Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi.

Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Africa. A total of 47 Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51% were male, their mean age was 34 years, and 65% were HIV-positive with a mean CD4 count of 268 cells/µl. Antituberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parameters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (Cmax) of 4.129 µg/ml (2.474 to 5.596 µg/ml), area under the curve from 0 to 24 h (AUC0-∞) of 21.32 µg/ml · h (13.57 to 28.60 µg/ml · h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, Cmax of 3.97 µg/ml (2.979 to 4.544 µg/ml), AUC0-24 of 22.5 (14.75 to 34.59 µg/ml · h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, Cmax of 34.21 µg/ml (30.00 to 41.60 µg/ml), AUC0-24 of 386.6 µg/ml · h (320.0 to 463.7 µg/ml · h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, Cmax of 2.278 µg/ml (1.694 to 3.098 µg/ml), AUC0-24 of 20.41 µg/ml · h (16.18 to 26.27 µg/ml · h), and half-life of 7.507 (6.517 to 8.696 h). The isoniazid PK data analysis suggested that around two-thirds of the participants were slow acetylators. Dose, weight, and weight-adjusted dose were not significant predictors of PK exposure, probably due to weight-banded dosing. In this first pharmacokinetic study of antituberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the Cmax and AUC0-24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further.

Pharmacokinetics of anti-TB drugs in Malawian children: reconsidering the role of ethambutol.

BACKGROUND: Current guidelines for dosing of anti-TB drugs in children advocate higher doses for rifampicin and isoniazid despite limited availability of paediatric data on the pharmacokinetics of these drugs, especially from Africa, where the burden of childhood disease remains high. METHODS: Thirty children aged 6 months to 15 years underwent intensive pharmacokinetic sampling for first-line anti-TB drugs at Queen Elizabeth Central Hospital, Blantyre, Malawi. Rifampicin, isoniazid, pyrazinamide and ethambutol were dosed at 10, 5, 25 and 20 mg/kg, respectively. Plasma drug concentrations were determined using sensitive, validated bioanalytical methods and summary pharmacokinetic parameters were estimated using non-compartmental analysis. RESULTS: The median (IQR) Cmax was 2.90 (2.08-3.43), 3.37 (2.55-4.59), 34.60 (32.30-40.90) and 1.20 (0.85-1.68) mg/L while the median (IQR) AUC0-∞ was 16.92 (11.10-22.74), 11.48 (7.35-18.93), 333.50 (279.50-487.2) and 8.65 (5.96-11.47) mg·h/L for rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. For all drugs, pharmacokinetic parameters relating to drug absorption and exposure were lower than those published for adults, though similar to existing paediatric data from sub-Saharan Africa. Weight and/or dose predicted at least one measure of exposure for all drugs. Age-related decreases in CL/F for rifampicin and pyrazinamide and a biphasic elimination pattern of isoniazid were observed. Predicted AUC0 -∞ for rifampicin dosed at 15 mg/kg was comparable to that of adults while the dose required to achieve ethambutol exposure similar to that in adults was 55 mg/kg or higher. CONCLUSIONS: These data support recently revised WHO recommendations for dosing of anti-TB drugs in children, but dosing of ethambutol in children also appears inadequate by comparison with adult pharmacokinetic data.

[Retinoblastoma in Malawi: why are admissions too late?]. / Retinoblastom in Malawi : Warum zu späte Einweisung?

BACKGROUND: A total of 82 % of stationary admissions with the diagnosis of retinoblastoma (2009-2011) to the tertiary ophthalmology unit in Blantyre, Malawi (n = 58) presented with advanced stage disease. PATIENTS AND METHODS: In another study in 2012 we sought to identify why children mostly presented in advanced stages of disease and whether the delay was unique to children with cancer. In-depth interviews (IDI) were conducted at the hospital with 40 parents or guardians of children with retinoblastoma, congenital cataract, congenital glaucoma and corneal perforation (10 each). RESULTS: Most delays and delayed admissions occurred at the family (27.5 %, 11 out of 40) and primary health centre levels (30.0 %, 12 out of 40). Lack of money for transport caused delays (15.0 %, 6 out of 40) at all care levels. In contrast, children with painful conditions presented to a health facility within 24 h of onset without any complaints about lack of money for transport. CONCLUSION: Education about retinoblastoma and other non-painful eye diseases could be improved by a poster campaign to both parents and professionals at all medical healthcare levels. Transport for such cases between the various healthcare centers should be provided free of charge. There is room for improvement in initial diagnosis, referral and management within the healthcare service in the tertiary sector.

