In vitro and in vivo activities of sparfloxacin against Mycoplasma pneumoniae.

The in vitro and in vivo activities of sparfloxacin against Mycoplasma pneumoniae were compared with those of erythromycin, levofloxacin, ofloxacin, and minocycline. The MICs of sparfloxacin, erythromycin, levofloxacin, ofloxacin, and minocycline for 90% of the 43 M. pneumoniae strains tested were 0.063, 0.016, 0.5, 1, and 0.5 microgram/ml, respectively. In the experimental pulmonary M. pneumoniae infection model in Syrian golden hamsters, sparfloxacin was as effective as erythromycin when orally administered at 15 mg/kg twice daily for 5 days and more effective than erythromycin when orally administered at 10 mg/kg once daily for 5 days. Sparfloxacin was more effective than levofloxacin and ofloxacin in both dosing regimens. The peak concentrations of sparfloxacin in hamster sera after administration of single oral doses of 15 mg/kg were almost the same as those in human sera after administration of single oral doses of 200 mg (the usual clinical dose), and the half-life of sparfloxacin in hamster serum was shorter than that in human serum after administration of a single oral dose of 200 mg. These results suggest that sparfloxacin may be clinically useful for the treatment of M. pneumoniae infections.     

In vitro and in vivo activities of macrolides against Mycobacterium leprae.

We previously demonstrated the potent in vitro activity of erythromycin against Mycobacterium leprae as determined by its effect on ATP pools and rates of palmitate oxidation and phenolic glycolipid I synthesis. In the present study, the relative in vitro activities of a number of new macrolides with superior pharmacokinetic properties were assessed. In addition, for the most active compounds, concentrations in serum were determined by bioassay during continuous administration in the feed of mice, and in vivo activity against M. leprae was assessed by the kinetic mouse footpad technique. Both clarithromycin and roxithromycin were more potent than erythromycin in vitro, with the former showing the highest activity in accelerating rates of ATP decay and reducing rates of palmitate oxidation. In mice, concentrations of clarithromycin in serum were higher than those of roxithromycin and erythromycin, with the latter undetectable even when administered at 0.1% (wt/wt) in the diet. When administered at 0.01% (wt/wt) in the diet, erythromycin and roxithromycin were unable to inhibit growth of M. leprae in mouse footpads whereas clarithromycin demonstrated bactericidal-type activity. On the basis of these data and other properties of macrolides, a clinical trial of clarithromycin in leprosy is warranted.     

四种国产大环内酯类抗菌药物体外抗沙眼衣原体和肺炎衣原体敏感性研究

目的 研究国产必特螺旋霉素、乙酰螺旋霉素、红霉素和阿奇霉素等4种大环内酯类药物对于沙眼衣原体和肺炎衣原体体外药物敏感性试验,评估其抗衣原体作用,以指导临床用药.方法 细胞培养和免疫荧光包涵体染色技术测定4种国产大环内酯类抗菌药物对于沙眼衣原体和肺炎衣原体体外MIC.结果 对于沙眼血清型B,必特螺旋霉素、红霉素和阿奇霉素体外MIC为0.5μg/ml,乙酰螺旋霉素为4μg/ml.对于沙眼血清型D,必特螺旋霉素与阿奇霉素体外MIC均为0.25μg/ml,红霉素0.5μg/ml,乙酰螺旋霉素2μg/ml.对于肺炎衣原体,红霉素体外MIC≤0.016μg/ml,阿奇霉素和必特螺旋霉素均为0.032μg/ml,乙酰螺旋霉素0.5μg/ml.结论 国产必特螺旋霉素、红霉素和阿奇霉素体外抗沙眼衣原体(血清型B和D)和肺炎衣原体作用可靠,但乙酰螺旋霉素则较差.     

In vitro activities of moxifloxacin and other fluoroquinolones against Mycoplasma pneumoniae

A total of 105 isolates of Mycoplasma pneumoniae were evaluated for susceptibility to moxifloxacin, sparfloxacin, levofloxacin, and ciprofloxacin. Moxifloxacin, a newly synthesized compound, showed the greatest activity. The MICs and MBCs at which 50 and 90% of isolates were affected were 0.15 (MIC(50) and MBC(50)) and 0.3 microg/ml (MIC(90) and MBC(90)) respectively. The results indicate that moxifloxacin might be promising an antimycoplasmal agent.     

