Martin Danis

Foscarnet Nephrotoxicity: Mechanism, Incidence and Prevention

Foscarnet is a pyrophosphate analogue that has been successfully used in severe cytomegalovirus (CMV) infections. Little is known of the incidence and mechanisms of foscarnet-induced nephrotoxicity as most data comes from recipients of renal allografts or from patients with severe underlying disease or with other nephrotoxic drugs. We have retrospectively analyzed the evolution of renal function after 56 courses of foscarnet. In addition, we have prospectively studied the protective effects of hydration on foscarnet nephrotoxicity (2.5 liters of saline/day during the night before the foscarnet therapy and throughout the course of treatment). Foscarnet-induced acute renal failure was defined as a rise in serum creatinine of at least 25% from the basal value. An increase in serum creatinine occurred in 37 cases out of the 56 courses of foscarnet (66%). The mean serum creatinine prior to foscarnet was 80.5 +/- 3.3 mumol/l and the mean increase was 190 +/- 28.3 mumol/l (range 80-1,000). Peak serum creatinine was higher than 200 and 300 mumol/l in 16 and 13 patients, respectively. Kidney obtained at autopsy from a 30-year-old male with AIDS, CMV pneumonitis and acute renal failure secondary to foscarnet administration showed an extensive tubular necrosis. In the group which was prospectively hydrated only 1 patient had an acute renal failure. The mean serum creatinine at the peak (96 +/- 4 mumol/l) and at the end of the treatment (83 +/- 4 mumol/l) was significantly lower (p less than 0.05) than in non hydrated patients. In conclusion, foscarnet is a highly nephrotoxic drug which induces acute tubular necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open study of 60 cases

Ivermectin is highly effective against animal intestinal nematodes and is used in the treatment of onchocerciasis in humans. A study was undertaken to compare the efficacy of the drug with that of albendazole in the treatment of uncomplicated strongyloidiasis. Sixty patients with confirmed Strongyloides stercoralis infection were enrolled in an open randomized study and given either albendazole, 400 mg/d for 3 d or ivermectin, 150-200 micrograms/kg in a single dose. Efficacy and tolerance were evaluated on days 7, 30 and 90. Each visit included a parasitological examination of 3 stool specimens, using saline and Kato smears and formalin-ether and Baermann concentrations. Fifty-three patients were eligible for evaluation. Parasitological cure was obtained in 24 of the 29 patients treated with ivermectin (83%) and in 9 of the 24 patients who were given albendazole (38%); ivermectin was significantly more effective than albendazole (P < 0.01). Clinical and biological adverse reactions were negligible in both treatment groups. The 20 patients who failed therapy were given a second treatment course with 150-200 micrograms/kg of ivermectin in a single dose or on 2 consecutive days. Sixteen patients were cured and the other 4 had only incomplete follow-up. Ivermectin therefore constitutes an acceptable therapeutic alternative for uncomplicated strongyloidiasis.

Illnesses in Travelers Returning from the Tropics: A Prospective Study of 622 Patients

BACKGROUND Although between 8 and 19% of travelers consult a doctor after returning from the tropics, the full spectrum of health complaints is unknown. METHODS We analyzed the relative frequency of travel-associated health complaints in all travelers (immigrants returning from visiting their home countries, expatriates, business travelers, and tourists) consulting our department between November 2002 and May 2003. RESULTS A total of 622 patients were studied (256 women, 366 men; median age 38 yr; 45.3% tourists, 33.8% immigrants, 14.1% expatriates, 6.7% business travelers). The median duration of travel was 36.9 days. The main destinations were Africa (57.6%) and Asia (26.4%). A total of 637 diseases were diagnosed, distributed as follows: skin diseases (23.4%), gastrointestinal infections (19.1%), respiratory tract infections (11.5%), malaria (8.8%), schistosomiasis (7.2%), viral hepatitis (4.1%), urinary tract infections (3.5%), sexually transmitted infections (3.5%), tuberculosis (2.7%), dengue fever (2.5%), and others (13.8%). Malaria and intestinal tract infections accounted for 21% and 23% of diagnoses in the 257 febrile travelers, respectively. Overall, 230 diagnoses (36.1%) corresponded to imported tropical diseases, the main imported diseases being malaria, schistosomiasis, amebiasis, gastrointestinal disorders caused by intestinal nematodes, and dengue fever. CONCLUSIONS Tropical diseases are not the leading cause of consultation in travelers returning from the tropics. Immigrants are the travelers most at risk of common tropical diseases, with the noteworthy exceptions of dengue fever and invasive schistosomiasis.

