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Background: When metronidazole is used in bismuth-based or proton pump inhibitor-based triple therapy, the cure rate of Helicobacter pylori is usually high. However, metronidazole-resistant H. pylori strains, which are increasing in frequency, are a major cause of failed H.␣pylori eradication. Aim: To evaluate the efficacy of non-metronidazole containing bismuth-based triple therapy for H. pylori infection. Methods: One-hundred and eighty H. pylori-positive patients with endoscopically documented peptic ulcer disease or functional dyspepsia were randomly assigned to one of three 1-week regimens containing tripotassium dicitrato bismuthate (also called colloidal bismuth subcitrate) 240 mg b.d. and two antibiotics: furazolidone 100 mg b.d. plus clarithromycin 250 mg b.d. (Group A); or clarithromycin 250 mg b.d. plus amoxycillin 1000 mg b.d. (Group B); or furazolidone 100 mg b.d. plus josamycin 1000 mg b.d. (Group C). H. pylori status was assessed by rapid urease test, histology and culture of gastric biopsy specimens taken from both the antrum and corpus, both before and at least 4 weeks after completion of therapy. Results: Thirteen patients dropped out (3 in group A, 5 in group B and 5 in group C). Based on an intention-to-treat analysis, the eradication rates achieved in groups A, B and C were 88% (53/60), 58% (35/60) and 77% (46/60), respectively. These differences were significant between groups A and B (P

We examined the effects of macrolide antibiotics on tumor angiogenesis, tumor growth and metastasis in the B16BL6 mouse melanoma and C57BL mouse system. Two 14-membered ring macrolide antibiotics, roxithromycin and clarithromycin, significantly reduced the dense capillary network area in a mouse dorsal air sac angiogenesis model, whereas a 15-membered ring macrolide, azithromycin, and a 16-membered ring macrolide, josamycin, did not show any inhibitory effect on angiogenesis at the same dose. Intraperitoneal administration of roxithromycin and clarithromycin at 50 mg/kg/day reduced the tumor size of B16BL6 melanoma to about 41% and 56%, respectively, of that of the control, and significantly suppressed pulmonary metastasis of B16BL6 cells in a spontaneous system. Azithromycin and josamycin, on the other hand, did not inhibit tumor growth or pulmonary metastasis of B16BL6 cells. Immunohistochemistry revealed that roxithromycin and clarithromycin reduced the tumor vascularity and increased apoptosis of the tumor cells in vivo. These results suggest that 14-membered ring macrolides have antiangiogenic and antitumor effects and might have possible therapeutic applications.

The potent 14-membered macrolide antibiotics displayed a strong NMR response in the TRNOESY experiments whereas their metabolites which do not retain antimicrobial activity gave essentially blank TRNOESY spectra. These TRNOESY experiments are here extended to a macrolide (josamycin) belonging to the 16-atom macrolide class in order to compare responses according to the macrocycle size. Analysis of transferred nuclear Overhauser effect (TRNOE) experiments resulted in a set of constraints for all proton pairs. These constraints were used in structure determination procedures based on molecular modelling to obtain a bound structure compatible with the experimental NMR data. This study allowed us to identify the binding structure at the ribosome for the active 16-membered macrolide. The different conformations existing in solution for this antibiotic in the free state will be compared and correlated with the binding conformation at the ribosome obtained with TRNOE experiments so as to establish a structure–activity relationship. The comparative results indicate that one conformation (called S3) pre-existing in the conformational equilibrium of macrocycle in solution and close to the major one S5, is preferred in the bound state.

The carcinogenicity of josamycin was examined in Fischer 344 (F344) rats. Groups of 50 males and 50 females were given the compound in their diet at concentrations of 0 (control), 1.25 or 2.5% for 104-weeks; these dose levels were selected on the basis of the results of a subchronic study, in which animals rather rejected 5% josamycin. All surviving rats were killed at wk 106. A variety of tumours developed in all groups, including the control group, but all the neoplastic lesions were histologically similar to those known to occur spontaneously in this strain of rats, and no statistically significant increase in the incidence of any tumour was found in the treated groups of either sex. Interestingly, the josamycin treatment significantly reduced the development of altered liver cell foci and chronic nephropathy in a dose-dependent manner. Thus, it was concluded that, under the present experimental conditions, josamycin is not carcinogenic in F344 rats.

A highly sensitive and specific method for the determination of josamycin in human plasma by LC-MS was developed and validated. Josamycin was extracted from human plasma by a single-step liquid-liquid extraction and analyzed by LC-MS via an electrospray ionization interface. Selected ion monitoring was used to detect josamycin and its internal standard. The intra-day precision and accuracy, expressed as C.V. and R.E., ranged from 2.8% to 13.5% and -10.3% to 7.6%, respectively. The lower limit of detection was 0.1 ng/ml and the lower limit of quantitation was set at 1 ng/ml when 0.5 ml of plasma was used. No endogenous interference was observed in human plasma obtained from drug-free volunteers.

The susceptibility of 40 erythromycin-resistant isolates of Streptococcus pyogenes and 40 multiply-resistant isolates of Streptococcus pneumoniae to six macrolide antibiotics, representing 14-, 15- and 16-membered lactone ring structures, was tested. The genetic basis for macrolide resistance in the strains was also determined. Both erm and mef determinants were encountered in the 36 S. pneumoniae isolates tested, but only mef in the five S. pyogenes isolates tested. All isolates showed cross-resistance among the 14-membered macrolides erythromycin, clarithromycin and roxithromycin and the 15-membered macrolide, azithromycin. However, the erythromycin-resistant S. pyogenes isolates retained full susceptibility to spiramycin and josamycin (16-membered agents). These latter two antibiotics were also more active than the other macrolides against erythromycin-resistant S. pneumoniae isolates, especially josamycin which was 8-64 times more active than erythromycin; spiramycin was only two to eight times more active than erythromycin.

An isocratic liquid chromatographic method is described using as stationary phase the very stable poly(styrene–divinylbenzene) PLRP-S (8 μm, 1000 A). The mobile phase was acetonitrile–0.2 M phosphate buffer, pH 10.0–water (52:20:up to 100, v/v/v), delivered at a flow-rate of 1.0 ml/min. UV detection was performed at 232 nm. The column was heated at 60°C. Josamycin propionate was separated from all impurities which were present in commercial samples. The main impurities were josamycin, leucomycin A4 propionate, josamycin 2′,9-dipropionate, josamycin 3″,9-dipropionate and platenomycin A1 propionate. Full factorial design was applied to evaluate the robustness of the method.