Remote and rapid pathological diagnosis in a resource challenged unit.

Malawi is one of the world's poorest countries, but despite this, has a dedicated paediatric oncology service. The service has been hampered by the inability to make a timely cytological diagnosis in the majority of patients. A telemedicine programme was commenced to help overcome this problem, and the results for the first 197 consecutive patients are described. The results are compared with the local reports where available. Most samples were fine needle aspirates (104/197-53%), but others included bone marrow aspirates, peripheral blood films and other fluid collections. A diagnosis was arrived at in 52% of the samples; there were 46 discordant results, 38 were when one or other of the local or distant teams were unable to make a diagnosis, and only 8 where the diagnoses of the 2 teams differed. Diagnoses were made and reports were compiled by the 'distant' team within 24 h and sent to the centre in Malawi. This simple telepathology initiative has had a positive impact on clinical management, and could be used in other less resourced centres twinned with better resourced ones.

[Rapidly progressing unilateral proptosis in a 6-year-old girl]. / Rasch fortschreitende unilaterale Proptosis bei einem 6-jährigen Mädchen.

This report describes the case of a 6-year-old girl who presented with painless swelling of the right orbit since 4 weeks and moderate proptosis. Tests revealed visual acuity RE 6/6, LE 6/6, normal intraocular pressure (IOP), anterior and posterior segments normal. Ultrasound examination showed multiple lesions in the spleen, normal liver, no abdominal mass and enlarged abdominal lymph nodes. Fine-needle aspirate results were not available at the time of clinical decision-making. In Malawi the treatment for all stages of Burkitt's lymphoma is intravenous cyclophosphamide (40 mg/kg on day 1 and oral cyclophosphamide 60 mg/kg on days 8, 18 and 28). Intrathecal hydrocortisone (12.5 mg) and methotrexate (12.5 mg) are given with each treatment cycle.

Endomyocardial fibrosis: the first report from Malawi.

Endomyocardial fibrosis (EMF) is a restrictive cardiomyopathy of unknown aetiology previously unreported in Malawi. Six Malawian children (three males) aged between 12 and 16 years who presented with EMF in 2009/10 are described. Five were from the Southern Highlands.

Case report: Evidence of rise in rabies cases in southern Malawi--better preventative measures are urgently required.

We describe five children who died of clinical rabies in a three month period (September to November 2011) in the Queen Elizabeth Central Hospital. From previous experience and hospital records, this number of cases is higher than expected. We are concerned that difficulty in accessing post-exposure prophylaxis (PEP) rabies vaccine may be partly responsible for this rise. We advocate: (a) prompt course of active immunisation for all patients with significant exposure to proven or suspected rabid animals. (b) the use of an intradermal immunisation regime that requires a smaller quantity of the vaccine than the intramuscular regime and gives a better antibody response. (c) improved dog rabies control measures.

Systematic review: neonatal meningitis in the developing world.

Meningitis is more common in the neonatal period than any other time in life and is an important cause of morbidity and mortality globally. Despite the majority of the burden occurring in the developing world, the majority of the existing literature originates from wealthy countries. Mortality from neonatal meningitis in developing countries is estimated to be 40-58%, against 10% in developed countries. Important differences exist in the spectrum of pathogens isolated from cerebrospinal fluid cultures in developed versus developing countries. Briefly, while studies in developed countries have generally found Group B streptococcus (GBS), Escherichia coli and Listeria monocytogenes as important organisms, we describe how in the developing world results have varied; particularly regarding GBS, other Gram negatives (excluding E. coli), Listeria and Gram-positive organisms. The choice of empiric antibiotics should take into consideration local epidemiology if known, early versus late disease, resistance patterns and availability within resource constraints. Gaps in knowledge, the role of adjuvant therapies and future directions for research are explored.

