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We isolated 111 H. pylori strains from the gastric mucosa of H. pylori-infected patients in Bhutan in 2010. The Epsilometer test was used to determine the minimum inhibitory concentrations (MICs) of amoxicillin (AMX), clarithromycin (CLR), metronidazole (MNZ), levofloxacin (LVX), ciprofloxacin (CIP), and tetracycline (TET).
Phx-3, one of the phenoxazine derivatives, is reported to have inhibitory effect on Mycobacterium species and Chlamydia pneumoniae but not Escherichia coli, Salmonella Typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus, Listeria monocytogenes. The bactericidal activities of Phx-3 against Helicobacter pylori strains have not been assessed. Then, we measured minimum inhibitory concentration of Phx-3 for Helicobacter strains and assessed the morphological and biochemical effects of Phx-3 on H. pylori. In present study, it has shown that H. pylori strains including clarithromycin resistant strain and Helicobacter musterae were killed effectively by the treatment with Phx-3. Furthermore, severe morphological changes such as membrane blebbing and formation of hollows in H. pylori were detected. In addition, induction of heat shock protein 60 was observed. Taken together, Phx-3 has antibacterial activity against Helicobacter pylori.
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A series of O-alkylated derivatives of erythromycin (EM) has been prepared and their biological properties were evaluated. Among them, clarithromycin (CAM, 6-O-methylerythromycin) exhibits most potent in vitro and in vivo antibacterial activities, higher acid-stability than EM and favorable pharmacokinetic properties as an antibiotic. CAM was originally synthesized via methylation of 2'-O,3'-N-bis(benzyl-oxycarbonyl)-N-demethylerythromycin in low yield, because of the less selectivity of 6-O-methylation. The selective 6-O-methylation was achieved using the erythromycin 9-oxime derivative as a key intermediate. By the further investigation on the protective groups of 9-oxime and desosamine moiety, the production process of CAM on an industrial scale has been established via methylation of 2',4''-O-bis(trimethylsilyl)erythromycin 9-[O-(1-isopropoxycyclohexyl)oxime] in more than 45% overall yield. CAM has the same antibacterial spectra as EM and is active against aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, Mycoplasma and Chlamydia. The activity of CAM against clinical isolates was 1 to 16 times higher than that of EM. The efficacies of CAM were 6 to 15 times superior to those of EM against systemic infections due to Gram-positive bacteria in mice. CAM also showed more potent therapeutic efficacies than EM against respiratory tract infections caused by S. pneumoniae and H. influenzae. CAM was well absorbed after oral administration, and its distribution to various tissues was significantly higher than that of EM in animals. The level of CAM in the lung was extremely high, which accounted 69 times that of EM. CAM was found to be distributed predominantly in the alveolar wall, especially in the alveolar epithelial cells, by microautoradiography. After oral administration in human, the serum level and urinary excretion of CAM were 5 and 20 times higher than those of EM, respectively. The major and active metabolite of CAM in human, (14R)-14-hydroxyclarithromycin, existed in significant quantity in the serum and urine, suggesting that the metabolite contributes to the excellent clinical efficacy of CAM. This paper describes the synthesis, structure-activity relationships, antibacterial activities, metabolism and clinical efficacies of CAM, a new macrolide antibiotic.
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Forty H. pylori-positive children (21 males; median age: 12.3 years) were consecutively treated with 10-day sequential therapy [omeprazole + amoxycillin for 5 days, and omeprazole + clarithromycin + tinidazole for other 5 days] and blindly randomized to receive either L. reuteri ATCC 55730 (10(8) CFU) or placebo. All children completed the Gastrointestinal Symptom Rating Scale (GSRS) at entry, during and after treatment. H. pylori status was assessed after 8 weeks by (13)C-urea breath test.
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Sensitivity data were obtained in 41 patients. Intention-to-treat analysis revealed that overall eradication was achieved in 60% (24/40). Eighteen strains (43.9%) were resistant to metronidazole, 21 (51.2%) were resistant to clarithromycin and 8 (19.5%) were resistant to both drugs. None of the strains were resistant to amoxicillin or tetracycline. We used mainly two kinds of quadruple therapy in the 39 patients. Despite good compliance with treatment based on omeprazole (20 mg/12 h), bismuth subcitrate (120 mg/6 h), tetracycline (500 mg/4 h) and clarithromycin (500 mg/ 12 h) (OBTC) eradication was achieved in only 9 of 19 patients (47.4%; CI: 24.4-71.1) (one patient failed to attend the urea breath test). Nineteen clarithromycin-resistant patients received amoxicillin (1,000 mg/12 h) instead of clarithromycin (OBTA) and this treatment was effective in 14 (73.7%; CI: 48.8-90.9). Eradication was achieved in one patient who was allergic to amoxicillin and resistant to clarithromycin and metronidazole and who received ciprofloxacin (500 mg/8 h) instead of clarithromycin (OBTCipro). No clinical factors associated with eradication failure were found.
