PubMed Health⌕ Search

Biomedical subjects

P R Donald

Publications and source records attributed to P R Donald.

At least 19 recordsLinked to original sources
PubMed1997

Genome and MIC stability in Mycobacterium tuberculosis and indications for continuation of use of isoniazid in multidrug-resistant tuberculosis.

Mycobacterium tuberculosis strains resistant to two or more of the first line antituberculosis drugs (MDR) are a serious threat to successful tuberculosis control programmes. For this retrospective study, 85 follow-up drug resistant isolates from 23 patients residing in a community with a high incidence of tuberculosis were collected and the level of in-vitro resistance to antibiotics determined quantitatively. PCR-SSCP and sequencing techniques were used to screen for gene mutations associated with resistance in 31 follow-up samples from a smaller group of eight patients. DNA fingerprint analysis was done on sequential isolates to confirm identity. Although treatment had a profound effect on changes in drug resistance patterns, the MIC for a particular agent remained constant in follow-up isolates. DNA fingerprinting and mutational analysis (14 different loci) showed that the genome of MDR strains of M. tuberculosis is relatively stable during the course of therapy. The rpoB gene was the most frequently mutated structural gene involved in drug resistance and a novel C to T mutation upstream of open reading frame (ORF)1 of the inhA operon was detected. No evidence was found of the presence of strain W (New York) in this group of MDR strains. The results stress the importance of confirming individuality of strains for the accurate calculation of frequencies of particular mutations associated with drug resistance, particularly in a high incidence area. Approximately one-half (47.8%) of the patients had isolates resistant to concentrations just above the critical concentration for isoniazid (MICs of 0.2-5 mg/L). Therefore, these patients and their contacts who develop primary drug-resistant tuberculosis may respond to higher dosages of treatment which could have a considerable impact on the cost and the ease of management of resistant tuberculosis.

Antitubercular Agents↗
PubMed1997

Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis.

The study was undertaken to show that polymorphic isoniazid elimination in humans is trimodal; that the acetylator genotype and eliminator phenotype of the individual patient are concordant; and that the differences in the pharmacokinetic parameters of fast, intermediate, and slow eliminator subgroups are statistically significant. Sixty adult patients of both sexes and of mixed race with tuberculosis participated in the trial. The apparent elimination rate constant (k, h(-1)) and the area under the isoniazid concentration-time curve (AUC, mg/L/h), over the interval 2 to 6 h after oral isoniazid were determined in all patients; NAT2 allele composition was determined in 47 patients. Serum INH concentrations were determined by HPLC and genotypes by PCR/restriction enzyme analysis. Three eliminator phenotypes could be distinguished, and concordance between the phenotype and the genotype of the individual could be demonstrated. The isoniazid concentration-time profiles of the three eliminator subgroups were significantly different (p < 0.05). The NAT2*12A allele, which codes for fast acetylation, has a high frequency in the population studied, the intermediate acetylator genotype is constituted of codominant fast and slow alleles, and the distribution of phenotypes/genotypes in the population is consistent with Hardy-Weinberg predictions. The therapeutic implications of polymorphic isoniazid metabolism are discussed.

Acetylation↗
PubMed1997

The early bactericidal activity of isoniazid related to its dose size in pulmonary tuberculosis.

Collections of sputum from 105 patients with newly diagnosed pulmonary tuberculosis were made before and at 1 and 2 d after the start of chemotherapy with isoniazid (INH) alone given to groups of patients in doses of 600 mg, 300 mg, 150 mg, 75 mg, 37.5 mg, 18.75 mg, and 9 mg daily, as well as from an untreated group. Counts of colony forming units (cfu) of Mycobacterium tuberculosis in the collections were set up on plates of selective 7H10 medium. The early bactericidal activity (EBA) of INH was defined as the decrease in log10 cfu/ml sputum/day during the first 2 d of treatment. A smooth curve relating EBA to log dose was obtained, with 600 mg INH yielding the highest mean EBA of 0.539, and 18.75 mg INH yielding the lowest EBA (0.111) that could be distinguished from the bactericidal activity of the untreated group. The ratio of the usual dose of 300 mg INH to the lowest dose, of 18.75 mg, that produced a detectable EBA, termed the therapeutic margin, was therefore 16, in contrast to the lower therapeutic margin of 4 for rifampin. The EBA was related to the INH acetylator genotype of patients treated with 600 mg or 9 mg INH.

