common clone, representing 10% of isolates and found in nearly one-third of all CF centres [Scott, F. W. & Pitt, T. L. (2004). J Med Microbiol 53, 609-615]. Using suppression subtractive hybridization, 54 sequences were identified as present in a Midlands 1 strain but were absent from strain PAO1. The distribution of 14 of these sequences amongst representatives of Midlands 1, other CF epidemic strains and unrelated P. aeruginosa CF isolates was determined using PCR assays. Using these data, a PCR-based test was developed that was specific for the Midlands 1 clone, which was confirmed using dot-blot hybridization. By applying the test to CF isolates from a CF centre in Liverpool, a Midlands 1 clone was identified. The identity was confirmed using typing by PFGE. The PCR test should facilitate a greater understanding of the distribution of the Midlands 1 strain in the UK and elsewhere.

Cystic Fibrosis↗
PubMed2006

Use of a variable amplicon typing scheme reveals considerable variation in the accessory genomes of isolates of Burkholderia pseudomallei.

Melioidosis, a disease caused by the bacterium Burkholderia pseudomallei, is endemic in southeast Asia and northern Australia. We used suppression subtractive hybridization (SSH) to identify sequences that varied between two B. pseudomallei isolates from Australia and determined the distribution of 45 SSH-derived sequences among a panel of B. pseudomallei and B. thailandensis isolates. Sequences exhibiting variable prevalence were included in a variable amplicon typing (VAT) scheme designed to score the presence or absence of 14 PCR amplicons. VAT analysis was carried out with 48 isolates from Thailand, which were typed by multilocus sequence typing (MLST), and 44 isolates from Australia of known MLST type. The VAT scheme could be used to divide the 48 isolates from Thailand into 23 VAT types and the 44 isolates from Australia into 36 VAT types. Some of the sequences included in the VAT scheme were more commonly PCR positive among isolates from Australia than among isolates from Thailand, and vice versa. No isolate from Australia was PCR positive for genomic island 11 or a putative transposase sequence, whereas four SSH-derived sequences were far more prevalent among the Australian isolates. Analysis based on the VAT scheme indicated that the isolates clustered into groups, some of which were mainly or exclusively from one geographical origin. One cluster included Australian isolates that were mostly associated with severe disease, including rare neurological melioidosis, suggesting that the content of the accessory genome may play an important role in determining the clinical manifestation of the disease.

Bacterial Typing Techniques↗
PubMed2006

Think outside the box: extrapulmonary manifestations of severe respiratory syncytial virus infection.

Extrapulmonary effects of severe respiratory syncytial virus (RSV) infection are not uncommon. Dr Eisenhut's systematic review of extrapulmonary manifestations of severe RSV infection clearly demonstrates clinical consequences peripheral to the lung parenchyma. The extrapulmonary impact of RSV infection raises questions as to whether these are direct RSV effects (i.e., RSV infection of site-specific tissue), secondary to parenchymal lung disease and its causative respiratory failure, or the result of inflammatory mediators dispersed from the provoked respiratory epithelium.

Animals↗
PubMed2006

Risk for tuberculosis among children.

Contacts of adults with tuberculosis (TB) are at risk for infection. Tests based on interferon-gamma (IFN-gamma) expression in response to Mycobacterium tuberculosis antigens may be more sensitive than the tuberculin skin test (TST). Risk for infection was assessed by using TST and an IFN-y-based assay (QuantiFERON Gold in Tube [QFT-IT] test) for 207 children in Nigeria in 1 of 3 groups: contact with adults with smear-positive TB, contact with adults with smear-negative TB, and controls. For these 3 groups, respectively, TST results were >10 mm for 38 (49%) of 78, 13 (16%) of 83, and 6 (13%) of 46 and QFT-IT positive for 53 (74%) of 72, 8 (10%) of 81, and 4 (10.3%) of 39 (p < 0.01). Most test discrepancies were TST negative; QFT-IT positive if in contact with TB-positive persons; and TST positive, QFT-IT negative if in contact with TB-negative persons or controls. TST may underestimate risk for infection with TB in children.

Adolescent↗
PubMed2006

Human bocavirus infection among children, Jordan.

Human bocavirus was detected in 57 (18.3%) of 312 children with acute respiratory infection (ARI) who required hospitalization in Jordan. It was also detected in 30 (21.7%) of 138 children with severe ARI, in 27 (15.5%) of 174 with mild or moderate disease, and in 41 (72%) of 57 with other pathogens.

Bocavirus↗
PubMed2005

Modulation of the intracellular accumulation of saquinavir in peripheral blood mononuclear cells by inhibitors of MRP1, MRP2, P-gp and BCRP.

BACKGROUND: The efflux transporters P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRP) and breast cancer resistance protein (BCRP) limit the accumulation of antiretrovirals in cell lines but it is more important to know whether the expression of these transporters in peripheral blood mononuclear cells (PBMC) impacts cellular drug concentrations. OBJECTIVES: To study the transport and accumulation of saquinavir (SQV) in PBMC and the effects of specific inhibitors of MRP1, MRP2, P-gp and BCRP. METHODS: Transport and accumulation of [H]-SQV was measured in PBMC in the absence or presence of specific and non-specific inhibitors of MRP1, MRP2, P-gp and BCRP. Flow cytometric, western blot and real-time PCR assays were used to examine the relative expression of the drug efflux transporters in the same batches of PBMC. RESULTS: MRP2 is present in PBMC. The expression of P-gp, MRP1, MRP2 (mRNA) and BCRP all displayed batch-to-batch variability. Specific and non-specific inhibitors of MRP1, P-gp and MRP2 significantly increased the baseline accumulation of SQV. Accumulation of SQV was not correlated with the expression of any single transporter. CONCLUSIONS: Multiple drug efflux transporters are important in the intracellular accumulation of SQV in PBMC. If drug efflux contributes towards virological failure, then all contributing transporters will need to be inhibited.

