Search PubMed⌕ Search

Biomedical subjects

J Grosset

Publications and source records attributed to J Grosset.

At least 19 recordsLinked to original sources
PubMed2004

Pharmacokinetic and pharmacodynamic issues in the treatment of mycobacterial infections.

The therapy of mycobacterial infections is challenging for a number of reasons. Because mycobacteria are not susceptible to many classes of antibacterial agents, treatment typically requires the use of antimicrobial drugs that are not commonly used and may have small therapeutic windows. For many species, procedures for drug susceptibility testing and optimal treatment regimens have yet to be defined. Finally, because mycobacteria are generally slow to succumb to antimicrobial agents, therapy must be given with multiple drugs for prolonged periods of time, making it necessary to monitor for drug toxicity, drug interactions, and patient nonadherence. Better understanding of the pharmacokinetics and pharmacodynamics of antimycobacterial agents should improve the therapy of mycobacterial infections. Using current treatment strategies for tuberculosis and Mycobacterium avium complex infections as examples, this review highlights basic pharmacokinetic and pharmacodynamic principles and the rationale for combination chemotherapy that should also be applicable to other mycobacterial infections.

Administration, Oral↗
PubMed2003

Impact of iron loading on the activity of isoniazid or ethambutol in the treatment of murine tuberculosis.

OBJECTIVE: To assess the impact of iron loading on the activity of isoniazid and ethambutol in the treatment of murine tuberculosis. DESIGN: Iron-loaded and iron-normal female Balb/C mice infected with 1.5 x 10(7) colony forming units of Mycobacterium tuberculosis were treated with either isoniazid or ethambutol for 28 days. RESULTS: For both treatments, the outcome was impaired by the iron loading: bactericidal activity of isoniazid was partially but significantly reduced and ethambutol bactericidal activity was totally inhibited. CONCLUSION: The treatment of tuberculosis in patients with iron loading should be longer than for normal patients or should contain an additional drug.

Animals↗
PubMed2003

Drug resistance among failure and relapse cases of tuberculosis: is the standard re-treatment regimen adequate?

OBJECTIVE: To determine acquired drug resistance among failure and relapse cases after treatment of new smear-positive tuberculosis. METHODS: A cohort of 2901 patients with new smear-positive tuberculosis was enrolled in Vietnam. Sputum samples were stored at enrolment. Upon failure or relapse, another sputum sample was collected. Both were cultured and underwent drug susceptibility testing and restriction fragment length polymorphism (RFLP) typing. RESULTS: Of 40 failure cases, 17 had multidrug resistance (MDR) at enrolment. At failure, 15 of the 23 (65%) patients without primary MDR had acquired MDR. Of 39 relapse cases and 143 controls, none had primary MDR. CONCLUSION: Primary drug resistance was a strong risk factor for failure and relapse and for acquiring further resistance. As 80% of failure cases had MDR, the standard re-treatment regimen appears inadequate for failure cases in this control programme with a very high cure rate among new cases.

Adolescent↗
PubMed2001

Mycobacterium xenopi spinal infections after discovertebral surgery: investigation and screening of a large outbreak.

BACKGROUND: Mycobacterium xenopi spinal infections were diagnosed in 1993 in patients who had undergone surgical microdiscectomy for disc hernia, by nucleotomy or microsurgery, in a private hospital. Contaminated tap water, used for rinsing surgical devices after disinfection, was identified as the source of the outbreak. Several cases were recorded in the 4 years after implementation of effective control measures because of the long time between discectomy and case detection. The national health authorities decided to launch a retrospective investigation in patients who were exposed to M xenopi contamination in that hospital. METHODS: Mailing and media campaigns were undertaken concurrently to trace exposed patients for spinal infections. Patients were screened by magnetic resonance imaging (MRI), and the scans were reviewed by a radiologist who was unaware of the diagnosis. Suspected cases had discovertebral biopsy for histopathological and bacteriological examination. FINDINGS: Of 3244 exposed patients, 2971 (92%) were informed about the risk of infection and 2454 (76%) had MRI. Overall, 58 cases of M xenopi spinal infection were identified (overall cumulative frequency 1.8%), including 26 by the campaign (mean delay in detection 5.2 years, SD 2.4, range 1-10 years). Multivariate analysis showed that the risk of M xenopi spinal infection was related to nucleotomy and high number of patients per operating session. INTERPRETATION: Failures in hygiene practices could result in an uncontrolled outbreak of nosocomial infection. Patients who have been exposed to an iatrogenic infectious hazard should be screened promptly and receive effective information.