Acetylation↗
PubMed1997

The early bactericidal activity of ciprofloxacin in patients with pulmonary tuberculosis.

The early bactericidal activity (EBA) of ciprofloxacin (CIP) was measured in 80 patients with previously untreated, smear-positive pulmonary tuberculosis by counting viable bacilli in sputum collections during the first 2 d of treatment. Groups of about 10 patients were treated daily with graded doses of CIP or with 300 mg isoniazid or with no drug. The mean EBA, defined as the fall in log CFU/ ml sputum/d, increased from -0.011 in the no drug group to 0.046, 0.092, 0.121, and 0.205 in the groups receiving 250, 500, 1,000, or 1,500 mg CIP, respectively, a highly significant trend. These results demonstrate the antimycobacterial activity of CIP in high dosage, though the mean EBAs of 0.55 and 0.66 in two groups receiving isoniazid were much higher.

Adult↗
PubMed1997

Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis.

OBJECTIVE: To study the effect of highdose prednisone on intracranial pressure (ICP), cranial computed tomographic (CT) findings, and clinical outcome in young children with moderate to severe tuberculous meningitis (TBM). STUDY DESIGN: Prospective, controlled, randomized study. METHODS: Continuous lumbar, cerebrospinal fluid pressure monitoring and contrasted CT scanning were performed in 141 consecutive children with TBM at admission. All children were then randomly allocated to a nonsteroid group (71 children) or a steroid group (70 children) who received prednisone (first 16 children, 2 mg/kg per day; next 54 children, 4 mg/kg per day) for the first month of treatment. ICP monitoring and CT scanning were repeated regularly, and clinical outcome was assessed after 6 months of antituberculosis treatment. RESULTS: No statistically significant difference in ICP or the degree of hydrocephalus (as demonstrated by CT scan) was found between the steroid and nonsteroid groups after the first month of treatment. Basal ganglia infarcts developed in 16% of children in the steroid group and 24% in the nonsteroid group during the first month of treatment. Neither this incidence nor the eventual size of infarcts present at admission differed significantly between the two treatment groups. Single or multiple tuberculomas were seen on the first CT scans of 7 children (5%), whereas tuberculomas developed in 11 children (8%) at treatment. Both the response of the tuberculomas to treatment and the incidence of new tuberculomas were significantly improved by steroid therapy. Basal enhancement was also significantly less in the steroid group after 1 month of treatment. Steroids lowered mortality in stage III TBM significantly. Similarly, more surviving children in the steroid group had IQs of greater than 75 than did the those in the nonsteroid group. No significant difference was found in the incidence of motor deficit, blindness, or deafness. CONCLUSIONS: Corticosteroids significantly improved the survival rate and intellectual outcome of children with TBM. Enhanced resolution of the basal exudate and tuberculomas by steroids was shown by serial CT scanning. Corticosteroids did not affect ICP or the incidence of basal ganglia infarction significantly.

Brain↗
PubMed1997

Adenylate kinase activity in the cerebrospinal fluid of children with tuberculous meningitis and its relationship to neurological outcome.