In vitro and in vivo activities of Q-35, a new fluoroquinolone, against Mycoplasma pneumoniae.

The in vitro potency and in vivo efficacy of Q-35, a new fluoroquinolone, against Mycoplasma pneumoniae were investigated by pharmacokinetic studies with M. pneumoniae-infected hamsters. By using fluoroquinolones, macrolides, and tetracyclines as references, Q-35 was found to possess the greatest mycoplasmacidal activity. The MIC for 90% of strains tested (MIC90) and the MIC50 were 0.78 and 0.39 microgram/ml, respectively, and the MBC for 90% of strains tested (MBC90) and the MBC50 were 3.13 and 0.78 microgram/ml, respectively. The MBC50-to-MIC50 ratio for Q-35 was 2. Furthermore, only Q-35 continued to be effective against 19 strains of erythromycin-resistant mutants of M. pneumoniae. The efficacies of fluoroquinolones against M. pneumoniae were also investigated by using an experimental hamster pneumonia model to measure the CFU of M. pneumoniae in the lungs. Q-35 and ofloxacin were efficacious following oral administration of 200 mg/kg/day for 5 days, initiated 24 h after infection, while ciprofloxacin was not active. Continuous administration of Q-35 for 10 days significantly reduced numbers of viable M. pneumoniae in the lungs. These results suggest that both Q-35 and ofloxacin are effective in the early phase of infection and, moreover, that Q-35 is also effective in the middle stage of infection, when progressive lung alterations and continuous increases in mycoplasmal growth occur. Peak levels of Q-35 in sera and lungs after oral administration were higher than those of ciprofloxacin but lower than those of ofloxacin. On the basis of these results, Q-35 appears to be a promising antimicrobial agent in chemotherapy of mycoplasmal infection.     

Antimycoplasmal activities of new quinolones, tetracyclines, and macrolides against Mycoplasma pneumoniae.

Fifty strains of Mycoplasma pneumoniae were tested for susceptibility to new quinolones, tetracyclines, and macrolides. Temafloxacin, ofloxacin, and ciprofloxacin possessed the most mycoplasmacidal activity against these organisms. The MBC for 50% of the strains (MBC50)-to-MIC50 ratio for each of these drugs was 4. The MBC50-to-MIC50 ratios for the tetracyclines and macrolides were markedly higher, within a range of 32 to 2,000. On the basis of these results, temafloxacin and ofloxacin might be promising antimicrobial agents for the treatment of mycoplasmal infection.     

In vitro activities of new macrolides and rifapentine against Brucella spp.

We have tested the in vitro activities of streptomycin, rifampin, tetracyclines, trimethoprim-sulfamethoxazole, erythromycin, four new macrolides (roxithromycin, azithromycin, clarithromycin, and dirithromycin), and rifapentine against 62 strains of Brucella spp. Azithromycin and clarithromycin were, respectively, eight- and twofold more active than erythromycins (MIC for 90% of strains = 2, 8, and 16 micrograms/ml, respectively). The activity of rifapentine was similar to that of rifampin (MIC for 90% of strains = 1 microgram/ml).     

In vitro selection and characterization of resistance to macrolides and related antibiotics in Mycoplasma pneumoniae

Macrolide-resistant mutants of Mycoplasma pneumoniae were selected in vitro from the susceptible reference strain M129, by 23 to 50 serial passages in subinhibitory concentrations of macrolides and related antibiotics, erythromycin A, azithromycin, josamycin, clindamycin, quinupristin, quinupristin-dalfopristin, pristinamycin, and telithromycin. Mutants for which the MICs are increased could be selected with all antibiotics except the streptogramin B quinupristin. Portions of genes encoding 23S rRNA (domains II and V) and ribosomal proteins L4 and L22 of mutants were amplified by PCR, and their nucleotide sequences were compared to those of the susceptible strain M129. No mutation could be detected in domain II of 23S rRNA. Two point mutations in domain V of 23S rRNA, C2611A and A2062G, were selected in the presence of erythromycin A, azithromycin, josamycin, quinupristin-dalfopristin, and telithromycin. Mutants selected in the presence of clindamycin and telithromycin harbored a single amino acid change (H70R or H70L, respectively) in ribosomal protein L4, whereas insertions of one, two, or three adjacent glycines at position 60 (M. pneumoniae numbering) were selected in the presence of both streptogramin combinations. Telithromycin was the sole antibiotic that selected for substitutions (P112R and A114T) and deletions ((111)IPRA(114)) in ribosomal protein L22. Three sequential mutational events in 23S rRNA and in both ribosomal proteins were required to categorize the strain as resistant to the ketolide. Azithromycin and erythromycin A were the only selector antibiotics that remained active (MICs, 0.06 and 1 micro g/ml, respectively) on their mutants selected after 50 passages.     