Adult↗
PubMed2001

Iron and Mycobacterium tuberculosis infection.

BACKGROUND: iron is known to play a role in the susceptibility to and outcome of several infections. In view of the increasing worldwide problem of tuberculosis, it may be important to ascertain whether this is also the case with this infection. OBJECTIVES: (1) to review studies conducted in vitro, in experimental animals, and in humans that provide evidence that iron status may influence the occurrence and outcome of tuberculosis. (2) To perform an in vivo study in mice, examining the effect of iron loading on experimental infection caused by a virulent strain of Mycobacterium tuberculosis. RESULTS: we studied the effect of iron loading on the growth in spleen and lungs of a virulent strain of M. tuberculosis, injected i.v. in female Balb/C mice. At sacrifice on day 42 after the experimental infection, the iron-loaded mice presented a significantly enhanced multiplication of M. tuberculosis in both the spleen and the lungs, when compared to the mice without iron loading. CONCLUSION: Most of the studies, including our experimental study in mice, tend to suggest that an excess of iron may enhance the growth of M. tuberculosis and worsen the outcome of human tuberculosis.

Animals↗
PubMed2001

Activities of new macrolides and fluoroquinolones against Mycobacterium ulcerans infection in mice.

Mice infected in the left hind footpad with 5 log(10) acid-fast bacilli of Mycobacterium ulcerans were divided into an untreated control group and 17 treatment groups that received one of the following regimens for 4 weeks (all doses in milligrams per kilogram): 100 mg of azithromycin (AZM), 100 mg of clarithromycin (CLR), or 50 mg of AZM for a duration of 5 days a week (daily), three times a week, or once weekly. In addition, the following regimens were administered daily: 100 mg of telithromycin (TLM), sparfloxacin (SPX), or moxifloxacin (MOX); 200 mg of levofloxacin (LVX); 100 mg of streptomycin (STR) or amikacin (AMK); 10 mg of rifampin (RIF); and the combination of 10 mg of RIF and 100 mg of AMK (RIF+AMK). After completion of treatment, mice were observed for 30 weeks. The effectiveness of treatment regimens was assessed in terms of the delay in median time to footpad swelling in treated mice compared with that in the untreated controls. Clear-cut bactericidal activity, i.e., an observed delay in footpad swelling that exceeded the period of treatment, was observed in the STR-, AMK-, and RIF+AMK-treated mice. However, all mice treated with either AMK or STR alone had swollen footpads before the end of the 30-week observation period, suggesting regrowth of M. ulcerans. In contrast, 50% of the mice treated with the RIF+AMK combination exhibited no lesion even after 30 weeks, suggesting cure. The remaining regimens could be assigned to one of three groups: (i) no activity (50 mg of AZM, 100 mg of AZM thrice weekly, TLM, and LVX); (ii) bacteriostatic activity, i.e., a delay in footpad swelling shorter than the 4-week treatment duration (100 mg of AZM daily or once weekly, CLR thrice or once weekly, and MOX); or (iii) weak bactericidal activity (CLR daily and SPX). The RIF+AMK combination and possibly RIF+STR warrant further study for the treatment of M. ulcerans infection in humans.

Animals↗
PubMed2001

Efficacies of clarithromycin regimens against Mycobacterium xenopi in mice.

Mice were infected intravenously with 3.5 x 10(7) CFU of Mycobacterium xenopi and treated with various clarithromycin-containing regimens or left untreated for 4 weeks. All nine of the clarithromycin-containing regimens reduced the CFU counts to the levels below the pretreatment values, indicating that these regimens had a bactericidal effect on M. xenopi in mice. The rifampin-isoniazid-ethambutol regimen was significantly less bactericidal than clarithromycin alone or clarithromycin-containing combined regimens.

Animals↗
PubMed2001

Effectiveness of once-weekly rifapentine and moxifloxacin regimens against Mycobacterium tuberculosis in mice.

