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.

[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.

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.

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.

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.

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

The outcome of non-typhoidal salmonella meningitis in Malawian children, 1997-2006.

INTRODUCTION: The clinical course and outcome of non-typhoidal salmonella (NTS) meningitis in Malawian children over a 10-year period (1997-2006) is described. METHODS: Demographic, clinical and laboratory data were collected for all children over 2 months of age admitted with salmonella meningitis to Queen Elizabeth Central Hospital from 1997 to 2006. In the 1st year, salmonellae were susceptible to chloramphenicol, and children received 2 weeks of chloramphenicol treatment. When NTS resistance to chloramphenicol started to appear in 1998, treatment was changed to ceftriaxone. From 2002, the duration of antibiotic therapy was extended to 4-weeks which included 2 weeks of intravenous ceftriaxone and a further 2 weeks of oral ciprofloxacin. RESULTS: The in-hospital case fatality rate (CFR) was 52.3% (48.2% until 2002 and 53.9% after prolonged antibiotic therapy was introduced). Of the survivors, one in 12 (8.3%) became completely well (sequelae-free) in the period 1997-2001 while 18 of 31 survivors (58.1%) made a complete recovery during 2002-2006 (p<0.01). After the 4-week course of antimicrobial therapy was introduced, the number of relapses or recurrences fell from nine in 15 (60%) survivors treated with chloramphenicol or ceftriaxone to three in 35 (8.7%) survivors who received 4 weeks of antibiotics (p<0.0001). CONCLUSION: In Malawi, salmonella meningitis has a CFR of approximately 50%, which has remained constant over many years. Residual morbidity, however, has decreased over 10 years, despite rising numbers of multi-drug-resistant cases of NTS. This improvement might be owing to better treatment and management and/or reduced pathogenicity of the multi-drug-resistant bacteria.

Spectrum and presentation of pediatric malignancies in the HIV era: experience from Blantyre, Malawi, 1998-2003.

BACKGROUND: Data on childhood cancers in Africa are sparse, particularly since the spread of HIV. We aimed to document the frequency of pediatric cancers presenting to a large central hospital in Malawi, detailing the presenting features, initial investigations, and HIV status of these children. PROCEDURE: A retrospective audit of the spectrum and clinical presentation of cancers among children (<16 years) seen at Queen Elizabeth's Central Hospital (QECH), between 1998 and 2003. RESULTS: Seven hundred seven children with cancer were seen, the number of cases per year increased over the time period; 50% (351) had Burkitt lymphoma, 13% (89) had retinoblastoma, and 9% (61) had Kaposi sarcoma, with a variety of other tumors comprising the remainder. Kaposi sarcoma markedly increased in frequency over time. Histological verification of diagnosis was available for 49% (348). The proportion of children with cancer who were tested for HIV increased over time, but varied by cancer type. Amongst those tested, the seroprevalence was 93% (52/56) for children with Kaposi sarcoma, 4% (11/289) for those with Burkitt lymphoma, 31% (8/26) for those with other non-Hodgkin lymphomas, 7% (1/15) for those with Hodgkin disease, and 5% (5/103) for those with other cancers. CONCLUSIONS: The number of cases seen per year has increased over the study period for almost all cancers, but in particular for Kaposi sarcoma. Burkitt lymphoma remains the commonest pediatric tumor in Malawi. In the case of Burkitt lymphoma, non-Hodgkin lymphoma, and Kaposi sarcoma there is a significant difference in the presentation of HIV-seropositive and -seronegative children.

Risk factors for TB infection and disease in young childhood contacts in Malawi.

BACKGROUND: Screening of children in household contact with smear-positive tuberculosis (TB) is universally recommended but seldom practiced in resource-poor settings. It has huge potential to reduce the burden of TB disease in children, particularly if streamlined to focus on those at greatest risk. AIMS: To assess the prevalence of infection and disease amongst children aged < or = 5 yrs in household contact with smear-positive TB. To identify which source case characteristics are risk factors for infection. METHODS: A prospective, hospital-based audit was conducted over a 17-mth period in Southern Malawi. Smear-positive adults were identified and encouraged to bring their children to the outpatient clinic, in accordance with the national TB programme guidelines. Full assessment was performed, including tuberculin skin test. RESULTS: 195 children aged < or = 5 yrs who were contacts of 161 source cases were assessed. Prevalences of TB infection and disease were high (45% and 23%, respectively). The likelihood of a child being infected was significantly greater with increasing smear-positivity of the source case, and also if the source case were female (OR 2.25, 95% CI 1.19-4.27, p = 0.01). CONCLUSIONS: The high prevalence of TB infection and disease in child contacts attending this hospital-based clinic supports the current policy of contact-screening in Malawi. However, community-based studies are needed to provide a more accurate assessment of prevalence and risks for child contacts.

Poor attendance at a child TB contact clinic in Malawi.

SETTING: Child tuberculosis (TB) contact clinic, Queen Elizabeth Central Hospital, Blantyre, Malawi. DESIGN: Patients registered with smear-positive pulmonary TB (PTB) were encouraged to bring childhood household contacts to the clinic for assessment and management. Data of TB cases registered over the same period were collected from the Blantyre District TB Office. RESULTS: Attendance at the contact clinic was very poor, representing only 7.7% of all adults registered with smear-positive PTB over 17 months, and was significantly lower for potential male source cases than females (OR 0.36, 95% CI 0.23-0.55, P < 0.001). DISCUSSION: Improved uptake and implementation of child contact management in Malawi is a challenge.

Low levels of pyrazinamide and ethambutol in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection.

Recent pharmacokinetic studies that included children found that serum drug levels were low compared to those of adults for whom the same dosages were used. This study aimed to characterize the pharmacokinetics of pyrazinamide and ethambutol in Malawian children and to examine the impact of age, nutritional status, and human immunodeficiency virus (HIV) infection. We conducted a pharmacokinetic study of children treated for tuberculosis with thrice-weekly pyrazinamide (n = 27; mean age, 5.7 years) and of a separate group of children treated with thrice-weekly ethambutol (n = 18; mean age, 5.5 years) as portions of tablets according to national guidelines. Malnutrition and HIV infection were common in both groups. Blood samples were taken just prior to oral administration of the first dose, and subsequent samples were taken at intervals of 2, 3, 4, 7, 24, and 48 h after drug administration. Serum drug levels were low in all children for both drugs; in almost all cases, the maximum concentration of the drug in serum (Cmax) failed to reach the MIC for Mycobacterium tuberculosis. The Cmax of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The Cmax of pyrazinamide was also lower for HIV-infected children and children with severe malnutrition, but these differences did not reach statistical significance. No differences were found for ethambutol in relation to age, HIV infection, or malnutrition, but the Cmax was <2 mg/liter in all cases. Studies of pharmacokinetic parameters and clinical outcomes obtained by using higher dosages of drugs for treatment of childhood tuberculosis are needed, and recommended dosages may need to be increased.