Cerebrospinal fluid (CSF) adenylate kinase activity was determined in 88 children (mean age 32.6 months) at stage II (n = 40) and stage III (n = 48) tuberculous meningitis (TBM) at, or shortly after, the initiation of treatment, and at weekly intervals thereafter for the first month of treatment, and in 60 children (mean age 40 months) investigated for, but later considered not to have meningitis. CSF adenylate kinase activity in this latter group ranged from 0 to 1.27 u/l (mean 0.59 u/l). Mean CSF adenylate kinase activity during the first week of therapy in children at stage II TBM (2.95 u/l; range 0-9.22 u/l) differed significantly (p = 0.03) from that in children at stage III TBM (5.62 u/l; range 0-18.93 u/l). CSF adenylate kinase activity did not differ between children at stage II and stage III TBM during any of the 3 subsequent weeks. CSF adenylate kinase activity was not related to CSF cell count, total protein or glucose concentration or intracranial pressure at any point during the first month of treatment, but was related to CSF lactate during the first week of therapy (p = 0.001). Consecutive determinations of CSF adenylate kinase activity were available in 34 children. Although CSF adenylate kinase activity tended to increase or decrease in keeping with changes in clinical condition this was not always the case. The close relationship of CSF adenylate kinase activity and lactate concentrations suggests that adenylate kinase activity reflects hypoxic cerebral metabolism and it was unusual for children with increased CSF adenylate kinase activity at the time of diagnosis to be clinically normal on completion of 6 months of antituberculosis treatment. Any treatment modality which significantly reduced CSF adenylate kinase activity in children early in the course of TBM would probably be of clinical benefit to the patients.

Adenylate Kinase↗
PubMed1997

Sociological and anthropological factors related to the community management of tuberculosis in the Western Cape communities of Ravensmead and Uitsig.

OBJECTIVE: To determine the sociocultural understanding of tuberculosis among patients and their household members. DESIGN: Qualitative descriptive study. SETTING: Two adjacent Western Cape suburbs with a population of approximately 35,000, a tuberculosis incidence of > 1,000/100,000 and a surface area of 2.42 km2. SUBJECTS: Twenty-three adult patients on treatment for tuberculosis and their adult household members. INTERVENTIONS: None. METHODOLOGY: Consecutive selected adult tuberculosis patients and their household members were interviewed with an open-ended interview schedule. General household and community conditions and non-verbal responses were recorded. RESULTS: There were relatively affluent but also severely deprived households with severe overcrowding. Substance abuse was common. Patients had limited understanding and knowledge about health, hygiene and the cause of tuberculosis. There was a perception of both physical and social distance between patients and health care providers. All patients relied exclusively on the conventional biomedical curative approach of the medical system to deal with tuberculosis.

Adult↗
PubMed1997

A prospective evaluation of children under the age of 5 years living in the same household as adults with recently diagnosed pulmonary tuberculosis.

SETTING: A South African suburb with a high tuberculosis incidence (> 800/100,000). OBJECTIVE: To determine the prevalence of tuberculosis infection and disease in children less than 5 years of age who were in close household contact with adults with pulmonary tuberculosis. DESIGN: Prospective clinical study. SUBJECTS: Children under 5 years of age (of whom > 98% had been BCG vaccinated in the neonatal period) in household contact with an adult with tuberculosis. INVESTIGATION: Clinical investigation, Mantoux skin testing, chest radiography, gastric aspirate culture for Mycobacterium tuberculosis. RESULTS: Of 155 children younger than 5 years in contact with 80 index cases (83% smear positive), 14% were infected and 34% diseased. Children aged under 2 years had more severe disease (endobronchial tuberculosis and bronchial compression). Of 154 household members aged over 5 years who were assessed, 17 had culture proven pulmonary tuberculosis (13 smear positive) and a further 16 were placed an antituberculosis treatment on the basis of radiological evidence. CONCLUSION: In a high tuberculosis incidence area evaluation of and chemoprophylaxis for childhood contacts of adults with pulmonary tuberculosis is a rewarding procedure. The detection of culture and smear positive pulmonary tuberculosis amongst adolescent and adult household contacts emphasizes the role of contact tracing in the detection of infectious cases of pulmonary tuberculosis and the prevention of the spread of tuberculosis.