In vitro activities of new oral beta-lactams and macrolides against Campylobacter pylori.

The in vitro activities of amoxicillin, cefuroxime, ceftetrame, cefetamet, cefixime, tigemonam, erythromycin, roxithromycin, and dirithromycin against 30 clinical isolates of Campylobacter pylori were determined by an agar dilution technique. Roxithromycin and amoxicillin (MICs for 90% of isolates tested, 0.01 and 0.06 micrograms/ml, respectively) were the most active antibiotics tested, but all strains were susceptible to all antimicrobial agents tested.     

In vitro activities of five quinolones against Chlamydia pneumoniae.

The in vitro susceptibilities of 10 strains of Chlamydia pneumoniae were determined for five quinolones, including ciprofloxacin, ofloxacin, fleroxacin, temafloxacin, and sparfloxacin. Sparfloxacin was the most active compound tested, followed by ofloxacin and temafloxacin. Ciprofloxacin and fleroxacin were the least active. The use of HEp-2 cells for testing C. pneumoniae resulted in larger inclusions but essentially the same endpoints as were seen with use of HeLa 229 cells.     

In vitro and in vivo efficacies of T-3811ME (BMS-284756) against Mycoplasma pneumoniae

T-3811, the free base of T-3811ME (BMS-284756), a new des-F(6)-quinolone, showed a potent in vitro activity (MIC at which 90% of the isolates tested are inhibited [MIC(90)], 0.0313 microg/ml) against Mycoplasma pneumoniae. The MIC(90) of T-3811 was 4-fold higher than that of clarithromycin but was 4- to 8-fold lower than those of trovafloxacin, gatifloxacin, gemifloxacin, and moxifloxacin and was 16- to 32-fold lower than those of levofloxacin, ciprofloxacin, and minocycline. In an experimental M. pneumoniae pneumonia model in hamsters, after the administration of T-3811ME (20 mg/kg of body weight as T-3811, once daily, orally) for 5 days, the reduction of viable cells of M. pneumoniae in bronchoalveolar lavage fluid was greater than those of trovafloxacin, levofloxacin, and clarithromycin (20 and 40 mg/kg, orally) (P < 0.05).     

In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis.

In tests with 18 drug-susceptible strains of Mycobacterium tuberculosis, the MIC at which 50% of the strains are inhibited by levofloxacin (LVFX) was one dilution less than that at which 50% of the strains are inhibited by ofloxacin (OFLO), but the MICs at which 90% of the strains are inhibited were similar. The in vivo activity of LVFX against M. tuberculosis was compared with the activities of isoniazid, OFLO, and sparfloxacin (SPFX). Mice were inoculated intravenously with 1.74 x 10(6) CFU of H37Rv, and treatments began the next day and were carried out six times weekly for 4 weeks. The severity of infection and effectiveness of treatment were assessed by survival rate, spleen weights, gross lung lesions, and enumeration of CFU in the spleen. In terms of CFU counts, the ranking of the anti-M. tuberculosis activities of the treatments used ran in the following order: LVFX (300 mg/kg of body weight) = SPFX (100 mg/kg) > isoniazid > SPFX (50 mg/kg) > OFLO (300 mg/kg) = LVFX (150 mg/kg) > OFLO (150 mg/kg) = LVFX (50 mg/kg). It seems, therefore, that the in vivo activity of LVFX is comparable to that produced by a twofold-greater dosage of OFLO. It is assumed that the maximal clinically tolerated dosage of LVFX is similar to that of OFLO, i.e., 800 mg daily, which is equivalent to 300 mg of LVFX per kg in mice. Because LVFX displayed powerful bactericidal activity, promising effects against human tuberculosis may be achieved if patients are treated with the maximal clinically tolerated dosage of LVFX.     