Mice infected with 1.6 x 10(7) CFU of Mycobacterium tuberculosis were treated 14 days later for 6 months with a regimen of once-weekly 10 mg of rifapentine and 75 mg of isoniazid per kg of body weight supplemented with either 150 mg of streptomycin per kg or 100 mg of moxifloxacin per kg during either both the 2-week daily initial and once-weekly continuation phases or only in the daily 2-week initial phase. On completion of treatment, all lung cultures were negative, except for three mice, each with a single colony: two whose rifapentine-isoniazid regimen was supplemented with streptomycin during the whole course of therapy and one whose rifapentine-isoniazid regimen had no initial daily phase, but was supplemented with streptomycin and moxifloxacin during the whole course of therapy. After 3 months of follow-up, positive lung cultures were obtained from 61 and 56% of mice supplemented with streptomycin during either the full course of therapy or only the daily 2-week initial phase, respectively, and 15 and 50% of mice supplemented with moxifloxacin during either the full course of therapy or only the daily 2-week initial phase, respectively. These results suggest that moxifloxacin has sterilizing activity against M. tuberculosis.

Animals↗
PubMed2000

Mycobacterial growth indicator tube versus the proportion method on Löwenstein-Jensen medium for antibiotic susceptibility testing of Mycobacterium tuberculosis.

The Mycobacterial Growth Indicator Tube, a reliable system for detection of mycobacterial growth, was compared with the reference proportion method on Löwenstein-Jensen medium for antibiotic susceptibility testing of Mycobacterium tuberculosis. A total of 62 clinical strains and four reference strains of Mycobacterium tuberculosis were tested for susceptibility to streptomycin, isoniazid, rifampicin and ethambutol. Of these, 36 were susceptible to all four antibiotics and 30 were resistant to at least one of them. Tests were repeated in cases of discrepant results. When each drug/strain combination was considered separately, the overall agreement between the two methods was 96.5% (98.4% for streptomycin, 95.3% for isoniazid, 96.9% for rifampicin and 95.3% for ethambutol) with regard to the initial testing and 98.8% (100, 98.5, 98.5 and 98.4%, respectively) after repeated testing. When the results were considered strain by strain, the agreement was 86% after the initial testing and 95% after repeated testing. The results were obtained after a mean time of 9.5 days. These results suggest that the Mycobacterial Growth Indicator Tube is a reliable method for testing susceptibility of mycobacterial strains to first-line antituberculous drugs.

Antitubercular Agents↗
PubMed2000

Bactericidal activities of HMR 3647, moxifloxacin, and rifapentine against Mycobacterium leprae in mice.

Bactericidal activities of HMR 3647 (HMR), moxifloxacin (MXFX), and rifapentine (RPT) against Mycobacterium leprae, measured by the proportional bactericidal technique in the mouse footpad system, were compared with those of the established antileprosy drugs clarithromycin (CLARI), ofloxacin (OFLO), and rifampin (RMP). Administered in five daily doses of 100 mg/kg of body weight, HMR appeared slightly more bactericidal than CLARI. In a single dose, MXFX at 150 mg/kg was more active than the same dose of OFLO and displayed exactly the same level of activity as RMP at 10 mg/kg; the combination MXFX-minocycline (MINO) (MM) was more bactericidal than the combination OFLO-MINO (OM); RPT at 10 mg/kg was more bactericidal than the same dose of RMP and even more active than the combination RMP-OFLO-MINO (ROM); the combination RPT-MXFX-MINO (PMM) killed 99.9% of viable M. leprae and was slightly more bactericidal than RPT alone, indicating that the combination PMM showed an additive effect against M. leprae.

Animals↗
PubMed2000

Activities of several antimicrobials against Mycobacterium ulcerans infection in mice.

