Solithromycin Can Specifically Induce Macrolide-Lincosamide-Streptogramin B Resistance.

Objectives: Solithromycin is a fluoroketolide that is considered to be a noninducing antibiotic for macrolide-lincosamide-streptogramin B resistance mediated by erm genes. The exact activity of solithromycin to induce erm gene expression remains to be determined. Materials and Methods: The potential of solithromycin to induce erm(A), erm(C), and erm(B) gene expression was examined using a lacZ reporter assay, double-disk diffusion test, and determination of the minimal inhibitory concentration after incubation with subinhibitory concentration of different antibiotics. Results: Neither solithromycin nor the ketolides telithromycin and cethromycin induced erm(A) or erm(C) gene expression. However, solithromycin could significantly induce erm(B) gene expression at levels greater than that seen for cethromycin and clindamycin, but less than that for erythromycin, rokitamycin, and telithromycin. Conclusion: Solithromycin does not induce erm(A) and erm(C) gene expression, but does induce erm(B) gene expression, although to a weaker extent than that seen for macrolides.

New chitosan derivatives for the preparation of rokitamycin loaded microspheres designed for ocular or nasal administration.

Acanthamoeba spp. are the causative agents of granulomatous amoebic encephalitis (GAE) and amoebic keratitis. Recent studies performed by Rassu et al. showed that, compared with the free drug, the loading of rokitamycin in chitosan microspheres improves and prolongs the in vitro antiamoebic activity of rokitamycin. This could be useful in transporting the drug for either ocular application to treat amoebic keratitis or nasal administration as an alternative route for the administration of the drug to the brain in GAE therapy. Starting from the previous study, our goal was to optimize the technological parameters in order to obtain chitosan microparticles loaded with rokitamycin and to evaluate the use of new quaternary ammonium chitosan derivatives in the preparation of spray dried microspheres containing the macrolide; these derivatives showed better characteristics (solubility, penetration enhancement) compared with chitosan itself. Toxicity studies on new polymers were performed. Spray dried loaded microspheres based on chitosan or chitosan derivatives were obtained by using appropriate preparative parameters. Microparticles containing chitosan derivatives showed similar or often better properties than formulations made of chitosan with respect to size, in vitro release behaviour and mucoadhesiveness thus making them more suitable for ocular or nasal administration. New polymers did not demonstrate cytotoxicity.

Rokitamycin induces a mitochondrial defect and caspase-dependent apoptosis in human T-cell leukemia Jurkat cells.

Macrolides are a well-known family of oral antibiotics whose antibacterial spectrum of activity covers most relevant bacterial species responsible for respiratory infectious disease. In recent years, it has been reported that macrolides have not only bactericidal activity but also direct immunomodulating activity in mammals. In this study, we observed new physiological activity of macrolides and examined whether various macrolides induce apoptosis in human leukemia cell lines. We investigated the effects of 13 different macrolides on the viability of Jurkat and HL-60 cells. Among all the macrolides used in this study, rokitamycin, a semisynthetic macrolide with a 16-member ring, effectively induced cell death. Rokitamycin induced DNA fragmentation and caspase activation, resembling the progression of apoptosis. Moreover, rokitamycin reduced the mitochondrial transmembrane potential and released cytochrome c from mitochondria to the cytosol, suggesting that mitochondrial perturbation is involved in rokitamycin-induced apoptosis. These results suggest that rokitamycin possesses not only bactericidal activity but also pro-apoptotic activity in human leukemia cells.

Generating signals of drug-adverse effects from prescription databases and application to the risk of arrhythmia associated with antibacterials.

BACKGROUND: Although it is well known that a variety of antibacterials may incidentally cause malignant arrhythmia, the list of drugs causing arrhythmia and the impact of these adverse effects are still uncertain. We investigated on this topic by using a large prescription database with different observational designs. METHODS: Prescription data on all incident users of several antibacterial and antiarrhythmic drugs over the period July 1997 through December 1999 were retrieved from the Drug Prescription Database (DPD) of the Italian Province of Varese. The association between the use of antibacterial and antiarrhythmic drugs was investigated by applying prescription sequence symmetry, cohort and nested case-control designs. RESULTS: Lower proarrhythmic effects were on an average obtained from prescription sequence symmetry approach with respect to both cohort and nested case-control. Evidence of association between exposure to drugs (erythromycin and ciprofloxacin) and the risk of arrhythmia was consistently found by the three approaches. No other signals were generated from the prescription sequence symmetry analysis. Two drugs (clarithromycin and levofloxacin) showed patterns compatible with an arrhythmic effect according to both cohort and nested case-control designs. CONCLUSIONS: Prescription databases are useful tools to explore drug safety through both conventional and emerging observational designs. In spite of its appealing features, prescription sequence symmetry design shows lower sensitivity with respect to conventional designs. Evidence about the association between the use of certain macrolides and fluoroquinolones and the onset of arrhythmia is confirmed by this study.

In vitro evaluation of the effectiveness of the macrolide rokitamycin and chlorpromazine against Acanthamoeba castellanii.

The present study demonstrates the in vitro effectiveness of the macrolide rokitamycin and the phenothiazine compound chlorpromazine against Acanthamoeba castellanii. Growth curve evaluations revealed that both drugs inhibit trophozoite growth in dose- and time-dependent ways. The effects of both drugs when they were used at the MICs at which 100% of isolates are inhibited were amoebistatic, but at higher doses they were amoebicidal as well as cysticidal. Experiments showed that when rokitamycin was associated with chlorpromazine or amphotericin B, rokitamycin enhanced their activities. Furthermore, low doses of rokitamycin and chlorpromazine, alone or in combination, blocked the cytopathic effect of A. castellanii against WKD cells derived from the human cornea. These results may have important significance in the development of new anti-Acanthamoeba compounds.

