Clinical trial of sparfloxacin for lepromatous leprosy

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Clarithromycin was administered to nine previously untreated lepromatous leprosy patients. Patients received two 1,500-mg doses on the first day, followed by 7 days of no treatment, in order to evaluate the potential efficacy of intermittent therapy. Patients then received 1,000 mg daily for 2 weeks followed by 500 mg daily for 9 weeks. The efficacy of therapy was monitored clinically, by changes in morphological index, mouse footpad infectivity, and radiorespirometric activity of Mycobacterium leprae obtained from serial biopsies and by serum levels of phenolic glycolipid I. Clarithromycin was well tolerated, with only minor side effects noted in two patients. Most patients showed reductions in morphological index and radiorespirometry 1 week after the first two doses. Within 3 weeks of starting treatment (total of 17 g of clarithromycin), biopsy-derived M. leprae specimens from all patients had a morphological index of zero, were noninfectious for mice, and had less than 1% of the radiorespirometric activity of pretreatment specimens. Reductions in serum phenolic glycolipid I levels were observed for most patients at 3 weeks. Significant clinical improvement was evident after 4 weeks of treatment. All analyses indicate that clarithromycin is rapidly bactericidal for M. leprae in humans.Clarithromycin is a new semi-synthetic macrolide with activity, pharmacokinetics, and gastric tolerance superior to those of erythromycin. Clarithromycin has demonstrated exceptional activity against Mycobacterium leprae both in vitro (3, 4) and in vivo (5, 7, 8, 11); its activity surpasses that of other macrolides (5,8) and approximates that of rifampin (5, 7).A recent clinical trial of 500 mg of clarithromycin daily against leprosy showed good activity as determined by loss of infectivity of biopsy-derived M. leprae for mice (10). Because of the exceptional tolerance of clarithromycin and increased half-life at increasing dosage (3) and considering the current use of intermittent rifampin therapy in leprosy, we evaluated the effect of both a single day's dose and a higher daily dose of clarithromycin for nine lepromatous leprosy patients and monitored efficacy by a number of rapid assays in addition to the mouse footpad assay. MATERUILS AND METHODSPatients and treatment. Nine male, previously untreated patients with multibacillary leprosy were recruited; all patients had at least one lesion with a bacteriologic index (BI) of >4+ and a morphologic index (MI) of >1% and of sufficient size so that five 6-mm skin punch biopsy specimens could be taken. By clinical evaluation, patients 1 to 3 were classified as borderline lepromatous and patients 4 to 9 were classified as polar lepromatous. Patients ranged from 14 to 56 (median, 31) years in age. Patients had neither a recent history nor signs or symptoms of lepra reactions upon admission. Examination procedures on admission and during the trial were as previously described (1).Patients, who were hospitalized at the Research Institute for Tropical Medicine, Manila, Philippines, for...

Section: Materuils and Methodsmentioning

confidence: 99%

Clinical trial of clarithromycin for lepromatous leprosy

Chan

Garcia-Ignacio

Chavez

et al. 1994

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“…Fluoroquinolones are new drugs for the treatment of leprosy (6,(8)(9)(10)16), but their use can lead to acquired quinolone resistance in M. leprae (4,11,13). DNA gyrase, a heterotetramer (GyrA 2 GyrB 2 ) enzyme solving DNA topological problems associated with DNA replication, transcription, and recombination (5), is the sole target of quinolones in M. leprae (7).…”

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Are All the DNA Gyrase Mutations Found in Mycobacterium leprae Clinical Strains Involved in Resistance to Fluoroquinolones?