Mycobacterium ulcerans inoculated into the footpads of mice at 6 x 10(3) CFU was shown to have a generation time of 6.5 days when estimated from weekly changes in microscopic counts of acid-fast bacilli (AFB) and 7.5 days when calculated from actual CFU enumerated on Lowenstein-Jensen egg medium incubated at 32 degrees C. Footpads became swollen at week 10 (W10) after infection, and all infected control mice were dead at W15 after infection. Daily (5 days/week) treatment with 100 mg of clarithromycin (CLR)/kg of body weight beginning the day after infection prevented swelling of footpads at W10. When initiation of treatment was delayed until obvious footpad swelling was observed, there was a reduction in both the increase in AFB counts and deterioration of swollen footpads and also a prolonged survival of the mice to W18. Mice infected in the hind footpads with 5 x 10(5) CFU of M. ulcerans were divided into an untreated control group and six treatment groups that received one of the following therapies for 8 weeks: 100 mg of CLR/kg, 25 mg of minocycline (MIN)/kg, 50 mg of sparfloxacin (SPX)/kg, 10 mg of rifampin (RIF)/kg, 10 mg of rifabutin (RBT)/kg, or 100 mg of amikacin (AMK)/kg. After completion of therapy, treated animals were observed for an additional 17 weeks. All control mice and mice treated with CLR, MIN, or SPX exhibited swollen footpads during the observation period. In contrast, of those animals treated with RIF, RBT, or AMK, none had footpad swelling and all inoculated cultures done after the W17 observation remained negative. These results suggest that RIF, RBT, and AMK may be effective in the treatment of human infection with M. ulcerans.

Animals↗
PubMed2000

Antituberculosis activity of once-weekly rifapentine-containing regimens in mice. Long-term effectiveness with 6- and 8-month treatment regimens.

The effectiveness of various once-weekly 10 mg/kg rifapentine (P)- containing regimens for treatment of tuberculosis was assessed in mice infected intravenously with 4.3 x 10(6) colony-forming units (cfu) of Mycobacterium tuberculosis H37Rv, and treated 14 d later with various combinations of rifampin (R), P, isoniazid (H), pyrazinamide (Z), ethambutol (E), or streptomycin (S). Control mice treated daily with either 2-mo HRZ + 4-mo HR or 2-mo HRZ + 6-mo HE were rendered spleen and lung culture-negative at 6 mo and 8 mo, respectively. Treatment failure with emergence of R-resistant bacilli occurred in all mice given once-weekly monotherapy with P for 6 mo. Once-weekly PH treatment was successful at 6 mo when it was preceded by a 2-mo daily phase with HRZ. When the initial daily phase was reduced to 2 wk, once-weekly PH-containing treatment was successful, at 6 mo, only if it was supplemented with S during the initial daily and the once-weekly phases, and at 8 mo if it was supplemented with daily H during the once-weekly phase. Without these supplements, once-weekly treatment failed in some mice with selection of R-resistant or H-resistant mutants.

Animals↗
PubMed2000

Combination of rifapentine-moxifloxacin-minocycline (PMM) for the treatment of leprosy.

To further the development of a multidrug regimen for treatment of leprosy that is suitable for monthly administration and fully supervisable, the bactericidal activities against Mycobacterium leprae of HMR 3647 (HMR), moxifloxacin (MXFX) and rifapentine (RPT) were measured by the proportional bactericide technique in the mouse footpad system, and compared with those of the established antileprosy drugs clarithromycin (CLARI), ofloxacin (OFLO) and rifampicin (RMP). Administered in five daily doses of 100 mg per kg body weight, HMR appeared slightly more bactericidal than CLARI, but the difference did not attain statistical significance. Administered as single doses, MXFX in a dosage of 150 mg per kg was more active than OFLO in the same dosage, and displayed the same level of activity as RMP in a dosage of 10 mg per kg; the combination MXFX-minocycline (MINO) (MM) was more bactericidal than the combination OFLO-MINO (OM); RPT in a dosage of 10 mg per kg was more bactericidal than RMP administered in the same dosage, and even more active than the combination RMP-OFLO-MINO (ROM); the combination RPT-MXFX-MINO (PMM) killed 99.9% of viable M. leprae, and was slightly more bactericidal than was RPT alone, indicating that the combination PMM showed an additive effect against M. leprae. These promising results justify a clinical trial among lepromatous patients, in which MM is being compared with OM, and PMM with ROM, in terms of efficacy and tolerance.

Animals↗
PubMed2000

The new challenges for chemotherapy research.