In vitro and in vivo activities of sedecamycin against Treponema hyodysenteriae.

Sedecamycin (lankacidin A), one of the lankacidin-group antibiotics, showed potent activity against Treponema hyodysenteriae. The MICs of sedecamycin against 79 field isolates of T. hyodysenteriae ranged from 0.78 to 12.5 micrograms/ml, the MIC for 90% of the strains tested (MIC90) being 3.13 micrograms/ml. The protective and therapeutic effects of sedecamycin were compared with those of carbadox, tiamulin, and lincomycin against experimental infection with T. hyodysenteriae in mice. The protective effect of sedecamycin was similar to that of carbadox, two times more potent than that of tiamulin, and three times greater than that of lincomycin. In the therapeutic test, sedecamycin showed activity similar to that of carbadox and was two times more active than both tiamulin and lincomycin. At doses of 10 mg or more of sedecamycin per kg, the recurrence of shedding of T. hyodysenteriae into the feces of mice was not detected for at least 8 weeks postmedication.     

In vitro and in vivo activities of clarithromycin against Mycobacterium avium.

There is no effective therapy to treat Mycobacterium avium complex infection in patients with acquired immune deficiency syndrome. Clarithromycin (A-56268; TE-031) is a new macrolide which is twofold more active than erythromycin against most aerobic bacteria. In addition, higher levels in serum and tissue are achieved with clarithromycin than with erythromycin. In this study, clarithromycin, erythromycin, difloxacin, temafloxacin, ciprofloxacin, rifampin, amikacin, and ethambutol were tested in vitro and in vivo against the M. avium complex. The MICs for 90% of strains tested were 4 micrograms/ml for clarithromycin, 64 micrograms/ml for erythromycin, 32 micrograms/ml for difloxacin, 8 micrograms/ml for temafloxacin, 4 micrograms/ml for ciprofloxacin, 4 micrograms/ml for rifampin, 32 micrograms/ml for amikacin, and 32 micrograms/ml for ethambutol. Beige mice were infected intravenously with 10(7) CFU of M. avium ATCC 25291. Treatment was started on day 6 after infection and was administered twice a day at 8-h intervals for 9 days. Clarithromycin was the most effective compound in these tests and was effective in reducing the viable bacterial counts in the spleen when it was administered subcutaneously or orally at a dose of 25 mg/kg. Amikacin was the only other compound which showed activity in vivo. The peak concentration in serum at which clarithromycin was active was approximately 1.0 microgram/ml.     

In vitro activities of garenoxacin and levofloxacin against Chlamydia pneumoniae are not affected by presence of Mycoplasma DNA

We studied 20 Chlamydia pneumoniae isolates obtained from respiratory sites and atheroma tissue of patients from various geographic areas to determine the susceptibilities of these isolates to a new des-fluoroquinolone, garenoxacin, and to levofloxacin. In addition, we assessed the cultures with these isolates by PCR for the presence or absence of Mycoplasma sp. DNA. Both the MIC at which 90% of isolates are inhibited (MIC₉₀) and the minimal bactericidal concentration at which 90% of isolates are killed (MBC₉₀) for garenoxacin were 0.06 μg/ml, and both the MIC₉₀ and the MBC₉₀ for levofloxacin were 2.0 μg/ml. The activity of garenoxacin against C. pneumoniae was 32-fold greater than that of levofloxacin. Mycoplasma sp. DNA was detected by PCR in 17 of 20 cultures. Mycoplasma amplicons from five Mycoplasma DNA-positive C. pneumoniae cultures were sequenced and found to represent four Mycoplasma species. Our data demonstrate that C. pneumoniae cultures frequently contain Mycoplasma DNA and that its presence in C. pneumoniae cultures does not appear to affect the susceptibility results for the two fluoroquinolones that we tested.     