Blotting, Western↗
PubMed2005

High prevalence of the plasmid-mediated quinolone resistance determinant qnrA in multidrug-resistant Enterobacteriaceae from blood cultures in Liverpool, UK.

OBJECTIVES: To determine the prevalence of the plasmid-mediated quinolone resistance qnrA gene in a selected collection of blood culture isolates of Enterobacteriaceae resistant to both ciprofloxacin and cefotaxime. METHODS: Over a 29 month period, a total of 47 non-repetitive isolates of Enterobacteriaceae resistant to both ciprofloxacin and cefotaxime were identified. Isolates were screened for the presence of the qnrA gene, class I integrons and bla(ESBL) by PCR. Transferability was examined by conjugation with the sodium azide-resistant Escherichia coli J53. All qnrA-positive isolates were examined for DNA-relatedness by PFGE. RESULTS: A total of 15 of the 47 test isolates (32%) were positive for the qnrA gene, and included single isolates of E. coli and Citrobacter freundii, 4 Klebsiella pneumoniae and 9 Enterobacter cloacae. All 15 qnrA-positive isolates carried class 1 integrons, and 11 the extended-spectrum beta-lactamase gene bla(SHV-12). By PFGE two K. pneumoniae and three E. cloacae, respectively, were considered clonally but not temporally related. Plasmid transfer of quinolone resistance was only achieved with single isolates of K. pneumoniae and E. cloacae. Both plasmids carried class 1 integrons with a pSAL-1-like gene cassette arrangement intl1-aadA2-qacEDelta-sul1. CONCLUSIONS: In this selected group of ciprofloxacin- and cefotaxime-resistant bacteria, carriage of the qnrA gene was high (32%). This compares with <2.0% as demonstrated in worldwide studies of laboratory collections of ciprofloxacin-resistant bacteria. The majority of qnrA-positive isolates in our study originated from high-dependency care units within our hospital, but were shown not to be clonal by PFGE. This is the first report of qnrA-positive Enterobacteriaceae in the United Kingdom.

Anti-Bacterial Agents↗
PubMed2005

Differential effects of beta-lactams on human IFN-gamma activity.

OBJECTIVES: To investigate whether a range of beta-lactam antibiotics conjugate to and hence reduce the activity of IFN-gamma, as has been shown for penicillin G. A selection of penicillins, cephalosporins, a monobactam (aztreonam), a beta-lactamase inhibitor (clavulanic acid), a carbapenem (meropenem) and the non-beta-lactam penicillin derivative d-penicillamine were tested for their effect on IFN-gamma activity. METHODS: Following exposure to a range of concentrations of these compounds, for varying lengths of time, IFN-gamma activity was assayed by induction of CD54 on the surface of the lung epithelial cell line A549, utilizing an ELISA. RESULTS: Clavulanic acid, cefoxitin and cefaloridine were the most potent inhibitors of IFN-gamma activity, followed by cefotaxime, ceftriaxone and phenoxymethylpenicillin. Ampicillin was less inhibitory than penicillin G, whilst meropenem and aztreonam had the least effect and d-penicillamine had no effect. The modulatory effect of these compounds was not due to a direct effect on CD54 induction. Unlike freshly prepared drugs, aged preparations of penicillin G and clavulanic acid had no significant effect on IFN-gamma activity. CONCLUSIONS: beta-Lactams differ in their capacity to modulate human IFN-gamma activity. This finding may have implications for the immunomodulatory effects of beta-lactams and for the design both of beta-lactams that do not affect the immune system and those which may be used therapeutically to target cytokine action.

Anti-Bacterial Agents↗
PubMed2005

A predominantly anti-inflammatory cytokine profile is associated with disease severity in meningococcal sepsis.

OBJECTIVE: This study aimed to determine whether an anti-inflammatory profile in meningococcal disease is associated with an increased risk of severe disease or septic shock. DESIGN AND SETTING: Prospective observational study in a tertiary care children's hospital. PATIENTS AND PARTICIPANTS: 63 children with confirmed meningococcal disease. INTERVENTIONS: Plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF) were assayed on admission. Receiver operator characteristic curve analysis was used to determine optimum thresholds for IL-1Ra:TNF, IL-1Ra:IL-6 and IL-1Ra:IL-8 ratios. MEASUREMENTS AND RESULTS: Median IL-1Ra:TNF and IL-1Ra:IL-6 ratios were significantly higher in severe disease with septic shock than in severe disease without septic shock and in non severe disease (IL-1Ra:TNF 263 vs. 185 vs. 108; IL-1Ra:IL-6 139 vs. 23 vs. 17). Median IL-1Ra:IL-8 ratios were not significantly different in the three groups. A significantly larger proportion of children with high IL-1Ra:TNF-alpha and IL-1Ra:IL-6 ratios developed severe disease with septic shock than those with a low ratios (95.2% vs. 4.8%; 76.2% vs. 23.8%). CONCLUSIONS: An anti-inflammatory profile appears to be associated with the development of severe disease and septic shock in meningococcal sepsis. This may imply that experimental new therapies of pro-inflammatory cytokine inhibition and anti-inflammatory cytokines in meningococcal disease could be detrimental.

Adolescent↗