Experimental in vitro efficacy study on the interaction of epiroprim plus isoniazid against Mycobacterium tuberculosis.

Thirty Mycobacterium tuberculosis strains (8: INH(R)/INH(R), 12: INH(R)/RIF(S), 10: INH(S)/RIF(S)) were examined against MICs of epiroprim (EPM) and isoniazid (INH) separately or in association. EPM alone proved to be insufficiently active against the various mycobacterial isolates (MIC > or =256 microg/ml). The observed average sensitivity to the association of EPM plus INH was, in contrast, considerably increased, as reflected by reduced MICs and lower percentages of resistant strains. MICs ranged between 16 and 32 microg/ml EPM and 2 and 4 microg/ml INH for INH(R) strains. All INH(S) isolates were inhibited by a concentration of 0.125 microg/ml EPM and 0.06 microg/ml INH. The fractional inhibitory concentration indices indicated an additive activity on INH(R)/RIF(R) strains and a synergistic activity on INH(R)/RIF(S) and INH(S)/RIF(S) strains. The synergistic activity of this drug association needs to be confirmed in an animal model.

Fansimef for prophylaxis of malaria: a double-blind randomized placebo controlled trial.

At a time when Fansimef, the fixed combination of mefloquine, sulfadoxine and pyrimethamine was considered for prophylaxis of falciparum malaria, a randomized double-blind study comparing the efficacy and tolerability of Fansimef with that of Lariam (mefloquine), Fansidar, chloroquine and placebo in malaria prophylaxis was performed in Thailand from July 1987 to January 1988. The study population of 602 adult males was recruited in Pak Tongchai District, some 360 km North-East of Bangkok, where multiresistant P. falciparum is endemic. All active treatments and placebo were given once weekly for 24 weeks with doses as follows: Fansimef: 125 mg mefloquine + 250 mg sulfadoxine + 12.5 mg pyrimethamine (1 half-strength tablet); Lariam: 125 mg mefloquine (1 half-strength tablet); Fansidar: 500 mg sulfadoxine + 25 mg pyrimethamine; chloroquine; 300 mg. A loading dose of 2 half-strength tablets was given in the Fansimef group in weeks 1 and 2 and in the Lariam group in weeks 1 to 4. The incidence of acute episodes of P. falciparum per 100 person months of prophylaxis was 0.17 each in the Fansimef and the Lariam groups, 1.18 in the Fansidar group, 0.69 in the chloroquine group and 0.64 in the placebo group (differences statistically not significant). Clinically adverse events were reported by 170 subjects (Fansimef 28, Lariam 29, Fansidar 41, choroquine 43, placebo 29; differences statistically not significant). The most frequent adverse events in all groups were headache, sleepiness, dizziness and weakness.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of 5.1-[NANP]19, a recombinant Plasmodium falciparum vaccine candidate, in adults.

In a randomized single-blind study, 13 healthy adult volunteers were subcutaneously immunized with 2 or 3 single 50 or 400 micrograms doses of a Plasmodium falciparum recombinant vaccine candidate designated 5.1-[NANP]19. The vaccine caused transitory reactions at the injection site. Eight (62%) volunteers had a greater than or equal to 4-fold increase of antibody titer against sporozoites in immunofluorescence assay, all 13 seroconverted in IgG enzyme-linked immunosorbent assay against [NANP]50 antigen, and in 6 (46%) a lymphocyte proliferation index greater than or equal to 3 against 5.1 antigen was observed. Seven volunteers were challenged with mosquitoes infected with P. falciparum. All developed detectable parasitemia after 7 to 12 days and all received drug therapy within 24 hours. One volunteer with a cellular response to 5.1 had two negative in vitro parasite cultures before treatment, despite overt parasitemia. He was the only challenged volunteer who remained free of malaria symptoms.

[Current drugs for the treatment of tropical malaria]. / Neue Medikamente für die Behandlung der Malaria tropica.