A simple and rapid method using high-performance liquid chromatography (HPLC) for the simultaneous determination of five macrolides (josamycin, kitasamycin, mirosamicin, spiramycin and tylosin) in meat has been developed. The drugs were extracted with 0.3% metaphosphoric acid-methanol (7:3, v/v), and the extracts were cleaned up on a Bond Elut SCX (500 mg) cartridge. The HPLC separation was performed on a Puresil 5C18 column (150 x 4.6 mm I.D.) with a gradient system of 0.025 M phosphate buffer (pH 2.5)-acetonitrile as the mobile phase at a flow-rate of 1.0 ml/min. The drugs were detected at 232 mn for josamycin, kitasamycin, mirosamicin and spiramycin, and 287 mn for tylosin. The calibration graphs were rectilinear from 2.5 to 100 ng for each drug. The recoveries at the level of 1.0 microgram/g were 70.8-90.4%, and detection limits were 0.05 microgram/g for each drug.

New products may be sought by modifying older fermentation products, exemplified by the semisynthetic antibiotic tilmicosin and other derivatives of tylosin. Another approach is to screen fermentation broths, exemplified by the discovery of the structurally-unique insecticidal macrolide spinosad. The polyketide class of fermentation products encompasses a wide diversity of chemical structures and biological activities. Important products include macrolide antibiotics (erythromycin, josamycin, tylosin), antifungal polyenes (amphotericin B), parasiticides (avermectin, milbemycin), and immunosuppressive agents (FK-506, rapamycin). The past history of success achieved by this class suggests it will remain an important source of new products. The discovery of new products may be divided into three approaches: 1) structural modifications of previously known compounds that improve or extend features of the parent molecules, 2) screening culture broths to identify new biologically-active compounds, and 3) manipulation of the biosynthetic pathways by which secondary metabolites are formed in order to produce new structures.

This article is an extensive review of current information available on the macrolide antibiotics. This includes antimicrobial spectrum, pharmacology, complications and side effects, and pediatric use of these drugs. These are important antibiotics, but careful selection of patients must be made and the physician must be alert for evidence of drug-drug interactions, which are not uncommon with several members of this class.

The bioavailability of josamycin from a tablet formulation (2 x Josacine 500 mg tablets) was investigated and compared with the bioavailability of a solution (containing 1 g drug and buffered at pH 4.0) following administration to six healthy human volunteers. Bioavailability profiles for the solution indicated that the drug was inherently rapidly absorbed with a mean Cmax of 1.64 +/- 0.67 mg L-1 attained at a mean tmax of 0.39 +/- 0.08 h. The AUC0-last was 1.510 +/- 0.687 mg h L-1. Bioavailability was significantly lower from the tablets than from the solution. Highly variable serum concentration-time profiles were obtained from the tablets and Cmax values ranged from 0.05 to 0.71 mg L-1 with a tmax range of 0.33-2.0 h. AUC0-last values ranged from 0.03 to 0.95 mg h L-1. Dissolution of josamycin from the tablets was generally unaffected at low pH (pH 1.2-5.0), but, rather, limited predominantly by tablet disintegration. However, dissolution was increasingly limited as the pH increased from 5.0 to 9.0. Besides poor disintegration, the particularly low intrinsic dissolution rate and solubility of josamycin at these pH values is likely to further reduce the dissolution rate. Comparison of the solution and tablet serum concentration-time profiles suggests that the absorption of josamycin from the tablets was dissolution rate limited. This is supported by the in vitro dissolution-pH topogram, which suggests that dissolution will be particularly rate limiting if dissolution of whole or parts of tablets occurs in gastro-intestinal fluid above pH 5.0.

Digitalis intoxication is usually accidental in children. We report the case of a young infant with congenital heart disease in whom the coadministration of digoxin and josamycin led to a 50% increase in the digoxin concentration, generating sinoatrial block and cardiac failure. Clinical and electrocardiographic symptoms very quickly resolved following immunotherapy with antidigitalis Fab fragments. Digoxin concentrations must be carefully monitored in patients concomitantly receiving macrolides to ensure that the digoxin dose can be readjusted if necessary.

Capillary electrophoresis (CE) provides high separation efficiency and thus is suitable for the analysis of complex mixtures of structurally similar compounds. The versatile nature of CE can be realised by controlling the chemistry of the inner capillary wall, by modifying the electrolyte composition and by altering the physicochemical properties of the analyte. A CE method has been developed for the separation of three macrolide antibiotics, erythromycin, oleandomycin and josamycin. A systematic approach was used to maximise analyte differential electrophoretic mobility by manipulating electrolyte pH, molarity and composition. In addition, some instrumental parameters such as capillary length and diameter and applied voltage were varied. The effect of the sample solvent and on-capillary concentrating techniques such as field amplified sample injection were investigated. Also, the influence of the injection of a water plug on the quantity of sample injected was demonstrated. The macrolides were completely resolved in less than 30 min in a 100 cm x 75 microm I.D. fused-silica uncoated capillary with a Z-shaped flow cell of path-length 3 mm. The analysis was performed in a 75 mM phosphate buffer (pH 7.5) with 50% (v/v) methanol and an applied voltage of 25 kV was selected to effect the separation.

The in-vitro activity of azithromycin, clarithromycin, erythromycin, josamycin, midekamycin, roxithromycin and clindamycin against 674 Gram-negative and Gram-positive clinical isolates, including methicillin-resistant Staphylococcus aureus, was determined by agar dilution, microdilution and agar diffusion with Mueller-Hinton medium according to the Deutsches Institut für Normung (DIN) 58940 guidelines. The results obtained by regression analysis and the error-rate-bounded method of Metzler-DeHaan indicate that common interpretative criteria (breakpoints) for test discs may be assigned to susceptible/resistant Gram-positive strains for all antibiotics tested. The following tentative DIN values are suggested for 15 microg macrolide discs: for susceptible Gram-positive and Gram-negative strains, an inhibition zone diameter (IZD) ofor = 26 mm at a corresponding MIC ofor = 2 mg/L; for resistant Gram-positive strains, an IZD ofor = 21 mm; for resistant Gram-negative strains, an IZD ofor = 19 mm at a corresponding MIC ofor = 8 mg/L. For Haemophilus influenzae only, breakpoints for azithromycin are suggested with IZDs ofor = 21 mm for susceptible andor = 18 mm for resistant.