[Rokitamycin in odontostomatology. Controlled study of doses]. / Rokitamicina in odontostomatologia. Studio controllato tra dosi.

BACKGROUND: Rokitamycin is a semisynthetic macrolide with a lactonic ring with 16 atoms, showing anti-bacterial action at concentrations near to MIC. A controlled clinical study is carried out, in parallel groups, whose aim was to assess the therapeutic action and safety of two dosage schemes of rokitamycin, in the short term treatment (5 days) of acute infective processes of odontostomatological origin. METHODS: Twenty patients (14 males, 6 females) were recruited for the trial, suffering from alveolitis, abscess, phlegmon, sialadenitis and suppurating cysts. The patients were divided in a randomized fashion into two groups: 10 patients were treated orally with 800 mg/day and 10 with 1200 mg/day. Rokitamycin was supplied in 400 mg tablets. RESULTS: The 5 days of treatment with rokitamycin determined the complete resolution of the infective process, with eradication of the germs originally isolated, all belonging to the Streptococcus genus. Clinical efficacy was evident by the third day of treatment, with a prompt improvement of symptoms (functional limitation, pain, tumefaction) and the return of body temperature to within normal limits, in a totally superimposable fashion between the two groups. Safety was excellent with both doses, with no side effects observed. CONCLUSIONS: The results of the study show that treatment with rokitamycin in the short term, at the usual dosage of 800 mg/day, is a valid therapeutic scheme in infective processes in odontostomatology.

[Comparative study of minimal inhibitory concentration (MIC) and minimal lethal concentration (MLC) values for tetracycline, monocycline, erythromycin and rokitamycin against eleven strains of Chlamydia trachomatis]. / Etude comparative des concentrations minimales inhibitrices (CMI) et des concentrations minimales léthales (CML) de la tétracycline, de la minocycline, de l'érythromycine et de la rokitamycine sur onze souches de Chlamydia trachomatis.

We evaluated the efficacy of tetracycline, minocycline, erythromycin and rokitamycin (rikamycine, TMS-19Q) in controlling in vitro propagation of Chlamydia trachomatis in HeLa 229 cells. Ten recent clinical isolates of Chlamydia trachomatis and one fast-growing strain were tested with inocula of 100-1,000 inclusion forming units per well of a 96-wheel microculture plate. Chlamydia trachomatis inclusions were detected by an immunoperoxidase-antiperoxidase procedure (PAP), including a genus-specific monoclonal antibody. Minimal inhibitory concentration (MIC) geometric means and ranges were respectively 0.128, 0.015-0.25 mg/l tetracycline, 0.001, less than or equal to 0.001-0.004 mg/l minocycline, 0.187, 0.031-0.5 mg/l erythromycin, and 0.005, less than or equal to 0.001-0.062 mg/l rokitamycin; minimal lethal concentration (MLC) geometric means and ranges were 6.79, 0.125-32 mg/l tetracycline, 0.225, 0.062-2 mg/l minocycline, 3.37, 1-32 mg/l erythromycin, and 0.112, 0.031-1 mg/l rokitamycin. Since rokitamycin appears to be the more bactericidal from the four antibiotics tested, clinical studies in sexually transmitted diseases are indicated.

Rokitamycin uptake by alveolar macrophages.

The ability of antibiotics to enter cells, especially phagocytic cells, may be an important factor affecting therapy for infections caused by organisms which survive and proliferate intracellularly. It is well known that macrolides and clindamycin have high intracellular penetration ability. We studied the uptake of rokitamycin (RKM), a new oral macrolide, using rabbit alveolar macrophages and 2 other macrolides for comparison. Intracellular concentrations of erythromycin and josamycin were, respectively, approximately 20 and 40 times higher than extracellular concentrations when they were incubated at an initial extracellular concentration of 5 micrograms/ml (I/E = 20.1 +/- 2.6, 40.8 +/- 7.4). In comparison to these 2 macrolides, the uptake of RKM was massive and very rapid. The cellular concentration of RKM was approximately 120 times higher than the extracellular concentration. Uptake of the 3 macrolides by rabbit alveolar macrophages at 4 degrees C was approximately 10% of that at 37 degrees C. This study demonstrated that RKM was rapidly and massively accumulated by alveolar macrophages, and that the drug accumulation depends on temperature. These observations suggest that RKM therapy may be very effective for the treatment of some infectious diseases.

[Clinical studies on TMS-19-Q.O tablets, the preparation of a new macrolide antibiotic, in the field of oral surgery].

Multicenter clinical trial or TMS-19-Q.O tablet was performed to evaluate the usefulness in oral surgery. The results obtained were as follows: Clinical efficacy was assessed by clinical points. The patients entered into the trial were 77 cases with periodontitis, 23 with pericoronitis, 92 with osteitis of jaw and 18 with other infections, and the each effective rates were 80.5, 60.9, 83.7 and 72.2%, respectively. Overall effective rate was 79.0%. Isolation frequency of organisms were 33.8% in periodontitis, 34.8% in osteitis of jaw and 17.4% in pericoronitis. Bacteria isolated were aerobic organisms (63.1%) and anaerobic organisms (36.9%). TMS-19-Q.O tablet was well tolerated, and no adverse reaction was observed.