The occurrence in the early 60's of stable resistance to chloroquine among Plasmodium falciparum strains in the Amazonas and on the Thai-Cambodian border has been a shock for all malariologists. This led to the search for new antimalarials without cross resistance with chloroquine. For each new drug, one of the major concerns was to define how rapidly parasites would develop resistance to this compound. Drug combinations were taken into consideration so as to achieve a delay in the appearance of resistance. The decision to test a triple combination has led to the development of Fansimef, a fixed combination with tablets containing 250 mg mefloquine, 500 mg sulfadoxine and 25 mg pyrimethamine. A very relevant delay in the development of resistance was found both in-vivo--in the P. berghei model--and in-vitro using P. falciparum. Fansimef has also been under investigations for malaria. Controlled clinical trials were performed in Africa, South America and South East Asia. The documentation for this new indication will be submitted to registration authorities in 1991. A preference alternative to continuous chemoprophylaxis is stand-by malaria treatment for travellers to regions where the malaria risk is relatively low. Stand-by treatment is under investigations in France and in Switzerland. In the search for alternative remedies against drug resistant P. falciparum malaria our attention was directed to Yingzhaosu, a new sesquiterpene peroxide of plant origin from traditional Chinese medicine. A short and convenient synthesis of this ring system gave access to a variety of structural analogues of Yingzhaosu.(ABSTRACT TRUNCATED AT 250 WORDS)

Resistance of internal and external parasites to antiparasitic drugs.

Resistance to drugs and pesticides among internal and external parasites is an increasingly widespread problem both geographically and taxonomically. The development of highly effective pesticides by the chemical industry has led to an overreliance on chemotherapy aimed at maximum animal production or public health improvement through parasite control. Resistance to antiparasitic agents has developed in protozoa, helminths and insects. Considerable research efforts are being made around the world in an attempt to formulate sustainable programs of parasite control and resistance management. More than 120 delegates attended a spirited discussion at a Round table on resistance of parasites to antiparasitic drugs at ICOPA VII. Herein we attempt to summarise the main points made at the meeting. The complete texts of the papers submitted for discussion are being published: Resistance of Parasite to Antiparasitic Drugs (Boray, Martin and Roush, editors), MSD AGVET Division of Merck and Co. Inc. Rahway, NJ.

Short course single daily ceftriaxone monotherapy for acute bacterial meningitis in children: results of a Swiss multicenter study. Part I: Clinical results.

In a prospective Swiss multicenter study, 119 children (aged three weeks to 15.5 years) with acute bacterial meningitis were treated with single daily doses of ceftriaxone (100 mg/kg on days one and two and 60 mg/kg thereafter). All patients were randomly assigned to either short course (four, six, seven days) or full course (eight, 12, 14 days) therapy depending on whether they had contracted meningococcal, Haemophilus influenzae type b or pneumococcal meningitis. Bacteriological cure was obtained in 92 children who fully completed the study and in all the 20 culture-positive of the 27 children secondarily excluded from the study for failure to meet all bacteriological and initial safety criteria for continuation in protocol (secondary exclusions). Complete clinical recovery was noted in 105 of 119 patients (88%) and was as frequent in the short course (91%) as in the full course (89%), and as in the secondary exclusion (81%) group. All patients survived. At follow-up examination three to six months after hospital discharge only seven infants and seven children (11.8%), mostly those with poor presentation on admission (p = 0.0012), showed residual neurological sequelae. Side effects of antibiotic therapy were minor but more frequent, albeit not statistically significant (p = 0.065), in children receiving the full course therapy. The results of this study suggest that short course treatment of acute bacterial meningitis in children with single daily ceftriaxone monotherapy is as efficacious as full course therapy and at least as well tolerated.

[Vaccination against malaria: initial trial with an ant-sporozoite vaccine, (NANP)3-TT (RO 40-2361) in Africa (Bobo-Dioulasso, Burkina Faso)]. / Vaccination contre le paludisme: premier essai avec un vaccin antisporozoïte, le (NANP)3-TT (RO 40-2361) en Afrique (Bobo-Dioulasso, Burkina Faso).