Challenges and outcome of Wilms' tumour management in a resource-constrained setting.

BACKGROUND: To review the results of Wilms' tumour patients in a tertiary referral hospital in a developing country and to find ways of improving long-term survival. PATIENTS AND METHODS: Between January 1998 and May 2004, 40 patients with Wilms' tumour (WT) were admitted to Queen Elizabeth Central Hospital. Their files were reviewed and general physical condition on admission, pre-operative investigations, management and outcome were noted. RESULTS: The mean age of presentation was 4.2 years with an equal distribution between the sexes. The mean BMI was 15 kg/m2 and more than 80% of the patients were either mildly (PCV <33%) or severely anaemic (PCV <24%). All patients presented with abdominal distension. Half of them had additional complaints including abdominal pain, haematuria, dyspnoea, oedema and or weight loss. Thirty-nine out of the forty patients received pre-operative chemotherapy. Of the 36 patients that underwent surgery, 32 underwent total nephrectomy, one a partial nephrectomy, and in three the tumour was irresectable. There were no intra-operative tumour ruptures. Only 15% of the patients completed their post-operative course of chemotherapy. The 1-year survival lies between 25% and 53%. Fifteen of the 36 patients operated were known to have a recurrence. CONCLUSION: The patients presented in an advanced stage of the disease. Survival rates are disappointing and recurrence rates are high. Some improvement in outcome may be expected with the implementation of more aggressive treatment protocols but early diagnosis, completion of treatment regimens are needed. Pro-active follow-up is essential to measure outcome.

Paediatric emergency care in resource-constrained health services is usually neglected: time for change.

Emergency care has been neglected in many resource-constrained countries and yet 50% of paediatric admissions die in the 1st 24 hours of admission. Carers may know how to manage clinical problems but there might not be a system in place to provide timely and appropriate care. This article reviews the needs--staffing, materials and physical layout--of a receiving hospital unit and describes how to set up a system of patient flow and care that prioritises and provides timely care, so that when a patient arrives in hospital the system does not fail them.

Impact of HIV infection and exposure on survival in critically ill children who attend a paediatric emergency department in a resource-constrained setting.

OBJECTIVE: To assess the impact of HIV infection and exposure on survival in critically ill children requiring resuscitation. METHODS: A 6-month descriptive prospective cohort study of all live admissions to the resuscitation room of an urban paediatric emergency department in Blantyre, Malawi. RESULTS: 583 children were resuscitated, of whom 401 (69%) survived to hospital discharge. 26% of all children tested positive for HIV infection (152/576), and this was highest in patients presenting with shock (66%; 162/247), clinically diagnosed septicaemia (57%; 125/218) and malnutrition (40%; 24/60). Of 152 HIV-seropositive children, 30 (20%) died within 24 h, while among 424 seronegative children 36 (8.4%) died within 24 h (p<0.001). Later deaths (>24 h) were also more common in HIV-seropositive children compared with HIV-uninfected patients (24.3% vs 12.3%; p<0.001). Survival to 24 h was 80% (122/152) and to discharge 56% (85/152) in HIV-seropositive children. In HIV-uninfected children survival to 24 h was 92% (388/424) and to discharge 79% (336/424). CONCLUSION: Early and late case death rates are greater in HIV-seropositive than in HIV-uninfected children. 80% of HIV-infected children survived the period most influenced by the process of resuscitation, that is, the first 24 h. HIV status alone should not influence the limitation of intervention decisions in the resuscitation room when faced with a critically ill child.

Development and evaluation of a new paediatric blood transfusion protocol for Africa.

Severe anaemia is a common childhood emergency in developing countries. Practical evidence-based guidance on when to transfuse, volume of transfusion and ideal duration of transfusion is lacking. The aim of this study is to develop a paediatric transfusion protocol for use in under-resourced environments and evaluate its usability in a busy African hospital setting. A paediatric transfusion protocol based on the WHO Guidelines was developed for the Queen Elizabeth Central Hospital (QECH), Blantyre, Malawi. On the basis of simple bedside clinical features of respiratory, cardiovascular and neurological compromise, the protocol allocates children with severe anaemia (haemoglobin