High Intrapulmonary Rifampicin and Isoniazid Concentrations Are Associated With Rapid Sputum Bacillary Clearance in Patients With Pulmonary Tuberculosis.

BACKGROUND: Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi. METHODS: Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0-8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models. RESULTS: Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. CONCLUSIONS: Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.

Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis.

BACKGROUND: Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis. METHODS: Malawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics. RESULTS: One-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2-18.0-fold) and 49.8-fold (95% CI, 34.2-65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell-plasma ratio, 15.0; 95% CI, 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response. CONCLUSIONS: We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.

Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa.

BACKGROUND: In sub-Saharan Africa, bacterial meningitis is common and is associated with a high mortality. Adjuvant therapy with corticosteroids reduces mortality among adults in the developed world, but it has not been adequately tested in developing countries or in the context of advanced human immunodeficiency virus (HIV) infection. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of dexamethasone (16 mg twice daily for 4 days) and an open-label trial of intramuscular versus intravenous ceftriaxone (2 g twice daily for 10 days) in adults with an admission diagnosis of bacterial meningitis in Blantyre, Malawi. The primary outcome was death at 40 days after randomization. RESULTS: A total of 465 patients, 90% of whom were HIV-positive, were randomly assigned to receive dexamethasone (233 patients) or placebo (232 patients) plus intramuscular ceftriaxone (230 patients) or intravenous ceftriaxone (235 patients). There was no significant difference in mortality at 40 days in the corticosteroid group (129 of 231 patients) as compared with the placebo group (120 of 228 patients) by intention-to-treat analysis (odds ratio, 1.14; 95% confidence interval [CI], 0.79 to 1.64) or when the analysis was restricted to patients with proven pneumococcal meningitis (68 of 129 patients receiving corticosteroids vs. 72 of 143 patients receiving placebo) (odds ratio, 1.10; 95% CI, 0.68 to 1.77). There were no significant differences between groups in the outcomes of disability and death combined, hearing impairment, and adverse events. There was no difference in mortality with intravenous ceftriaxone (121 of 230 patients) as compared with intramuscular ceftriaxone (128 of 229 patients) (odds ratio, 0.88; 95% CI, 0.61 to 1.27). CONCLUSIONS: Adjuvant therapy with dexamethasone for bacterial meningitis in adults from an area with a high prevalence of HIV did not reduce mortality or morbidity. In this setting, intramuscular administration was not inferior to intravenous administration of ceftriaxone for bacterial meningitis. (Current Controlled Trials number, ISRCTN31371499 [controlled-trials.com].).

Palliative care needs of patients living with end-stage kidney disease not treated with renal replacement therapy: An exploratory qualitative study from Blantyre, Malawi.

BACKGROUND: The burden of end-stage kidney disease (ESKD) in sub-Saharan Africa is increasing rapidly but the palliative care needs of patients living with ESKD are not well described. Resource limitations at both health system and patient level act as major barriers to patients receiving renal replacement therapy (RRT) in the form of dialysis. We undertook an exploratory qualitative study to describe the palliative care needs of patients with ESKD who were not receiving RRT, at a government teaching hospital in Blantyre, Malawi. METHODS: A qualitative, explorative and descriptive design was used. Study participants were adults aged > 18 years with an estimated glomerular filtration rate < 15 ml/min on two separate occasions, three months apart, who either chose not to have or were not deemed suitable for RRT. Data were collected by means of semi-structured interviews. RESULTS: In October and November 2013, interviews were conducted with 10 adults (7 women with median age of 60.5 years). All were hypertensive and four were on treatment for HIV. Four themes emerged from the data: changes in functional status because of physical symptoms, financial challenges impacting hospital care, loss of role within the family and the importance of spiritual and cultural beliefs. CONCLUSION: This study reports on four thematic areas which warrant further quantitative and qualitative studies both in Malawi and other low-resource settings, where a growing number of patients with ESKD unable to access RRT will require palliative care in the coming years.

Post exposure prophylaxis of HIV transmission after occupational injuries in Queen Elizabeth Central Hospital, Blantyre, Malawi, 2003 - 2008.

Health care worker (HCW) in Malawi may acquire HIV infection through occupational injuries, in particular since HIV prevalence among inpatients and incidence of occupational injuries are high. A post exposure prophylaxis (PEP) programme for occupational injuries at Queen Elizabeth Central Hospital (QECH) commenced in 2003. We performed an audit of this programme from 2003 through 2008. 203 Occupational injuries were reported. The majority were needle stick injuries (76.3%). Half of the clients were in a training position. A dual ART regimen was most frequently prescribed. Triple therapy use increased over time and was more frequent in expatriate students. Many nurses and clinical officers were not fully vaccinated for HBV. Based on previous incidence data, occupational injuries were likely to be underreported. Data on side effects were incomplete, however PEP discontinuation due to side effects occurred only twice. Follow up visits were poorly attended, therefore the efficacy of PEP could not be evaluated. Prevention efforts for occupational injuries should be increased and specifically target HCWs in training positions. Measures to improve quality of the PEP programme include effective publicity campaigns, compulsory Hepatitis B vaccination and active tracing of HCWs who default follow up after PEP.