The vaccine (NANP)3-TT is a synthetic peptide of the circumsporozoite protein (CS) of Plasmodium falciparum coupled to tetanus toxoid (TT) as protein carrier and adsorbed to aluminium hydroxide as adjuvant. The objectives of the study were to assess the immunogenicity and the protective efficacy of the vaccine in an area where malaria is endemic. The study was conducted in a zone of irrigated rice cultivation known as the Vallée du Kou to the North of Bobo-Dioulasso. Malaria transmission is permanent in the Vallée with maxima in July and November. The study was conducted from June to December 1988. It was a controlled randomised, double blind, prospective vaccine trial. A total of 123 infants from 3 to 5 months of age were randomly assigned to three groups. Group I (controls) received three doses of TT alone, group II received two doses of TT and one of (NANP)3-TT and group III received three doses of (NANP)3-TT. These vaccines were administered simultaneously with the Enlarged Program of Immunisation (EPI) vaccines. The clinical parasitological and immunological status of the children was then monitored over a period of five months. No systemic reactions to the vaccine were observed in the infants either immediately after administration or during the follow-up. Minor local tumefactions were observed in only 3% of the children. The vaccine was found to be immunogenic with a peak IgG response at day 75, when 56% (group II) and 60% (group III) showed antibody titres of at least four times that seen at day 0. The response, however, was a short duration; by day 150 the average antibody titres were not significantly different between the three groups. The incidence and the level of parasiaemia and the incidence of clinical malaria were also not significantly different for each of the three groups during the period of the study. The association of (NANP)3 with tetanus toxoid was not shown to be immunologically inhibitive. The results, despite not showing a protective effect for the vaccine (NANP)3-TT, have shown its immunogenicity and therefore suggest that further development of this vaccine may be worthwhile.

Interferon-alpha and synthetic peptide malaria sporozoite vaccine in non-immune adults: antibody response after 40 weeks.

Adults with no known immunity to sporozoites received, i.m., at weeks 0 and 8 two single 200 micrograms doses of a peptide Plasmodium falciparum sporozoite vaccine conjugated to tetanus toxoid ((NANP)3-TT) plus placebo (group 1) or interferon-alpha (IFN-alpha) (group 2) and were followed for antibody responses at weeks 4, 12 and 40. Peak antibody responses were observed at week 12. At week 40, a greater than or equal to 4-fold increase in antibody titre to sporozoites in IFA, or to (NANP)50 in ELISA was still detectable in 6 of 12 (50%) volunteers in group 1 and in 16 of 25 (64%) in group 2. Peak antibody titres in IFA and ELISA decreased with a rate of 0.8% and 0.5% per week, respectively.

Effects of interferons on immune response to a synthetic peptide malaria sporozoite vaccine in non-immune adults.

A Plasmodium falciparum sporozoite vaccine, composed of a synthetic dodecapeptide (NANP)3 coupled to tetanus toxoid (TT), was injected, at weeks 0 and 8, into non-immune volunteers in two randomized double-blind placebo-controlled trials. In the first trial, 37 volunteers received the vaccine simultaneously with placebo (group 1), 0.5 x 10(6-) (group 2), or 1.5 x 10(6) U (group 3) of recombinant human interferon-alpha (= IFN-alpha). In the second trial, 35 other volunteers received the vaccine with placebo (group 4), 0.25 x 10(6) (group 5), or 1.0 x 10(6) IU (group 6) of interferon-gamma (= IFN-gamma). Immunizations were well tolerated and resulted in seroconversion rates (greater than or equal to 4-fold increase of antibody titre in immunofluorescence or enzyme-linked immunosorbent assays) of 67-100% of volunteers. IFN-alpha significantly enhanced the IgG antibody titres in ELISA to malaria peptide.

Clinical experience with 1000 patients treated with cefetamet pivoxil.

Clinical studies have been carried out world-wide on cefetamet pivoxil, a new orally active cephalosporin. This paper reports on the first 1000 patients treated with the antibiotic; another 505 patients received standard antibiotics, mainly cefadroxil and cefaclor, for comparison. The results show that single doses of 1500 and 1200 mg cefetamet pivoxil were fully effective in gonorrhoea. Comparative trials in uncomplicated urinary tract infection indicate a significant superiority of a single dose of 2 g cefetamet pivoxil (n = 158; 90.0% cure) versus 2 g cefadrox (n = 162; 77.0% cure). In complicated urinary tract infections, a comparable outcome was achieved with a single daily dose of 2 g cefetamet pivoxil for 10 days (n = 99; 90% cure) and 1 g cefadroxil twice daily for 10 days (n = 98; 76.5% cure). The clinical response rate in acute exacerbation of chronic bronchitis was 89.4% in the group receiving cefetamet pivoxil (136 patients) and 83% in the cefaclor-treated group (n = 122). Treatment with 1000 or 2000 mg cefetamet pivoxil achieved a (bacteriological) success rate of 96% compared to 95% with cefaclor in acute ear, nose and throat-infections (n = 91). Overall, based on 894 isolated pathogens prior to therapy, the bacteriological response rate was 90% and it would appear that in vivo the spectrum of this cephalosporin covers a wide range of Gram-negative and Gram-positive pathogens, including urinary pathogens, but excluding Enterococci and Pseudomonas. Cefetamet pivoxil proved to be well tolerated. Mild to moderate adverse events were reported in 7.1% of patients but only 2 of the 1000 patients treated with cefetamet pivoxil were withdrawn because of diarrhoea, which subsided rapidly. There were no clinically relevant deviations in laboratory parameters.