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Results from the studies were pooled. All regimens were well tolerated with only 1 drop-out because of side effects. Cure rates per protocol/intention to treat were 96%/95% for RBC-CLA dual therapy, 89%/86% for RBC-TET-MET triple therapy, and 93%/92% for RBC-AMO-CLA triple therapy. From 126 patients, a pretreatment antibiogram was available. Metronidazole resistance did not affect the performance of RBC-CLA or RBC-AMO-CLA. In the RBC-TET-MET group, 97% (32/33) with a metronidazole sensitive strain were cured vs 57% (four of seven) with a resistant strain. Of three patients with a pretreatment clarithromycin resistant strain; one failed RBC-CLA dual therapy and two failed RBC-AMO-CLA triple therapy.
Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the pharmacokinetics and pharmacodynamics of the drugs.
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A multicenter, retrospective study was performed in immunocompetent children <14 years of age with microbiologically confirmed NTM lymphadenitis treated at 6 hospitals in Madrid, Spain, during 2000-2010. We compared children with M. lentiflavum and Mycobacterium avium-intracellulare complex infection.
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Four weeks after the operation, the P. gingivalis-injected and CAM-treated mice showed a significant decrease in the aortic diameter in comparison with the mice only injected with P. gingivalis. Histopathologically, the samples obtained from the P. gingivalis-injected and CAM-treated mice showed less elastic degradation. Moreover, the plasma MMP-2 concentration of the CAM-treated mice decreased significantly.
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All but one patient completed treatment. Side-effects were rare and mild in all groups. The eradication rate was 93.8% in group OCT, 59.4% in group CT, 31.3% in group OC and 6.3% in group C. Pre-treatment metronidazole resistance was 12.8%, clarithromycin 1.1% and, to both antibiotics, 2.1%. In patients with pre-treatment metronidazole resistance, the eradication rate was 75% in group OCT and 33% in group CT. Post-treatment resistance to clarithromycin was induced in 28.5% of the failures in group C, but in none of group OC. Resistance to both antibiotics occurred in 22.2% of the failures in group CT and in none of group OCT.
Retrospective study to compare the efficacy of different treatment regimens in 28 patients with folliculitis decalvans.
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In 2003, we identified an outbreak of clinically distinct lesions involving the hands and feet associated with a public wading pool in Edmonton, Alberta, Canada. A total of 85 cases were identified. The management and follow-up of 41 children and 1 adult patients is presented. Skin lesions occurred within a median incubation period of 29 days and approximately 88 days for the adult patient. Lesions resolved within a median of 58 days and approximately 150 days for the adult patient. Patients were treated with clarithromycin, topical antibiotic dressings, and/or incision and drainage of pustules or followed without treatment. All resolved without complication. The pool was closed and cleaned. The M. abscessus hand-and-foot disease is characterized by the onset, mainly in children, of tender, erythematous papules, pustules, and abscesses with a self-limited course. This is the first documented M. abscessus outbreak associated with wading pool exposure.
Active efflux systems and reduced cell-wall permeability are considered to be the main causes of mycobacterial intrinsic resistance to many antimicrobials. In this study, we have compared the Mycobacterium smegmatis wild-type strain mc2155 with knockout mutants for porins MspA (the main porin of M. smegmatis) and MspC, the efflux pump LfrA (the main efflux pump system of M. smegmatis) and its repressor LfrR for their ability to transport ethidium bromide (EtBr) on a real-time basis. This information was then correlated with minimum inhibitory concentrations (MICs) of several antibiotics in the presence or absence of the efflux inhibitors chlorpromazine, thioridazine and verapamil.
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Data on anti-H. pylori therapies from a large number of publications are pooled into a few groups based on the combination of drugs, regardless of dosage, duration, etc., of the therapy. A mean success rate is calculated for all studies with subanalysis with regard to study design, size, doses and duration.