Adolescent↗
PubMed1996

A decade of experience with Mycobacterium tuberculosis culture from children: a seasonal influence on incidence of childhood tuberculosis.

SETTING: A tertiary care hospital in the Western Cape Province of South Africa from November 1983-October 1993. OBJECTIVE: Evaluation of the source of all cultures of Mycobacterium tuberculosis from children aged < 13 years and documentation of the mean time for culture with Löwenstein-Jensen (LJ) medium and a radiometric method (Bactec). RESULTS: One thousand six hundred and sixty cultures of M. tuberculosis were obtained from 1204 children (638 (53%) males and 566 (47%) females). The median time to a positive culture result was 65 days with LJ medium and 23 days with Bactec (P < 0.0001). Gastric aspirate provided 1298 cultures (78%) from 983 children (82%) of whom 52% were aged < 2 years. Ninety-six positive sputum specimens were from 79 children (7%) of whom 70% were > 5 years. Significantly more positive cultures were obtained during the late winter and early spring (P < 0.001), and a similar trend was found for tuberculous meningitis. CONCLUSION: The use of a radiometric culture method has expedited the confirmation of tuberculosis in childhood in our hospital. Even in children < 3 months of age the diagnosis of tuberculosis can often be confirmed by culture. The documented increase in childhood tuberculous disease in spring suggests an increased transmission of tuberculous infection in autumn and winter in our community.

Age Distribution↗
PubMed1996

Pediatric meningitis in the Western Cape Province of South Africa.

During the 9 years 1985-1993 a prospective survey of all cases of meningitis in children < 13 years of age presenting to our hospital in the Western Cape Province of South Africa was carried out. Two-thousand-nine-hundred-and-twenty cases of meningitis were identified. The commonest form of bacterial meningitis was tuberculous meningitis (TBM) diagnosed in 282 children (mean age 2.94 years). N. meningitidis identified in 220 children (mean age 2.87 years), Haemophilus influenzae in 156 children (mean age 1.15 years) and S. pneumoniae in 106 children (mean age 2.14) were the next commonest causes of bacterial meningitis diagnosed. One-hundred-and-eighteen cases of bacterial meningitis were confirmed in infants < 1 month of age and the commonest bacteria identified were group B beta-haemolytic Streptococcus in 27, E. coli in 21, Klebsiella species in 11, and Candida species in 15 neonates. The emergence of TBM as the predominant cause of bacterial meningitis in childhood at our hospital is probably a reflection of the worsening tuberculosis situation in the Western Cape Province of South Africa.

Adolescent↗
PubMed1996

The 5-year outcome of multidrug resistant tuberculosis patients in the Cape Province of South Africa.

Little is known about the outcome of multidrug resistant (MDR) tuberculosis (TB) in developing countries. In this study, 443 patients with MDR-TB, defined as resistance to two or more antituberculosis drugs, were identified over the 2-year period 1987 and 1988 in the Cape Province of South Africa. The 5-year outcome of the 343 (77%) patients that could be traced by questionnaire was evaluated retrospectively during 1992 and 1993. Of these, 240 (70%) were resistant to both isoniazid (H) and rifampicin (R) with or without resistance to other first-line antituberculosis drugs and 103 (30%) were resistant to H or R and/or other antituberculosis drugs. Mortality was 116 (48%) and 28 (27%) in these groups respectively with a significantly greater risk of death in the first group. Only 114 (33%) of all the MDR-TB patients were cured after 5 years, 50 (15%) were respiratory disabled and 44 (13%) were still bacteriology positive. Twenty-four (7%) patients were lost during follow-up. Taking into account the high costs involved in treating MDR-TB patients and the scarce resources available in developing countries, more emphasis should be placed on direct observed therapy to cure newly diagnosed infectious drug sensitive tuberculosis patients, thus preventing MDR-TB rather than treating it.

Adolescent↗
PubMed1996

Genotyping of Mycobacterium tuberculosis with additional markers enhances accuracy in epidemiological studies.