Erythromycin (EM) and its 14-member macrolide analogues have attracted attention for its effectiveness in a variety of airway diseases, including diffuse panbronchiolitis (DPB), sinobronchial syndrome, and chronic sinusitis. However, its mechanisms of action remain unelucidated. We evaluated the effects of several antibiotics on IL-8 expression by normal and transformed human bronchial epithelial cells, an important source of this potent chemokine involved in cell recruitment into the airways. EM and clarithromycin (CAM) uniquely suppressed mRNA levels as well as the release of IL-8 at the therapeutic and noncytotoxic concentrations (% inhibition of IL-8 protein release: 25.0 +/- 5.67% and 37.5 +/- 8.99%, respectively, at 10(-6) M). The other antimicrobes, including a 16-member macrolide josamycin, showed no effect. Bronchial epithelial cells from very peripheral airways as well as from main bronchi were obtained from patients with chronic airway inflammatory diseases, and EM and CAM inhibited IL-8 release from these cells. Among five patients who underwent bronchoscopy before and after macrolide treatment, four showed decreased levels of IL-8 expression in airway epithelium as assessed by reverse transcription and polymerase chain reaction. Our findings showed these 14-member macrolides had inhibitory effect on IL-8 expression in human bronchial epithelial cells, and this new mode of action may have relevance to their clinical effectiveness in airway diseases.

The aim of this study was to determine the etiologic agents associated with community-acquired pneumonia in 104 French children ages 18 months to 13 years. Potential respiratory pathogens were identified in 87 (85%) cases; these included respiratory syncytial virus in ten, other viruses in 20,Streptococcus pneumoniae in 14, andMycoplasma pneumoniae (diagnosed by serologic procedures) in 43. Of 32 patients withMycoplasma pneumoniae infection who were initially treated with beta-lactam antibiotics, 30 failed treatment. Recovery from mycoplasma infection occurred rapidly in patients treated with macrolide antibiotics (which included spiramycin in 31 patients, josamycin in 7, and erythromycin in 3); however, cough persisted in 12 patients for one month. The high frequency ofMycoplasma pneumoniae infection in community-acquired pneumonia in children over 18 months of age must be considered when selecting an antibiotic for initial therapy.

Resume Lors d'un essai clinique randomise ouvert, nous avons etudie la cinetique d'eradication de Streptococcus pyogenes chez 48 patients presentant une angine aigue traitee per os par 10 jours de penicilline V ou 5 jours de josamycine. Des prelevements oropharynges ont ete pratiques quotidiennement chez chaque patient. Les deux antibiotiques ont permis une reduction de 3 ou 4 log du taux initial de S. pyogenes apres 48 heures de traitement, la plupart des patients presentant alors une culture negative. Les prelevements realises 48 heures apres la fin du traitement ont confirme l'eradication de S. pyogenes . Des controles realises a 30 jours puis a 3 ou 4 mois ont montre que certains patients s'etaient a nouveau colonises, certains S. pyogenes isoles ne presentant pas le meme serotype M que celui retrouve lors de l'episode initial aigu. Cette etude souleve le probleme du role de l'entourage dans la recolonisation des patients ainsi que la valeur des prelevements a distance, 3 a 6 semaines apres la fin du traitement antibiotique.

The mechanism of macrolide therapy in chronic sinusitis patients is unclear. The authors studied the effect of macrolides on interleukin (IL)-8 secretion from cultured human nasal epithelial cells. Epithelial cells harvested from the nasal polyps of patients with chronic sinusitis were primary-cultured, and secreted IL-8 in culture media was measured by enzyme immunoassay. The cells secreted considerable amounts of IL-8 constitutively and in response to lipopolysaccharide. The secretion was significantly inhibited by 10(-5) M of erythromycin, clarithromycin, roxithromycin, and josamycin. 10(-6) M erythromycin still showed the inhibitory effect, whereas the same concentration of josamycin did not. These results indicate that macrolide antibiotics may act as an immunomodulator to reduce IL-8 in inflammatory sites and, at least partially, account for the clinically discrepant effects between 14- and 16-membered ring macrolides in long-term low-dose therapy for chronic sinusitis.

Six derivatives of sixteen-membered macrolides possessing 4-O-acyl-alpha-L-cladinose as a neutral sugar were synthesized via 3"-methylthiomethyl ether intermediates in reasonable yield. Introduction of a methyl group on the 3"-hydroxyl group of midecamycin A1 was effective for enhancing its antibacterial activity. All these derivatives exhibited excellent therapeutic effects in mice, and some of them showed improved pharmacokinetics compared with the natural antibiotics (mycarose type) in mice. Facile synthesis of 9-O-acylated analogues are also described.

The occurrence and seasonal variability of five groups (tetracycline, quinolone, chloramphenicol, macrolide and sulfonamide) of antibiotics were investigated in the surface water of four reservoirs. The dissolved concentrations of 29 antibiotics were in the ngL(-1) level. Trace levels of all target antibiotics were analyzed using solid-phase extraction followed by liquid chromatography electrospray tandem mass spectrometry. All of the antibiotics were detected at all sampling sites, indicating widespread occurrence of antibiotics in the study area. The detection of florfenicol, josamycin, kitasamycin, spiramycin and sulfameter is the first report of these compounds in reservoir samples. The results showed an association between the presence of some antibiotics at Panjiakou reservoir and cage culture of fish. Twenty-three types of antibiotics showed significant seasonal variations (p

The prevalence of cytomegalovirus infection (CMVI) dictates the necessity of its in-depth investigation in the patients presenting with the signs of chronic inflammatory diseases of sexual organs. The objective of the present study was to estimate the effectiveness of combined laser therapy of inflammatory diseases of the urogenital tract accompanied by the reactivation of CMVI concomitant with other infections. The examination of 158 women presenting with cytomegalovirus infection revealed clinical and laboratory characteristics of the microbiocenosis. These data may be used to improve the effectiveness of diagnostic and therapeutic strategies for such patients. The combined treatment of the patients with the reactivated form of CMVI using josamycin and doxycycline monohydrate in combination with panavir and low-intensity laser irradiation based at the "Matrix-Urolog" laser complex resulted in the favourable outcome of therapy in the majority of the patients.