Detection of Aspergillus Galactomannan Antigenemia To Determine Biological and Clinical Implications of Beta-Lactam Treatments

ABSTRACT Detection of Aspergillus galactomannan (GM) in serum with the Platelia Aspergillus enzyme immunoassay (EIA) is useful for diagnosing invasive aspergillosis. From May 2003 to November 2004, 65 patients who did not develop aspergillosis had at least two positive sera while receiving a beta-lactam treatment (GM index [GMI], ≥0.5). Of the 69 treatment episodes scored, 41 consisted of a beta-lactam other than piperacillin-tazobactam (n = 29), namely, amoxicillin-clavulanate (n = 25), amoxicillin (n = 10), ampicillin (n = 3), or phenoxymethylpenicillin (n = 2). In all cases, antigenemia became negative 24 h to 120 h upon stopping the antibiotic. Monitoring of 35 patients, including 26 with hematological malignancies, revealed three antigenemia kinetic patterns: each was observed with any drug regimen and consisted of a persistent GMI of >2.0 (65.7%), >0.5, and ≤1.5 (25.7%) or a variable GMI (14.3%) from the onset of antibiotic therapy. All available drug batches given to 26 patients cross-reacted with the EIA. Galactomannan titration in batches failed to predict the GM titers in the five patients studied at cumulative doses of ampicillin or amoxicillin-clavulanate, regardless of the time lapse between serum sampling and infusion period. Our results show that beta-lactams other than piperacillin-tazobactam may lead to false presumption of aspergillosis. The resulting kinetic patterns of GM antigenemia are variable, and sampling serum prior to the next beta-lactam dose may not decrease GMI below the threshold. Consequently, testing of suspected antibiotic batches remains the only indicator of possible false EIA positivity.

In Vitro Activities of 25 Quinolones and Fluoroquinolones against Liver and Blood Stage Plasmodium spp.

ABSTRACT The in vitro activities of 25 quinolones and fluoroquinolones against erythrocytic stages of Plasmodium falciparum and against liver stages of Plasmodium yoelii yoelii and P. falciparum were studied. All compounds were inhibitory for chloroquine-sensitive and chloroquine-resistant P. falciparum grown in red blood cells. This inhibitory effect increased with prolonged incubation and according to the logarithm of the drug concentration. Grepafloxacin, trovafloxacin, and ciprofloxacin were the most effective drugs, with 50% inhibitory concentrations of <10 μg/ml against both strains. Only grepafloxacin, piromidic acid, and trovafloxacin had an inhibitory effect against hepatic stages of P. falciparum and P. yoelii yoelii; this effect combined reductions of the numbers and the sizes of schizonts in treated cultures. Thus, quinolones have a potential for treatment or prevention of malaria through their unique antiparasitic effect against erythrocytic and hepatic stages of Plasmodium.

What is known about the prevention of congenital toxoplasmosis

The French programme for the prevention of congenital toxoplasmosis consists of the diagnosis and treatment with spiramycin of acute infections during pregnancy and monthly follow-up of all identified seronegative women. The major flaw is that the efficacy of spiramycin in preventing contamination of the fetus, or at least in reducing the extent of the infection, has never been evaluated in a randomised placebo-controlled clinical trial. Its evaluation would require the follow-up of children born to mothers contaminated during pregnancy for more than 6 months, a goal that is difficult to obtain in current practice. The cost of the programme depends largely on the proportion of non-immune women of childbearing age. Since the modes of contamination are known and are linked to living habits, it should be possible to reduce the risk of infection during pregnancy by adequate health education. This approach is still to be evaluated.