[Malaria in Switzerland]. / La malaria en Suisse.

Some 200 cases of malaria are officially reported yearly in Switzerland. It is estimated that 2000-8000 Swiss travellers are infected by the anopheles mosquito annually, with 90% protected by chemoprophylaxis. An attack of malaria appears to have a better prognosis when the symptoms start in Africa, since treatment is initiated immediately, than in industrialized countries where the mortality is 1-4%. Failure to inquire into travel history is often responsible for the delay in initiating treatment. Severe falciparum malaria is treated by repeated slow quinine infusions followed by 1500 mg sulfadoxine, 75 mg pyrimethamine and 750 mg mefloquine (single dose). This adult dose corresponds to 3 tablets of Lariam and 3 of Fansidar (or 3 of Fansimef). The increase in chloroquine resistance among falciparum strains has led to the use of Fansidar for chemoprophylaxis, followed by the use of mefloquine when Fansidar resistance occurs. The dosage of mefloquine is 250 mg weekly (1 tablet Lariam) for 4 weeks, followed by 1 tablet every fortnight. Treatment is continued for 1 month after return. If the risk of transmission is low, chemoprophylaxis may be replaced by prescription of a reserve drug to be taken in case of fever and headache. A sulfadoxine-pyrimethamine-mefloquine combination (i.e. 3 tablets Fansimef) has been tested in this indication. Ineffective chemoprophylaxis may lead to atypical clinical syndromes, e.g. anemia, hepatosplenomegaly and jaundice, without episodes of fever. HIV positive subjects may risk travelling in tropical countries if they have undergone correct chemoprophylaxis.

Cefetamet pivoxil a new oral cephalosporin: clinical evaluation.

Cefetamet pivoxil, an oral cephalosporin, was given to 683 patients; 414 received standard antibiotics. 1.5 and 1.2 g of cefetamet pivoxil were fully effective in gonorrhea. In two trials in uncomplicated urinary tract infections (UTI) 2 g cefetamet as a single dose was significantly superior (93.3% cure) to 2 g cefadroxil (74.4% cure) and 90.8% vs. 74.7% cure. Results in complicated UTI with 2 g cefetamet for 10 days were 87.9% cure and 71.4% cure with cefadroxil. In acute exacerbation of chronic bronchitis 88% were cured with cefetamet (101 patients) and 80% with cefaclor (n = 94). In acute ear-nose-throat infections, the response rate was 89% and 93% with 1 or 2 g cefetamet per day, respectively. Adverse events were noticed in 6% of the 683 cefetamet-treated patients; they were rapidly reversible.

Intranasal interferon (rIFN-alpha A, Ro 22-8181) for contact prophylaxis against common cold: a randomized, double-blind and placebo-controlled field study.

The prophylactic efficacy of low-dose intranasal recombinant leucocyte interferon alpha (rIFN-alpha A, Ro 22-8181) was investigated under field conditions in 147 families (n = 587 participants), randomized to receive placebo or rIFN-alpha A intranasally in daily doses of 1.5 or 0.3 X 10(6) IU. Treatment was started within 2 days after the appearance of an index case in the household and was continued for 5 days. Clinical data of the index case and of all members of the household were recorded for 10 days. In index cases and all ill contact persons nasal washes were collected for rhinovirus isolation and immunochemical detection of other respiratory viruses. The local tolerance of the intranasal rIFN-alpha A was excellent. Both doses of rIFN-alpha A failed to exert therapeutic effects on established common cold or to prevent the spread of common cold within families. Prophylactic treatment with 1.5 X 10(6) IU did however shorten the duration of the cold (median of 2 days vs. 4 in the placebo group, P = 0.01) and reduced the severity of any ensuing common cold (median total score of 10.5 vs. 30, P less than 0.001). No correlation was found between viral etiology (55% rhinoviruses vs. 13% other respiratory viruses, n = 122 nasal washes) and prophylactic efficacy or clinical severity.