Severe respiratory disease arising from influenza virus infection has a high fatality rate. Neutrophil myeloperoxidase (MPO) has been implicated in the pathogenesis of severe influenza-induced pneumonia because extracellularly released MPO mediates the production of hypochlorous acid, a potent tissue injury factor. To search for candidate anti-influenza compounds, we screened leucomycin A3 (LM-A3), spiramycin (SPM), an erythromycin derivative (EM900, in which anti-bacterial activity has been eliminated), and clarithromycin (CAM), by analyzing their ability to inhibit MPO release in neutrophils from mice and humans. When each candidate was injected into mice infected with a lethal dose of A/H1N1 influenza virus (PR-8), LM-A3 produced the highest survival rate (80.9%). We found that LM-A3 induced beneficial effects on lung pathology and viral proliferation involved in the regulatory activity of MPO release, pro-inflammatory cytokines and interferon-α production in the lung. SPM and EM900 also induced positive survival effects in the infected mice, whereas CAM did not. We further found that these compounds inhibit virus proliferation in human pneumonia epithelial A549 cells in vitro. LM-A3 showed effective action against influenza A virus infection with high anti-viral activity in human host cells, indicating the possibility that LM-A3 is a prospective lead compound for the development of a drug for human influenza. The positive survival effect induced by EM900 suggests that pharmacological architectures between anti-bacterial and anti-influenza virus activities can be dissociated in macrolide derivatives. These observations provide valuable evidence for the potential development of novel macrolide derivatives that have strong anti-viral but no anti-bacterial activity.

Mycoplasma pneumonia is responsible for multisystemic infection. Pulmonary symptoms are most common in children. We describe herein two unusual severe forms of M. pneumoniae infection without initial pulmonary symptoms. The first case is an 8-month-old boy who was hospitalized in the pediatric intensive care unit with severe sepsis. There were no initial pulmonary symptoms, nor obvious clinical infection. Initial blood tests and x-ray did not aid the diagnosis. The blood tests came back positive for M. pneumonia. Pulmonary symptoms eventually appeared 24h later, and there was a pneumonia outbreak on the chest radiograph. The boy was given josamycin and improved quickly. The second case concerns an 8-year-old child who was hospitalized in the pediatric intensive care unit with toxic shock. No clinical infectious origin was found. A broad-spectrum antibiotic therapy was started with ceftriaxone and josamycin. The M. pneumoniae blood test came back positive, which confirmed the diagnosis of septic shock in M. pneumoniae, requiring adjustment of the antibiotic therapy. Current guidelines for the choice of probabilistic antibiotic therapy in case of severe sepsis do not include the case of M. pneumoniae. The early initiation of antibiotic therapy plays a major role in the prognosis of these patients. It seems useful to search for M. pneumoniae in cases of severe atypical infections, particularly in the absence of pulmonary symptoms.

SENLAT syndrome, also known as TIBOLA/DEBONEL, is an emerging disease in France. The major symptoms are necrotic eschar on the scalp associated with painful cervical lymphadenopathy. It occurs mainly in women and children during the cold seasons after a bite by a Dermacentor tick, responsible for transmitting Rickettsia slovaca or Rickettsia raoultii. Cutaneous swabs are safe, easy and reliable tools that should be used routinely by physicians to confirm diagnosis. In this particular disease, they should be preferred to serology, which is less sensitive. Doxycycline is the antibiotic of choice for this syndrome.

1 Colchicine poisoning, which is relatively rare, is associated with significant morbidity and mortality. Whilst a new treatment modality, in the form of colchicine-specific Fab fragments is on the horizon, currently available therapy is largely supportive.2 The elimination of colchicine occurs primarily by hepatic metabolism, following a first-order process, with significant enterohepatic circulation. Renal extraction is responsible for approximately 20% of colchicine elimination.3 We report a case of colchicine intoxication, compli cated by the presence of co-ingestants, in which serum colchicine concentrations remained quasi-constant over the 3 days of the patient's survival, consistent with marked alterations both in metabolism and excretion. The initial presentation was relatively benign but the subsequent course was one of severe colchicine poisoning, resulting in death.4 Severe colchicine toxicity appears to have resulted in a vicious cycle of progressive organ dysfunction and impaired elimination.5 Josamycin, one of the co-ingestants and an inhibitor of P-glycoprotein, the membrane pump responsible for multidrug resistance, may have played a significant role in impeding the cellular and biliary elimination of colchicine. Co-ingested opioid and anticholinergic compounds may have altered colchicine absorption and gastrointestinal transit.6 This case serves as a reminder of the need for attention to co-ingested drugs, to early aggressive therapy, and if available, to consideration of immunotherapy.

Several previous investigators have reported that long-term administration of certain macrolides is efficacious in patients with persistent pulmonary Pseudomonas aeruginosa infections, even though the clinically achievable concentrations of these medications are far below their MICs. In the present study, we examined how sub-MICs of macrolide antibiotics affect the viability of and protein synthesis in several strains of P. aeruginosa. We report that 48 h, but not 12 or 24 h, of growth on agar containing a clinically achievable concentration of azithromycin (0.5 microgram/ml, 1/128 the MIC) significantly reduces the viability of strain PAO-1. Similar effects were seen with erythromycin and clarithromycin at 2 micrograms/ml (1/128 and 1/64 the respective MICs), whereas josamycin, oleandomycin, ceftazidime, tobramycin, minocycline, and ofloxacin had no effect on viability, even following 48 h of incubation with concentrations representing relatively high fractions of their MICs. The bactericidal activity of azithromycin seen following 48 h of incubation was not limited to strain PAO-1 but was also seen against 13 of 14 clinical isolates, including both mucoid and nonmucoid strains. Although viability was not decreased prior to 48 h, we found that 4 micrograms of azithromycin per ml inhibits protein synthesis after as little as 12 h and that protein synthesis continues to decrease in a time-dependent manner. We likewise found that P. aeruginosa accumulates azithromycin intracellulary over the period from 12 to 36 h. These results suggested that sub-MICs of certain macrolides are bactericidal to P. aeruginosa when the bacteria are exposed to these antibiotics for longer periods. Exposure-dependent intracellular accumulation of the antibiotic and inhibition of protein synthesis may partially account for the antipseudomonal activity of macrolides over relatively prolonged incubation periods.