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A very favorable outcome after chemotherapy of 122 cases of M. kansasii lung disease was reported by Dr. Mizutani, who emphasized RFP as the "Key drug", and concluded that three-drug combination (not two-drug), including RFP (RFP.INH.EB or SM) for 1 year, could be a standard regimen for M. kansasii lung disease at the time of the moment. In addition, the following itemes were discussed. (1) In cases resistant to RFP, one could possibly replace RFP by TH, one of new quinolones (NQ), or the new macrolide (NM) (clarithromycin, CAM). (2) In low grade resistant cases to INH (0.1 microgram /ml) or EB (2.5 micrograms/ml), the replacement of the drugs may not be necessary, however, in higher-grade resistance to INH or EB, many cases were looked for the change of drugs according the results of the questionnaire done by the author. The present status of basic preclinical evaluations of new drugs were presented by Dr. Tomioka, who summarized in vitro and in vivo antimycobacterial activities of NMs and NQs. The most potent activity among NMs was demonstrated in CAM, which is probably the candidate for M. kansasii and possibly for M. avium complex (MAC) disease, followed by roxithromycin (RXM) and azithromycin (AZM) in sequence. NQs including the ones under development were generally potent against Mycobacterium tuberculosis, M. kansasii and M. fortuitum. NQs were not potent enough for MAC. In addition, the author discussed more suitable in vitro techniques which should reflect in vivo evaluations, and proposed the observation of in vitro bactericidal activity using both Cmax (maximal in vivo concentration) and C (0-8h) (the average concentration during 8 hours after administration) of drugs, and also the assessment of bactericidal activities of drugs in macrophages as better choices. As additional comments, the results of in vitro activities of NQs and NMs against MAC were supplemented by two authors, Dr. Tsuyuguchi and Dr. Kawahara. The assessment using 7 H 9 liquid medium by the former author demonstrated the potent activities of both CS-940* and sparfloxacin (SPFX), followed by AM-1155*, ciprofloxacin (CPFX), levofloxacin (LVFX), OPC-17116*, NM-394* in sequence. The author gave attention also to a high Cmax in CS-940*. In vitro activities with 7 H 11 agar medium reported by Dr. Kawahara demonstrated generally higher activities against M. avium than M. intracellulare, and reported potent activities of CPFX, SPFX, LVFX, grepafloxacin (GPFX), AM-1155*, and DU-6859 a* among 14 NQs tested. The author reported a rather potent activity of CAM against MAC followed by RXM and AZM in sequence. There was an impression that the MICs in both liquid and agar medium were comparable. (* : under development). The present status in the treatment of MAC lung disease was precisely reported by Dr. Harada, who summarized the results of survey both in 13 National Chest Hospitals (by questionnaire) and in the author's Hospital. The former survey demonstrated that 73% of the cases with the initial chemotherapy became consecutively negative for 6 months in the span of 9 months observation, which clearly showed the early response of MAC disease was rather favorable, in spite of very few cases with 4 drug-or more combinations. However, longer the follow up, the percentage of negative cases went down, which suggested bacteriological relapse occurred in relatively high percentage of the early converted cases. The evaluation of 117 cases of pulmonary MAC disease in the author's Hospital disclosed 2 drug-combination, RFP and INH, was clearly less potent than 3-drug combination, RFP.IHN.SM or EB, and 1 year after the begining of initial chemotherapy, around 60% of cases were negative, while only a little more than 40% of cases were negative in retreatments. The author suggested that around 50% of MAC lung disease may progress with episodes of "relapse". Death occurred 20% in the cases
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A low rate of recurrence of H. pylori infection was found in patients with dyspeptic symptoms. H. pylori isolates demonstrated a high invitro clarithromycin resistance.
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The present series demonstrates that acute disseminated encephalomyelitis in children occurs predominantly in winter or spring and often follows an upper respiratory tract illness for those along the southern coast of Anatolia (Mediterranean region). Early treatment with immunomodulative agents is recommended and is likely to result in a favorable outcome or full recovery. This study also suggests benefit from antiviral and antibiotic treatment initiated as soon as possible after the onset of illness.
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All of the isolates(36/36) were sensitive to amikacin and cefoxitin, and only 1 isolate(1/36) was resistant to clarithromycin, but more isolates(29/36) were resistant to ciprofloxacin, doxycycline, imipenem and sulfamethoxazole.For M.chelonae, only 2/16 were resistant to linezolid, and 7/16 resistant to tobramycin.For M.abscessus, more than 12/20 were resistant to linezolid and 16/20 resistant to tobramycin. The agreement between broth microdilution MICs and Etest MICs for 9 drugs was 149/324.With amikacin, clarithromycin, doxycycline and imipenem, the agreement for interpretive category was excellent(35/36), followed by sulfamethoxazole(34/36), which corresponded to rarely very major error of 2/36.With ciprofloxacin and tobramycin, agreement for interpretive category was 31/36 and 26/36.With cefoxitin and linezolid, the agreement of Etest MICs was the lowest(14/36), resulting in the resistant category.
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Both triple 1-week, low-dose omeprazole therapies gave good eradication rates with infrequent side-effects.