Two highly polymorphic Mycobacterium tuberculosis genomic domains, characterized by hybridization to the oligonucleotide (GTG)5, were identified as potential DNA fingerprinting probes. These domains were cloned [pMTB484(1) and pMTB484(2K4), respectively] and shown to be useful for genotype analysis by Southern blotting. These probes were used to genotype geographically linked strains of M. tuberculosis previously shown to have identical IS6110 fingerprints. Subsequent DNA fingerprints generated with MTB484(1) and MTB484(2K4) showed a high degree of polymorphism, allowing subclassification of IS6110-defined clusters into composites of smaller clusters and unique strains. Correlation of the molecular data with patient interviews and clinical records confirmed the sensitivity of these probes, as contacts were established only within subclusters. These findings demonstrate the requirement for multiple probes to accurately classify M. tuberculosis strains, even those with high copy numbers of IS6110. The enhanced accuracy of strain typing should, in turn, further our understanding of the epidemiology of tuberculosis.

Bacterial Typing Techniques↗
PubMed1996

Early bactericidal activity of ethambutol, pyrazinamide and the fixed combination of isoniazid, rifampicin and pyrazinamide (Rifater) in patients with pulmonary tuberculosis.

The early bactericidal activity (EBA) of ethambutol, pyrazinamide and the fixed combination of isoniazid, rifampicin and pyrazinamide (Rifater: Mer National) was evaluated in patients with pulmonary tuberculosis who were sputum-positive on microscopy for acid-fast bacilli. Twenty-eight patients (mean age 33 years and weight 51 kg on average; range 40-59 kg) were studied. The fall in viable counts of Mycobacterium tuberculosis in sputum collections during the 2 days following the start of treatment was estimated from counts of colony-forming units (CFUs) of M. tuberculosis per ml of sputum cultured on selective 7H10 agar medium. The EBA for ethambutol determined in 9 patients was 0.245 +/- 0.046, log10 CFU/ml sputum/day, that for pyrazinamide was 0.003 +/- 0.014 log10 CFU/ml sputum/day and that for Rifater 0.558 +/- 0.054 log10 CFU/ml sputum/day. The results obtained are similar to those reported in a previous study of the first 2 days of treatment, but in smaller numbers of patients, and confirm the moderate EBA of ethambutol while pyrazinamide is again shown to have very little EBA. Rifater has a marked EBA which may be due mainly to the action of isoniazid. This methodology may be valuable in the rapid evaluation of the bactericidal activity of new antituberculosis agents and the comparison of different dose sizes of agents of the same class.

Adolescent↗
PubMed1996

The use of a geographical information system (GIS) to evaluate the distribution of tuberculosis in a high-incidence community.

OBJECTIVE: To determine the geographical distribution of tuberculosis in the two Western Cape suburbs with the highest reported incidence of tuberculosis. DESIGN: Descriptive illustrative study. SETTING: Two adjacent Western Cape suburbs covering 2.42 km2 with a population of 34,294 and a reported tuberculosis incidence of > 1,000/100,000. SUBJECTS: All patients notified as having tuberculosis over a 10-year period (1985-1994). INTERVENTIONS: None OUTCOME MEASURE: The geographical distribution of the cases was determined using a geographical information system (GIS) and the National Population Census (1991). RESULTS: One thousand eight hundred and thirty-five of the 5,345 dwelling units (34.3%) housed at least 1 case of tuberculosis during the past decade and in 483 houses 3 or more cases occurred. These cases were distributed unevenly through the community, with the tuberculosis incidence per enumerator subdistrict (ESD) varying from 78 to 3,150/100,000 population. CONCLUSION: In a small area with a high incidence of tuberculosis, the cases are spread unevenly through the community and there are certain houses where tuberculosis occurs repeatedly. This information should be used to direct health services to concentrate on certain high-risk areas.

Adolescent↗