1. Tacrolimus, an immunosuppressive macrolide, is metabolized by enzymes of the cytochrome P450 3A subfamily. In this study, 34 drugs were tested for their interactions with tacrolimus metabolism by human liver microsomes. 2. Fifteen drugs which inhibit the in vitro metabolism of tacrolimus were identified: bromocriptine, corticosterone, dexamethasone, ergotamine, erythromycin, ethinyloestradiol, josamycin, ketoconazole, miconazole, midazolam, nifedipine, omeprazole, tamoxifen, troleandomycin and verapamil.

高速液体クロマトグラフィー(HPLC)を用いた食肉中のマクロライド系抗生物質(MLs),キタサマイシン(KT)及びジョサマイシン(JM)の簡易かつ迅速な残留分析法を検討した.MLsは一般に構造が類似した複数の成分から構成されており,KTはロイコマイシンA1,A3～A9等の多成分からなる混合物である.一方,JMはKTを構成するロイコマイシンA3と同一物質である.KTの分離には,カラムにPuresil 5C18(150×4.6mm),移動相には0.05Mリン酸塩緩衝液(pH2.5)-アセトニトリル(58:42)を用い,流量は毎分0.5ml,測定波長は232nmとした.試料の前処理法は,0.3%メタリン酸-メタノール(7:3)で除タンパクと同時に抽出し,陽イオン交換樹脂が充てんされたBond Elut SCX カートリッジ(500mg)でクリーンアップを行った.本法における鶏肉,鶏肝臓,豚肉,豚肝臓,牛肉,牛肝臓等に対する添加回収率は1μg/gの添加で76.8～91.5%,検出限界は0.05μg/gであった.

Fifty-four Japanese strains of Mycoplasma hyosynoviae isolated from porkers during 1980 to 1995, and 107 Japanese strains of M. hyorhinis isolated from piglets with respiratory disease during 1991 to 1994 were investigated for the in vitro activities of 13 antimicrobial agents [josamycin, tylosin, spiramycin, kitasamycin, erythromycin, lincomycin (LCM), kanamycin (KM), chloramphenicol (CP), thiamphenicol (TP), tiamulin (TML), oxytetracycline (OTC), chlortetracycline (CTC), and enrofloxacin (ERFX)] by the agar dilution method. Of the drugs tested TML showed the highest activity with minimum inhibitory concentration (MIC) of 0.013 to 0.1 microgram/ m/ (MIC90; 0.05 microgram/ml) against strains of M. hyosynoviae, and 0.2 to 0.78 microgram/ml (MIC90; 0.39 microgram/ml) against strains of M. hyorhinis. ERFX, LCM, most of the 16-membered macrolide antibiotics and tetracyclines also showed low MICs against both mycoplasma species. The susceptibility of KM, CP and TP to the mycoplasmas was considered to be of a secondary grade. Two of 54 strains of M. hyosynoviae, and 11 of 107 strains of M. hyorhinis showed resistance to all 14- and 16-membered macrolide antibiotics tested. Tetracyclines (OTC and CTC) showed a relatively broad MIC distribution from 0.1 to 6.25 micrograms/ml against the M. hyosynoviae strains tested. All of the strains isolated during 1980 to 1984 were susceptible at the concentration of 0.78 microgram/ml or less (MIC90; 0.78 microgram/ml) to OTC and 1.56 micrograms/ml or less (MIC90; 1.56 micrograms/ml) to CTC, while the susceptibility of strains isolated recently, during 1994 to 1995, was more than 0.78 microgram/ml (MIC90; 3.13 micrograms/ml) to OTC, and more than 1.56 micrograms/ml (MIC90; 6.25 micrograms/ml) to CTC.

For six clinical isolates of Chlamydia trachomatis , in vitro susceptibility to erythromycin, azithromycin, and josamycin has been determined. Four isolates were resistant to all the antibiotics and had the mutations A2058C and T2611C ( Escherichia coli numbering) in the 23S rRNA gene. All the isolates had mixed populations of bacteria that did and did not carry 23S rRNA gene mutations.

Resume Les auteurs ont teste, au cours d'une etude multicentrique randomisee menee en ouvert, l'efficacite et la tolerance de la josamycine donnee a la posologie journaliere de 2 g (ou 50 mg/kg/j) en deux prises pendant 5 jours comparativement a la penicilline V donnee a la posologie de 3 millions d'UI en trois prises par jour pendant 10 jours dans l'angine aigue a streptocoque beta-hemolytique du groupe A (SsHGA) de l'enfant et de l'adulte jeune. Cent trente patients ont ainsi ete randomises dans le groupe josamycine et 135 dans le groupe penicilline V, les deux groupes etant homogenes a l'exception des pathologies cardiovasculaires significativement plus frequentes chez les patients traites par la penicilline V. Les taux d'eradication bacteriologique et de guerison clinique ont ete similaires en fin de traitement dans les deux groupes. La tolerance etait egalement identique dans les deux groupes avec 6 evenements intercurrents dans le groupe josamycine et 2 dans le groupe penicilline V. Les auteurs concluent que la josamycine pendant 5 jours est un traitement aussi efficace des anguines aigues a SsHGA que la penicilline V 10 jours.

An isocratic liquid chromatographic method for the assay and purity control of josamycin using wide-pore poly(styrene-divinylbenzene) as the stationary phase is presented. Josamycin has been well separated from all the related leucomycins, present as impurities in commercial samples. Wide-pore PLRP-S 8 μm 1000 A has shown the best selectivity. The separation has been carried out at 65°C with a mobile phase of 2-methyl-2-propanol/0.2 mol/l potassium phosphate buffer pH 10.5/water (24.5: 5: 70.5, V/V) and a flow rate of 1.0 ml/min. UV detection has been performed at 232 nm. The total analysis time has been about 40 min. The method has been used to analyse commercial bulk samples and tablets containing josamycin base.