Scientific knowledge is constantly expanding, and needs are changing; therefore, efforts must be made to adapt the treatment of leprosy and the manner in which it is implemented to the newly identified needs. Because an effective vaccine against leprosy remains to be identified, multidrug therapy (MDT) is the only tool available for leprosy control. At present, therefore, the priority is to make MDT available in all endemic countries for all patients, even those living in difficult-to-access areas. The remaining important issues in chemotherapy research are to improve the quality of leprosy case-finding, improve the quality of MDT, identify the areas in which leprosy patients are not receiving proper MDT, and find the means necessary to ensure delivery to all of appropriate MDT. The MDT regimens recommended by the World Health Organization are of too long duration, require correct classification of the patients as PB or MB, and rely upon the daily self-administration of dapsone and clofazimine to prevent selection of rifampicin resistant mutants among MB patients. Thus, research leading to the development of new drug regimens should be directed toward overcoming the shortcomings of the presently recommended regimens. The drugs required to permit use of regimens of shorter duration, that may be employed among both PB and MB patients, and that enable fully supervised drug administration may be already in hand, and the necessary clinical trials to confirm efficacy and acceptability should be carried out.

Drug Therapy, Combination↗
PubMed2000

Twenty-five years of tuberculosis in a French university hospital: a laboratory perspective.

OBJECTIVE: To determine the impact of recent changes in the epidemiology of tuberculosis in France and other industrialised countries on the primary trends of tuberculosis case rates in a French university hospital. DESIGN: Descriptive study of all 4549 culture-positive tuberculosis cases hospitalised at Pitié-Salpêtrière Hospital between 1972 and 1996. RESULTS: From 1972, there was a decline of 5% per year in the tuberculosis case rate, which levelled off in 1983. The proportion of tuberculosis patients who were human immunodeficiency virus (HIV) positive increased from 2% in 1983 to 28% in 1990, and thereafter remained stable. The proportion of foreign-born tuberculosis patients also increased, from 40% in 1972 to 55% in 1985. These two changes affected drug resistance patterns. Drug resistance was more common among foreign-born than among French-born patients, whether previously treated or not. Resistance to rifampicin and multidrug resistance among previously untreated patients was highly related to HIV co-infection. Extrapulmonary sites of tuberculosis were more often smear-positive in HIV-positive than in non-HIV-positive patients (22.8% vs 12.6%), and bacteraemia was diagnosed almost exclusively in HIV-positive patients. CONCLUSION: The changes in clinical and bacteriological tuberculosis patterns at the hospital level over the last 25 years have paralleled those observed at national and international level in industrialised countries, including a slowing in the decrease in the case rate, due in part to the HIV epidemic, a higher proportion of foreign-born patients and an increase in drug resistance.

AIDS-Related Opportunistic Infections↗
PubMed2000

Surveillance of Mycobacterium tuberculosis drug resistance in France, 1995-1997. AZAY Mycobacteria Study Group.

OBJECTIVE: To measure the rate of primary and secondary drug resistance of Mycobacterium tuberculosis on an ongoing basis. DESIGN: Data on all culture-positive tuberculosis were collected prospectively from 1995 through 1997 from a microbiological laboratory network of 19 university hospitals throughout France, and submitted quarterly to the National Reference Centre for Surveillance of Mycobacterial Diseases. RESULTS: A total of 2998 patients were included in the study. Among the 2333 (78%) previously untreated patients, 8.6% had isolates resistant to any drug, 4.8% to streptomycin (SM) alone, 1.2% to isoniazid (INH) alone, 1.8% to SM + INH, and 0.3% to INH + rifampicin (RMP) or multidrug resistance (MDR). Foreign birth was independently associated with a higher risk of primary resistance to any drug (odds ratio [OR] 1.5). Among the 268 (9%) previously treated patients, 20.9% had isolates resistant to any drug, 6.3% to SM alone, 3.4% to INH alone, 4.1% to SM + INH, and 3.7% to INH + RMP. Foreign birth (OR = 2.3), and human immunodeficiency virus positive status (OR = 4.4) were independently associated with a higher risk of secondary resistance to any drug. CONCLUSION: During the last 30 years there has been no increase in resistance to any drug among previously untreated patients. As expected, secondary resistance was highly associated with foreign birth. MDR-TB remains a rare event in France.

AIDS-Related Opportunistic Infections↗