Resurgence of Blackwater Fever in Long-Term European Expatriates in Africa: Report of 21 Cases and Review

Blackwater fever (BWF) is a severe clinical syndrome, characterized by intravascular hemolysis, hemoglobinuria, and acute renal failure that is classically seen in European expatriates chronically exposed to Plasmodium falciparum and irregularly taking quinine. BWF virtually disappeared after 1950, when chloroquine superseded quinine. We report 21 cases of BWF seen in France from 1990 through 1999 in European expatriates who lived in sub-Saharan Africa. All patients had macroscopic hemoglobinuria, jaundice, and anemia. Acute renal failure occurred in 15 patients (71%), 7 of whom required dialysis. The presumed triggers of BWF were halofantrine (38%), quinine (24%), mefloquine (24%), and halofantrine or quinine (14%). Glucose-6-phosphate dehydrogenase (G6PD) activity was normal in the 14 patients who underwent this test. Low-level P. falciparum parasitemia was found in 8 patients. All 21 patients survived. Our data and 13 cases reported in the literature suggest a resurgence of classic BWF among Europeans living in Africa and a need to discuss attendant therapeutic implications.

Localized cutaneous leishmaniasis imported into Paris: a review of 39 cases.

Background  Localized cutaneous leishmaniasis (LCL) is a common cause of dermatosis in travelers returning from the tropics. We describe the epidemiological, clinical, and biological aspects and therapeutic outcome of imported LCL.

New Active Drugs against Liver Stages of Plasmodium Predicted by Molecular Topology

ABSTRACT We conducted a quantitative structure-activity relationship (QSAR) study based on a database of 127 compounds previously tested against the liver stage of Plasmodium yoelii in order to develop a model capable of predicting the in vitro antimalarial activities of new compounds. Topological indices were used as structural descriptors, and their relation to antimalarial activity was determined by using linear discriminant analysis. A topological model consisting of two discriminant functions was created. The first function discriminated between active and inactive compounds, and the second identified the most active among the active compounds. The model was then applied sequentially to a large database of compounds with unknown activity against liver stages of Plasmodium. Seventeen drugs that were predicted to be active or inactive were selected for testing against the hepatic stage of P. yoelii in vitro. Antiretroviral, antifungal, and cardiotonic drugs were found to be highly active (nanomolar 50% inhibitory concentration values), and two ionophores completely inhibited parasite development. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed on hepatocyte cultures for all compounds, and none of these compounds were toxic in vitro. For both ionophores, the same in vitro assay as those for P. yoelii has confirmed their in vitro activities on Plasmodium falciparum. A similar topological model was used to estimate the octanol/water partition of each compound. These results demonstrate the utility of the QSAR and molecular topology approaches for identifying new drugs that are active against the hepatic stage of malaria parasites. We also show the remarkable efficacy of some drugs that were not previously reported to have antiparasitic activity.

Severe imported Plasmodium falciparum malaria, France, 1996-2003.

Little is known about severe imported Plasmodium falciparum malaria in industrialized countries where the disease is not endemic because most studies have been case reports or have included <200 patients. To identify factors independently associated with the severity of P. falciparum, we conducted a retrospective study using surveillance data obtained from 21,888 P. falciparum patients in France during 1996-2003; 832 were classified as having severe malaria. The global case-fatality rate was 0.4% and the rate of severe malaria was ≈3.8%. Factors independently associated with severe imported P. falciparum malaria were older age, European origin, travel to eastern Africa, absence of chemoprophylaxis, initial visit to a general practitioner, time to diagnosis of 4 to 12 days, and diagnosis during the fall-winter season. Pretravel advice should take into account these factors and promote the use of antimalarial chemoprophylaxis for every traveler, with a particular focus on nonimmune travelers and elderly persons.