We studied the efficacy of the long-term administration of 14-membered ring macrolides in treating patients with diffuse panbronchiolitis (DPB) (34 patients) and bronchiectasis (BE) (40 patients). Oral administration of erythromycin (400 or 600 mg), roxithromycin (150 or 300 mg) or clarithromycin (200 or 400 mg) given daily for at least 2 months, was evaluated. The efficacy of erythromycin, roxithromycin, and clarithromycin in DPB was 19/24 (79%), 6/7 (86%), and 2/3 (67%), respectively. Efficacy of these agents in BE exceeded 50%. We determined the effect of these macrolides on the activity of polymophonuclear leukocytes (PMNs) obtained from healthy volunteers. There were no significant differences between the effects of these 14-membered ring macrolides and josamycin, a 16-membered ring macrolide which was previously found to be ineffective in treating DPB. Thus, the effectiveness of the 14-membered ring macrolides in treating DPB appears to depend on mechanism(s) other than alterations in PMN activity.

We compared the activities of telithromycin, erythromycin, azithromycin, josamycin, penicillin G, amoxicillin, cefpodoxime, and ceftriaxone against invasive and noninvasive non-penicillin-susceptible Streptococcus pneumoniae isolates recovered from children. Of the 186 isolates tested, 89% were positive for erm (B) by PCR. Telithromycin had the lowest MICs, with MICs at which 90% of the isolates tested are inhibited of 0.032 and 0.25 μg/ml for erythromycin-sensitive and -resistant isolates, respectively.

In order to investigate the susceptibility of mixed infection of Ureaplasma Urealyticum (UU) and Mycoplasma Hominis (MH) to 7 kinds of antimicrobial agents and comparison with that of UU infection in NGU patients, the in vitro susceptibility was determined by using microdilution method. The positive results were analyzed. The results showed that the sequence of susceptibility to 7 kinds of antimicrobial agents for both UU infection group and UU-MH mixed infection group was almost the same from the highest susceptibility to the lowest accordingly: Josamycin, Doxycycline, Minocycline, Sparfloxacin, Roxithromycin, Ofloxacin and Azithromycin. The total drug resistance rate for UU-MH mixed infection group (97.67%) was significantly higher than that for UU infection group (44.67%, P < 0.01). The highest drug resistance rate in UU group and UU-MH mixed infection group was 31.33% (Ofloxacin) and 90.48% (Azithromycin) respectively. UU-MH mixed infection showed an increased drug resistance and changes of drug resistance spectrum.

Fetoplacental insufficiency, developed against the background of urogenital chlamydiosis, leads to increase of perinatal morbidity and mortality, reaching in some regions up to 46%., Фетоплацентарная недостаточность, развивающаяся на фоне урогенитального хламидиоза, приводит к повышению показателей перинатальной заболеваемости и смертности, достигая в ряде регионов 46%.

The aim of the study was to estimate the diagnostic and treatment patterns in the management of acute nongonococcal urethritis (NGU) in males in some cities of Russia. Retrospective cross-sectional study was conducted in 2009 in 5 centers of 4 cities in the Central Part of Russia (Kaluga, Pskov, Smolensk - 2 centres and Tula). The data on the diagnostic and treatment approaches to the management of NGU in male subjects16 years old were collected and analyzed with the use of specially designed case report forms. 556 cases of acute urethritis were analyzed during the study. The diagnosis of NGU was confirmed in 401 cases. The average age of the patients was 29.8 years (16-68 years). The following diagnostic methods were used in 95% of the cases: urethral smear microscopy (314/82.4%), C. trachomatis - PCR (113/29.7%), ELISA (155/40.7%); T. vaginalis - PCR (106/27.8%); U. urealyricum and M. hominis, respectively - bacteriology (140/36.7% and 126/33.1%), PCR (110/28.9% and 108/28.3%); M. genitalium - PCR (110/28.9%). The treatment patterns included antimicrobials AMs alone in 60.3, and AMs + non-AMs in 37.8% of the cases. The most frequently prescribed AMs were azithromycin (27.5%), fluconazole (16.4%), doxycycline (13.6%), metronidazole (11.2%), ofloxacine (7.3%), ceftriaxone (4.4%), josamycin (4.2). According to the results use of the standard methods for NGU diagnosis was rather rare. The use of PCR for atypical pathogens was the following: C. trachomatis 29.7%, U. urealyticum 36.7%, M. hominis 28.9%, M. genitalium 28.3%. Doubtful culture methods were used for detection of U. urealyticum and M. hominis (36.7% and 33.1%). The AMs treatment in some cases was not in compliance with the up-to-date practical guidelines for STD and NGU.

A child with Job's syndrome was treated for pneumonia due to Mycoplasma pneumoniae . A mixed population of wild-type bacteria and an A2059G mutant was detected during josamycin treatment failure. The same multilocus variable-number tandem-repeat analysis (MLVA) type (MLVA type I) was isolated before and after treatment failure. The child recovered after ciprofloxacin treatment.

The prevalence and antimicrobial susceptibility of Ureaplasma urealyticum and Mycoplasma hominis collected during 2004–2011 were determined. A total of 9956 individuals was analyzed. Identification was performed by use of the mycoplasma IST-2 kit. Antimicrobial susceptibility against doxycycline, josamycin, ofloxacin, erythromycin, tetracycline, ciprofloxacin, azithromycin, clarithromycin, and pristinamycin was also tested by use of this commercial kit. Our results show a prevalence of 1856 positive patients for genital mycoplasmas (18.6 %). Among positive cultures, 89 and 1.1 % of isolates were Ureaplasma urealyticum and Mycoplasma hominis, respectively. For 9.8 % of isolates both urogenital mycoplasmas were grown. Doxycycline was the most active tetracycline for mycoplasma infections, and this is still the drug of first choice. Among macrolides, josamycin and clarithromycin are the most active agents against ureaplasmas; josamycin is also active against mycoplasmas and is an alternative to tetracyclines and erythromycin for mixed infections, especially for pregnant women and neonates. Fluoroquinolones had low efficacy against urogenital mycoplasmas. For Ureaplasma urealyticum, cross-resistance was found between erythromycin and macrolides (except josamycin) (40–80 %) and between erythromycin and ciprofloxacin (79 %). Antibiotic resistance over the test period did not vary significantly. Because of geographical differences among antibiotic resistance, local in-vitro susceptibility testing is recommended to avoid failure of therapy.