Matrat

Cambau

Jarlier

et al. 2008

Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.Mycobacterium leprae still causes serious chronic disease, and treatment may fail because of poor drug adherence and emergence of resistance (4,10,11,13,18,19). Fluoroquinolones are new drugs for the treatment of leprosy (6,(8)(9)(10)16), but their use can lead to acquired quinolone resistance in M. leprae (4,11,13). DNA gyrase, a heterotetramer (GyrA 2 GyrB 2 ) enzyme solving DNA topological problems associated with DNA replication, transcription, and recombination (5), is the sole target of quinolones in M. leprae (7).M. leprae has the longest doubling time (ϳ14 days) among bacteria and cannot be cultivated in vitro (12). Consequently, the only way to test antibiotic activity is the mouse footpad leprosy model, which is labor intensive and expensive and requires 8-to 12-month experiments (12). Therefore, our aim was to evaluate the consequences of the DNA gyrase mutations described in M. leprae clinical strains (4, 11, 13) on the quinolone inhibition of DNA gyrase as a prerequisite for the development of rapid genetic susceptibility tests. We demonstrated that the GyrA G89C and A91V alterations are implicated in resistance to quinolones whereas the GyrB D205N alteration is not.Plasmids carrying M. leprae genes gyrA and gyrB containing the mutations corresponding to the GyrA G89C or A91V (4, 13) and GyrB D205N (11) alterations were generated from the respective wild-type gyrA and gyrB genes of M. leprae cloned previously (14), with the QuikChange site-directed mutagenesis kit (Stratagene). For the oligonucleotides used for mutagenesis, see Table S1 in the supplemental material. Wildtype and modified GyrA and GyrB proteins were purified as described previously (14). DNA supercoiling and DNA cleavage experiments were carried out as described previously (1,2,14). Nalidixic acid, oxolinic acid, ofloxacin, moxifloxacin, gatifloxacin, and garenoxacin were from Sigma or from the respective laboratories.The 50% inhibitory concentrations (IC 50 s) of gatifloxacin, moxifloxacin, and ofloxacin for the enzymes modified in GyrA were 3-to 11-fold higher (GyrA G89C) and 5-to 8-fold higher (GyrA A91V) than for the wild-type enzyme ( Fig. 1; Table 1). The concentrations of fluoroquinolones and garenoxacin required for the conversion of 25% of the DNA to the linear form (CC 25 s) were 12-to 17-fold higher for the DNA gyrase GyrA A91V than those measured for the wild-type enzyme ( Fig. 2; Table 1). As observed previously for the wild-type Mycobacterium tuberculosis and M. leprae DNA gyrases (1, 14), the two classical nonfluorinated quinolones nalidixic acid and oxolinic acid did not lead to the formation of a DNA cleavable complex with the DNA gyrase GyrA A91V (Table 1). DNA cle...

“…The infectivity for mice of 5, 50, 500, or 5,000 acid-fast bacilli (AFB) from skin biopsy homogenates was determined as previously described (3). A footpad was scored as positive for M. leprae if any bacilli were observed in 60 high-power fields (1 acid-fast bacillus per 60 high-power fields is equivalent to 5 x 103 AFB per footpad).…”

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“…The patients' ages ranged from 12 to 32 years (median, 20 years), and the patients had neither a recent history nor signs or symptoms of lepra reactions upon admission. Examination procedures on admission and during the trial were as previously described (3).…”

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Clinical trial of fusidic acid for lepromatous leprosy

Franzblau

Chan

Garcia-Ignacio

et al. 1994

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Fusidic acid was assessed for antileprosy activity in nine lepromatous leprosy patients. Patients received fusidic acid at either 500 mg/day for 12 weeks or 750 mg/day for 4 weeks followed by 500 mg/day for 8 weeks. All patients showed time-dependent clinical improvement and decreases in bacillary morphological index, radiorespirometric activity and PCR signal, and in serum phenolic glycolipid I. Fusidic acid appears to be a weakly bactericidal antileprosy agent which may have a role in the multidrug treatment of leprosy pending an evaluation of lepra-reaction-suppressive activity. 64 ,ug/ml (11, 18, 23) and, when combined with ethambutol, against some Mycobacterium avium complex strains (18).Fusidic acid is active against Mycobacterium leprae both in axenic medium and in macrophage culture as determined in the BACTEC 460 system (50% inhibition at 1.25 to 2.5 ,ug/ml) (9). An earlier attempt to detect antileprosy activity of fusidic acid in the mouse footpad was unsuccessful (7), possibly because of poor absorption of this compound in mice (14).On the basis of the in vitro activity against M. leprae and human pharmacokinetic properties, a clinical trial of filmcoated sodium fusidate (Fucidin; Leo Pharmaceutical) was conducted with lepromatous leprosy patients. In addition to clinical response, morphological index (MI), and mouse footpad infectivity, patient response was also monitored by measurement of serum phenolic glycolipid I antigen as well as radiorespirometry (10) The patients were hospitalized and received either (i) 500 mg of fusidic acid daily for 8 weeks (patients 1 to 5) or (ii) 750 mg of fusidic acid daily for 4 weeks followed by 500 mg daily for 4 weeks (patients 6 to 9). For all patients, this treatment was followed by an additional 4 weeks of administration of 500 mg of fusidic acid daily as outpatients in order to evaluate the clinical response further.The degree of clinical improvement was assessed according to previously described criteria (3). Serum and 6-mm skin punch biopsy samples were collected just prior to initiation of treatment and at 2-week intervals for 8 weeks. Part of each biopsy sample was processed for mouse footpad assay, radiorespirometry, and MI. The remaining portion was processed separately for PCR. The BI was determined from skin slit smears from at least six sites.The procedure of Cho et al. (6) for measuring phenolic glycolipid I antigen levels was followed. Scoring was based on the relative intensity of color development from the reaction of peroxidase with 4-chloro-1-naphthol.The infectivity for mice of 5, 50, 500, or 5,000 acid-fast bacilli (AFB) from skin biopsy homogenates was determined as previously described (3