Evaluation of the safety and efficacy of micronized halofantrine in the treatment of semi-immune patients with acute, Plasmodium falciparum malaria.

The efficacy of the standard formulation of halofantrine hydrochloride has been compromised by the formulation's irregular bio-availability. A micronized preparation of the drug has now been evaluated in the treatment of malaria in northern Tanzania. Overall, 100 patients with mild to moderate Plasmodium falciparum malaria were recruited and treated with the preparation over 18 h. Those weighing > 40 kg were each given three, 500-mg doses and those weighing less were given roughly equivalent doses/kg. The 95 evaluable patients were all successfully treated, with a mean fever-clearance time of 22.5 h (range 4-76 h) and a mean parasite-clearance time of 35.6 h (range 15-66 h). There were no relapses. Abdominal pain was the commonest adverse event reported (22 cases). A single patient died suddenly in the recovery phase; the cause of this event was not determined. Further studies are required to evaluate the pharmacokinetics of the halofantrine formulation under field conditions.

Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis.

The fluoroquinolones are promising new antituberculous agents. A randomized controlled trial of 200 adult patients with sputum smear-positive pulmonary tuberculosis was conducted in Tanzania. Patients received either a trial regimen (HRC) consisting of isoniazid (300 mg), rifampin (600 mg), and ciprofloxacin (750 mg) or a control regimen (HRZE) consisting of isoniazid (300 mg), rifampin (600 mg), pyrazinamide (25 mg/kg), and ethambutol (15 mg/kg). The 168 evaluable patients all had negative smears and cultures by month 6, but the time to conversion to negativity was longer for the HRC group than for the HRZE group because of the poor response of patients infected with human immunodeficiency virus (HIV) to the HRC regimen. Relapse was more frequent in the HRC group. The sterilizing activity of ciprofloxacin does not appear to be equal to that of the combination of pyrazinamide and ethambutol, but the difference in outcome was significant only among HIV-infected patients.

Nutritional status and weight gain in patients with pulmonary tuberculosis in Tanzania.

We assessed nutritional status in 200 adult Tanzanian patients with smear-positive pulmonary tuberculosis before, during, and after 6 months of tuberculosis treatment; 148 patients (74%) were successfully followed for 12 months. Marked nutritional impairment was present on admission: 77% of males and 58% of females had a body mass index (BMI) below 18.5; approximately one-fifth had BMI < 16.0. The length of hospital stay and gender, rather than microbiological response, were the major determinants of weight gain during treatment. Patients infected with human immunodeficiency virus (HIV) gained more weight than uninfected patients. Most patients lost weight after completing treatment and returning home. At 12 months, 32% of male and 19% of female patients considered cured of tuberculosis had BMI < 18.5. It is concluded that patients with tuberculosis from this area of Tanzania frequently have evidence of malnutrition both before and after treatment for tuberculosis. Weight gain during therapy appeared to be an unreliable indicator of overall treatment response. However, the results also demonstrated that nutritional rehabilitation can be successfully achieved even in HIV-positive tuberculosis patients and in patients with a suboptimal response to therapy.

PIP: The authors assessed nutritional status in 200 adult Tanzanian patients with smear-positive pulmonary tuberculosis (TB) before, during, and after 6 months of TB treatment. 148 patients were successfully followed for 12 months. Upon admission, 77% of males and 58% of females had a body mass index (BMI) below 18.5, with about 20% having BMI less than 16.0. Most patients lost weight after completing treatment and returning home. At 12 months, 32% of male and 19% of female patients considered cured of TB had BMI less than 18.5. The length of hospital stay and gender, rather than microbiological response, were the major determinants of weight gain during treatment. Patients infected with HIV gained more weight than uninfected patients. The authors conclude that TB patients in Tanzania frequently have evidence of malnutrition both before and after treatment for TB. Weight gain during therapy appeared to be an unreliable indicator of overall treatment response. The study also demonstrated that nutritional rehabilitation can be successfully achieved even in HIV-positive TB patients and in patients with a suboptimal response to therapy.

Clinical features and serum beta 2-microglobulin levels in HIV-1 positive and negative Tanzanian patients with tuberculosis.

Serum beta 2-microglobulin (beta 2M) rises in the later stages of HIV disease and has therefore been used to monitor progression to AIDS. However, little work has been done on patients co-infected with HIV and tuberculosis. We studied clinical features and serum beta 2-M in 35 Tanzanian patients treated for pulmonary tuberculosis (9 HIV-positive, 26 HIV-negative). The provisional WHO clinical definition of AIDS for use in Africa was fulfilled by 89% of the HIV-positive and 65% of the HIV-negative patients. Median serum beta 2-M on admission was slightly higher in HIV-positive (3.17 mg/l) than in HIV-negative (2.85 mg/l) patients. Serum beta 2-M fell during treatment in 17/24 (71%) of HIV-negative and 3/7 (43%) HIV-positive patients followed up for 6 months. We conclude that serum beta 2-M is frequently raised in active tuberculosis, and is therefore an unreliable indicator of the stage of HIV disease in co-infected patients. The WHO clinical definition of AIDS also proved unreliable in patients with tuberculosis.

Restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolated from patients with pulmonary tuberculosis in northern Tanzania.

Isolates of Mycobacterium tuberculosis from 88 patients with pulmonary tuberculosis in northern Tanzania were subjected to IS6110 restriction fragment length polymorphism (RFLP) analysis. Of 88 isolates, 73 fell into 11 groups of which 9 contained 2-5 isolates. Of 2 large homology groups one, group H (20 isolates), was isolated only from patients resident in the Kilimanjaro region, whereas 79% of isolates from other groups came from this region. A significant association (P = 0.023) was found between another group, M (24 isolates) and isolation from patients of the Masai tribe. The data from this pilot study support the idea that IS6110 RFLP analysis provides information which may be of value in the control of tuberculosis in Africa.

Polymerase chain reaction for assessing treatment response in patients with pulmonary tuberculosis.

The use of the polymerase chain reaction (PCR) for assessing treatment response in tuberculosis was investigated. Serial sputum samples were analyzed from 10 Tanzanian patients treated for smear-positive pulmonary tuberculosis, including 4 who relapsed after initially successful treatment. A one-tube nested PCR with a colorimetric detection system was compared with microscopy and culture. Samples were found to be negative by microscopy before they were by PCR or culture, often remaining positive 1-2 months longer by PCR than by culture. For the 76 samples available for both culture and PCR, there was a 76% (58/76) agreement between the methods. Nine samples were negative by culture but positive by PCR; 7 were either negative (5) or equivocal (2) by PCR despite being positive by culture. Two of the 4 relapse cases were detected earlier by PCR than by culture. These results demonstrate that PCR is a promising method for assessing treatment response in pulmonary tuberculosis.

Early bactericidal and sterilizing activities of ciprofloxacin in pulmonary tuberculosis.

The early bactericidal and sterilizing activities of ciprofloxacin were evaluated in the treatment of adult patients with smear positive pulmonary tuberculosis. Two randomized prospective studies were performed in Northern Tanzania. In study 1, ten patients received either 750 mg ciprofloxacin or 300 ng isoniazid daily for 7 days. Counts of colony-forming units (cfu) of Mycobacterium tuberculosis in early morning sputum were performed. In study 2, twenty patients received either a standard regimen of rifampin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E) (regimen HRZE) or a trial regimen of ciprofloxacin (C), isoniazid (H), and rifampin (R) (regimen HRC). Sputum colony counts were performed for 8 wk. Patients were tested for antibodies to human immunodeficiency virus (HIV)-1. The results demonstrate that ciprofloxacin alone has useful early bactericidal activity, resulting in a mean daily fall of 0.20 log10cfu/ml/day during 7 days compared with 0.25 log10cfu/ml/day for isoniazid. When HRZE and HRC regimens were compared, the HRC regimen appeared to be inferior in its sterilizing ability, with a culture conversion rate of 67% at 2 months compared with 100% for HRZE. The difference in outcome was most marked in HIV-1 positive patients. The role of ciprofloxacin in combination regimens may be as a bactericidal rather than a sterilizing agent.

A new micronized formulation of halofantrine hydrochloride in the treatment of acute Plasmodium falciparum malaria.

The current formulation of halofantrine hydrochloride has poor absorption and bioavailability. A newly developed micronized formulation was evaluated for efficacy, safety and tolerance in the treatment of acute Plasmodium falciparum malaria. The study was conducted at a plantation hospital in northern Tanzania, where chloroquine resistance is common. Sixty in-patients with mild or moderate malaria were treated with 375-750 mg micronized halofantrine hydrochloride given in 3 equal doses, 6 h apart. Patients were followed up for 28 d after therapy. Treatment was associated with rapid parasite clearance (mean clearance time = 34.8 h), fever clearance (mean time = 20 h), and clinical improvement (70% of patients were free of all presenting symptoms within 2 d). The formulation was well tolerated clinically, although 3 patients (5%) developed mild pruritus after treatment which may have been drug-related. Haematological and biochemical studies did not indicate any significant toxicity. One patient, whose immediate recovery was uneventful, was found to have a headache and low parasitaemia 3 weeks after treatment. He was readmitted to the study and treated as before. Parasitaemia, fever and headache cleared rapidly and he remained aparasitaemic for 28 d.

A field evaluation of the formol-detergent method for concentrating faecal parasites.

A faecal parasite concentration method which utilizes a formalin-detergent solution has recently been described. This technique was evaluated under field conditions in the Out-Patient Department of a hospital in Northern Tanzania. Fifty faecal samples were examined by saline wet preparation and following formol-detergent concentration. Forty-one different parasite identifications were made by both techniques. Ten parasites were found only on saline wet preparation, and 20 were found only in the formol-detergent concentrate. The method necessitates a 24-h delay in sending a report, which is not justified by the small improvement in diagnostic yield. The authors believe that a modification of the technique may yet achieve acceptable results.