The present clinical immunological study included 90 women of reproductive age presenting with mycoplasma infection of the lower urogenital tract. Low-frequency ultrasonic radiation was shown to successfully correct the disbalance in the system of congenital immunity that manifested itself as marked dysfunction of neutrophil granulocytes. The local application of low-frequency ultrasonic radiation normalized concentration of neutrophil defensins in cervical secretion as well as the number and function of neutrophils themselves.

To examine the in vivo effects of the 15-member macrolide, azithromycin (AZM), on mucus hypersecretion, we induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal instillation of ovalbumin (OVA) in OVA-sensitized rats, or by intranasal lipopolysaccharides (LPS) instillation. Oral administration of AZM (5–10 mg/kg) or clarithromycin (CAM, 5–10 mg/kg) significantly inhibited OVA- and LPS-induced mucus production, whereas josamycin (JM) or ampicillin (ABPC) showed no effect. In vitro effects of AZM on airway epithelial cells were examined using NCI-H292 cells and human nasal epithelial cells cultured in air-liquid interface. Mucus secretion was evaluated by enzyme-linked immunosorbent assay using an anti-MUC5AC monoclonal antibody. AZM or CAM significantly inhibited tumor necrosis factor-α (TNF-α) (20 ng/mL)-induced MUC5AC secretion from NCI-H292 cells at 10−6–10−7 M, whereas JM or ABPC showed no effect. AZM significantly inhibited TNF- 𝛼 (20 ng/mL)-induced MUC5AC secretion from human nasal epithelial cells at 10−4 M. MUC5AC mRNA expression was also significantly inhibited. These results indicate that the 15-member macrolide, AZM, exerts direct inhibitory effects on mucus secretion from airway epithelial cells and that it may be useful for the treatment of mucus hypersecretion caused by allergic inflammation and LPS stimulation.

The effect of three macrolide antibiotics, midecamycin acetate, josamycin, and clarithromycin, on human T-cell function was investigated in vitro. Midecamycin acetate and josamycin suppressed the proliferative response of peripheral blood mononuclear cells stimulated by polyclonal T-cell mitogens at concentrations between 1.6 and 8 micrograms/ml. At higher concentrations (40 to 200 micrograms/ml), all these drugs showed a marked inhibitory effect. At concentrations of 1.6 to 40 micrograms/ml, these drugs suppressed interleukin-2 (IL-2) production induced by mitogen-stimulated T cells, but not the expression of IL-2 receptor (CD25), in a dose-dependent manner. Therefore, the suppressive action on T-lymphocyte proliferation seems to be based on the ability of these drugs to inhibit IL-2 production by T cells. The drug also inhibited mixed lymphocyte reaction at the same concentrations. Combined treatment with these macrolides and the known immunosuppressants such as FK506 and cyclosporin A resulted in an increased inhibition of T-cell proliferation. The immunomodulatory properties of the antibiotics may have clinical relevance for modulation of the immune response in transplant patients and in patients with inflammatory diseases.

Two macrolide-resistance determinants were cloned from a mycinamicin (Mm)-producing Micromonospora griseorubida strain in Streptomyces lividans and Streptomyces parvulus. One of the cloned genes, designated myrA, was cloned as a gene which conferred strong resistance to Mm and tyiosin (Ty), but not to erythromycin (Er) or josamycin (Jm) on S. lividans. Another gene, named myrB, was cloned as an ErRencoding gene which conferred MLS resistance (to macrolide, lincosamide and streptogramine B antibiotics) on S. parvulus. Both myrA and myrB were sequenced and the corresponding ORFs were determined. The deduced amino acid (aa) sequence of myrA showed no similarity to proteins in the available databases, suggesting that an unknown mechanism of macrolide resistance is exerted by the MyrA protein. The deduced aa sequence of myrB exhibited high similarity to 23S rRNA methyltransferases (MTases), such as ErmE and CarB, from a variety of microorganisms.

We have previously reported that erythromycin at sub-inhibitory concentrations enhanced the serum sensitivity of some Pseudomonas aeruginosa strains. To explore the mechanism of this effect, we have now examined the influence of macrolide antibiotics on outer membrane proteins and lipopolysaccharide (LPS) of P. aeruginosa. The strains S-6 and PAO-1 of P. aeruginosa were used as susceptible and resistant strains respectively to assess enhancement of serum sensitivity by erythromycin. The strain S-6 became more serum-sensitive when grown on agar with sub-MICs of erythromycin or azithromycin, but not of josamycin, whereas no change was observed in the serum sensitivity of the strain PAO-1 after growth with any of these antibiotics. The analysis of outer membrane proteins showed that erythromycin treatment resulted in a reduction in the amount of the 38 kDa protein (OprF) and in a prominent increase of 41 kDa protein band in the strain S-6, but not in the strain PAO-1. By an immunoblotting assay, this 41 kDa protein was shown to be highly reactive to the immune serum against untreated P. aeruginosa. LPS of the strain S-6 were examined by SDS acrylamide gel electrophoresis. The treatment with erythromycin or azithromycin, but not with josamycin, reduced the amounts of LPS species with lower molecular weights although the levels of LPS species with high molecular weights were similar to those of untreated bacteria. These results suggest that the enhanced serum sensitivity of P. aeruginosa by erythromycin is associated with changes in bacterial surface components, such as outer membrane proteins and LPS.