Glucocorticoids increase in vitro and in vivo activities of antibiotics against Chlamydophila pneumoniae

The in vitro and in vivo antichlamydial activities of dexamethasone and beclomethasone alone and in combination with an antibiotic were tested. In vitro, dexamethasone and beclomethasone decreased the number of inclusion-forming units versus the control number (P < 0.001). The combination of glucocorticoids with azithromycin, telithromycin, or levofloxacin was more active than antibiotics used alone (P < 0.001). The combination, tested in a murine Chlamydophila pneumoniae infection model, produced similar results.     

In vitro and in vivo activities of SCH 56592 against Blastomyces dermatitidis.

The new triazole derivative SCH 56592 has been tested in a National Committee for Clinical Laboratory Standards-adapted in vitro susceptibility test, and its activity against 12 isolates of Blastomyces dermatitidis yeast-like forms has been compared with those of amphotericin B, itraconazole, and fluconazole. SCH 56592 was the most active of the four compounds, with an MIC at which 90% of the isolates are inhibited of 0.06 microgram/ml and a minimal fungicidal concentration at which 90% of the isolates are inhibited of 4 micrograms/ml. The results of the treatment of mice infected with B. dermatitidis with three different doses of SCH 56592 (25, 5, or 1 mg/kg of body weight), amphotericin B (1 mg/kg), or itraconazole (150 mg/kg) confirmed the potent activity of SCH 56592. Survival was prolonged at each dose of SCH 56592, and sterilization of the lungs occurred in the high-dose group but not in the groups treated with itraconazole or fluconazole. SCH 56592 is a promising new azole antifungal drug that should be studied in humans with blastomycosis.     

In vitro and in vivo activities of sparfloxacin and reference drugs againstChlamydia pneumoniae

The activities of sparfloxacin and reference drugs againstChlamydia pneumoniae were compared by using in vitro and in vivo methods. The minimum inhibitory concentration (MIC) (μg/ml) ranges of sparfloxacin, levofloxacin, tosufloxacin, grepafloxacin, AM-1155, DU-6859a, clarithromycin, azithromycin, and minocycline for sixC. pneumoniae strains (two standard and four clinical strains) were 0.031 to 0.063, 0.25 to 0.5, 0.063 to 0.125, 0.063 to 0.125, 0.063 to 0.125, 0.031 to 0.063, 0.016 to 0.031, 0.125 to 0.25, and 0.016 to 0.031, respectively. The in vitro potency of sparfloxacin againstC. pneumoniae was similar to that of clarithromycin, minocycline, and DU-6859a, and higher than that of the other fluoroquinolones and azithromycin. Fatal pneumonia was induced in cyclophosphamide-treated leukopenic mice by intranasal inoculation withC. pneumoniae KKpn-2. Infiltration of the lung by neutrophils and lymphocytes was confirmed by histopathologic examination. Oral treatment with the various antichlamydial agents was given for seven days; sparfloxacin and minocycline had the lowest ED₅₀ (effective treatment dose in 50% of the mice; given as mg/kg per dose) (1.11 each), followed by DU-6859a (1.92), tosufloxacin (2.09), grepafloxacin (2.41), clarithromycin and azithromycin (2.48 each), AM-1155 (2.77), and levofloxacin (>10). These results suggest that sparfloxacin may be an effective agent forC. pneumoniae infection in humans.     

In vitro and in vivo activities of formycin B against Trypanosoma cruzi.

The inosine analog formycin B was examined for in vitro and in vivo activities against Trypanosoma cruzi. concentration of formycin B as low as 0.1 microgram/ml markedly inhibited intracellular multiplication of T. cruzi strains both in macrophages and in L929 cells. Mice infected with 10(5) blood form trypomastigotes of the highly virulent strain Y of T. cruzi were completely protected against death by treatment with 11.8 or 5.9 mg of formycin B per kg administered intraperitoneally each day for 19 days. Four different strains of T. cruzi were used, and each was susceptible to formycin B administered either intraperitoneally or orally. Parasitological cure, however, was not achieved with any of the treatments used, including prolonged treatment for up to 10 weeks. Formycin B has a remarkable capacity for inhibiting the in vitro intracellular replication of T. cruzi and protecting mice against death due to the acute infection with the organism. It does not appear, however, to be able to completely eliminate T. cruzi from infected mice.