The efficacies of macrolide antibiotics, rokitamycin, leukomycin, josamycin and erythromycin were investigated against 63 strains of M. pneumoniae included FH strain which were isolated from clinical specimens obtained in 1986-1987, 1991, 1992-1993. Values of MICs and MBCs of these antibiotics were evaluated by two methods, broth dilution method and M. pneumoniae L cell infection system. In broth dilution method, MIC50 and MBC50 of rokitamycin were 0.0063-0.025 microgram/ml and 0.025-0.2 microgram/ml respectively. The ratios of MBC50/MIC50 were 1-32. MIC50 of leukomycin, josamycin and erythromycin were 0.0063-0.05 micrograms/ml, 0.0025-0.05 microgram/ml, and 0.0125-0.05 microgram/ml respectively. MBC50 of these drugs were 0.0125-50 micrograms/ml, 25-50 micrograms/ml, and 25-50 micrograms/ml respectively. The ratios of MIC50/MBC50 were 2-800, 500-2000, 500-4000. MIC50 of rokitamycin and leukomycin to the isolates during period from 1992-1993 were higher as compare to those of isolates during 1986 to 1991. On the other hand, rokitamycin markedly reduced the numbers of CFU in the growth phase when added at the concentrations of 16 and 4 times the MIC, but the other macrolides were reduced slightly CFU at the concentrations of 4 times, the MIC. In L cell infectious system, MIC50 and MBC50 of rokitamycin were 0.005-0.0125 microgram/ml and 0.05-0.1 microgram/ml respectively. The ratios of MBC50/MIC50 were 1-2 Ratios of leukomycin, josamycin, and erythromycin were 0.05-0.1 microgram/ml, 0.05-0.2 microgram/ml and 0.050-0.1 microgram/ml respectively. The MBC50 of these drugs were 0.2-0.4 micrograms/ml, 0.8-1.6 microgram/ml, 0.8-1.6 microgram/ml. Ratios of MBC50/MIC50 were 2-8, 4-32, 8-32.(ABSTRACT TRUNCATED AT 250 WORDS)

To explore the effects of mycoplasma and chlamydia infections on tubal infertilityand to assess the antibiotic susceptibility and resistance of female urogenital, and consequently to guide clinical rational drug use.327 tubal infertility women as infertility group and 286 healthy pregnant women as control group were randomly selected, detected chlamydia trachomatis (CT), ureaplasma urealyticum (UU) and mycoplasma hominis (MH) in cervical secretions and drug resistance of UU and MH.CT infection rates (14.99%), UU infection rates (23.24%), UU + MH infection rates (29.05%),CT + UU + MH infection rates (9.17%) and total infection rates (88.99%) in infertility group is higher than those (order: 2.80%, 6.99%, 8.39%, 4.55%, 29.02%) in the control group, comparisons of two groups are statistically significant differences (P0.05), the susceptibility of UU to roxithromycin (sensitivity is 96.05%), josamycin (sensitivity is 96.05%), tetracycline (sensitivity is 82.89%), vibramycin( sensitivity is 92.11%) and clarithromycin (sensitivity is 96.05%) were relatively high and low to ciprofloxacin and acetyl spiramycin. The susceptibility of MH to josamycin (sensitivity is 95.83%), vibramycin (sensitivity is 91.67%), minocin (sensitivity is 83.33%) and actinospectacin (sensitivity is 75.00%) were relatively high and low to erythromycin, azithromycin, roxithromycin and clarithromycin. UU + MH was only sensitive to josamycin (sensitivity is 90.52%), high resistance (77.89% -91.58%) to erythromycin, azithromycin, acetyl spiramycin, ciprofloxacin, ofloxacin, azithromycin and clarithromycin.Infection of CT, UU, MH and tubal infertility have certain relevance,the rates of CT, UU and MH infection in tubal infertility patients higher than fertile people. For many commonantibacterial drugs, UU, MH and UU + MH has strong resistance, the etiology detection and using adapted antibios should be taken seriously in clinical treatment.

The European Pharmacopoeia (Ph. Eur.) prescribes a selective and sensitive liquid chromatography/ultraviolet (LC–UV) method for the separation of the 16-membered ring macrolide josamycin and its related compounds. Since josamycin is obtained by fermentation, several closely related substances can be found in the sample. Several impurities have already been identified using reference substances. However, many peaks in the chromatogram cannot be correlated with known compounds or correspond to structures which were not described previously. The hyphenation of LC to mass spectrometry (MS) is a very useful tool for the characterization of impurities. The existing LC–UV method however uses non-volatile buffers, while for LC/MS a volatile mobile phase is required. In this study, each peak from the non-volatile system was collected separately and reinjected into a LC system using volatile mobile phase constituents. This way, the analyte could be separated from the buffer salts. Mass spectral data of this macrolide antibiotic were acquired on a LCQ ion trap mass spectrometer, equipped with an electrospray ionization (ESI) probe operating in the positive ion mode. The identity of the unknown compounds was deduced using the MS/MS and MS n collision-induced dissociation spectra of reference substances, combined with knowledge about the nature of functional group fragmentation behavior. The impurity profiling was done on 30 peaks in a josamycin bulk sample. This way, 12 compounds reported in the literature and Ph. Eur. were found in the bulk sample. Furthermore, 12 novel related substances were characterized and 18 compounds were partially characterized.

The influence of pH, ionic strength and buffer concentration on the stability of josamycin has been investigated. The pH-rate profile for josamycin over the pH range 1–12 was characterised and the equation describing the profile determined. Results indicated that josamycin is subject to specific acid catalysis whilst catalysis in alkali media appeared to be more complex. The rate constant for catalysis by hydronium ion ( k H ) was 54.11 M −1 · h −1 and the rate constant for catalysis by hydroxide ion ( k OH ) was 60.35 M −1 · h −1 . Catalysis due to water was insignificant and the water catalysed rate constant was found to be 3.37 × 10 −5 h −1 . The pH of maximum stability was determined as pH 6.5 whilst degradation at pH 1.0 and 12.0 is about five orders of magnitude greater than at pH 6.5. The degradation of josamycin in acid is subject to a significant primary salt effect; however, no secondary salt effect was evident. Concentration vs. time profiles for josamycin in acidic media were biphasic which indicated that the degradation reaction did not follow a simple pathway whereby josamycin degrades directly to products. Further investigations suggest that josamycin undergoes a reversible isomerisation step, with subsequent degradation of josamycin and possibly its isomer, by cleavage of the mycarose moiety to desmycarose compounds. Studies to determine the stability of josamycin in simulated gastric fluids demonstrated that acid degradation could be appreciable after oral administration. However, extensive degradation in vivo will only occur at the most acidic gastric pH's of about pH 1.0 to 2.0.