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Microdialysis is an increasingly employed technique for the determination of tissue pharmacokinetics. A high-performance liquid chromatography method for the quantitative determination of caspofungin in human microdialysates with amperometric detection is described. Since microdialysis of caspofungin is performed with a 100,000 molecular mass cut-off membrane, microdialysates contain protein that was precipitated at pH 4 with acetonitrile. Addition of 1-propanol (33%, v/v) to the sample extract improved the analytical recovery to 81-89%. Caspofungin and the internal standard clarithromycin were separated isocratically on a cyanopropyl silica column using acetonitrile-0.05 M citrate (33:67, v/v), adjusted to an apparent pH of 6.9, at a flow rate of 1.0 ml/min, and amperometric detection at +950 mV oxidation potential. Within-day and between-day imprecision and inaccuracy were <11%. The lower limit of quantification was 0.07 microg/ml. The method was applied to in vitro microdialysis experiments. Ringer's solution containing 1% (w/v) human albumin was used for the perfusing and surrounding medium, respectively. Albumin did not entirely prevent adsorption of caspofungin to the surface of membrane and/or tubing. When the binding-sites were saturated with albumin plus caspofungin prior to the start of sampling, the percentage of drug appearing in the microdialysate ("recovery") remained stable over the concentration range tested.
In order not to exceed recommended dosages, the 238 H. pylori-infected children, aged 3 to 15 years (mean 8.6), were divided in two weight categories receiving at weights 13-22 kg: lansoprazole 15 mg once-daily and amoxicillin 500 mg twice-daily with metronidazole 250 mg twice-daily or clarithromycin 250 mg once-daily; at weights 23-45 kg: lansoprazole 15 mg and amoxicillin 750 mg with metronidazole 500 mg or clarithromycin 250 mg, all administered twice daily. H. pylori status was assessed by culture and a monoclonal-based antigen-in-stool test (Premier Platinum HpSA PLUS) and side effects by structured questionnaires.
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Secondary metabolites have been found to have interesting applications over and above their well-known medical uses, e.g., as antimicrobials, etc. These alternative applications include antitumor, cholesterol-lowering, immunosuppressant, antiprotozoal, antihelminth, antiviral and anti-ageing activities. Polyene antibiotics, such as amphotericin B, are of use as antiprion agents, antitumor drugs and against leishmaniasis. Other microbial natural products that show antibiotic activity are used against cancer e.g., doxorubicin, neomycin, β-lactams, bleomycin and rapamycin. Macrolide antibiotics, such as erythromycin, clarithromycin and azithromycin, improve pulmonary function in patients suffering from panbioncholitis. Pigments like prodigiosin and shikonin have antitumor activity, while violacein has anti-ulcer and antitumor activity and also acts as an antiprotozoal agent. Statins, in addition to lowering cholesterol and LDL levels, also decrease elevated C-reactive protein (CRP) levels independent of their cholesterol effects. Immunosuppressants have many alternative effects: (i) Cyclosporin is proving useful in treatment of inflammatory disease such as asthma and muscular dystrophy. (ii) Rapamycin is extremely useful in preventing restenosis of stents grafted in balloon angioplasty. (iii) Tacrolimus and ascomycin help in treating inflammatory skin disease such as allergic contact dermatitis and psoriasis. Artemisinin, an antimalarial agent, is also showing antitumor activity. Other natural products, including those from plants (betulinic acid and shikonin), animals (bryostatins) and microbes (squalestatin and sophorolipids) have a multiplicity of potentially useful actions. Unexpected functions of known secondary metabolites are continuously being unraveled, and are fulfilling some of the needs of present day medicine and show great promise for the future.
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A vast number of Helicobacter pylori treatment trials have been conducted. Regimens may vary in efficacy in different patient populations.
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We initiated a prospective noncomparative trial of treatment for lung disease due to Mycobacterium avium complex (MAC) in human immunodeficiency virus-negative patients, with a regimen of clarithromycin (1000 mg), rifabutin (300-600 mg), and ethambutol (25 mg/kg) administered 3 times per week. Fifty-nine patients were enrolled. Twelve (20%) were lost to follow-up, and 6 (10%) developed clarithromycin intolerance. The remaining 41 patients (69%) completed the initial 6 months of therapy. The sputum of 32 of these patients (78%) converted to negative. When results were compared with the sputum response rates at 6 months in previous studies with a regimen including daily clarithromycin and regimens including intermittent (3 times per week) azithromycin with the same companion drugs, no differences in treatment responses were evident. Adverse reactions related to rifabutin were a major problem, and for 24 (41%) of 59 patients the dosage was decreased or the drug was withdrawn. Intermittent (3 times per week) administration of clarithromycin appears to be as effective as daily administration in effecting sputum conversion in pulmonary MAC disease.
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Gallium maltolate is not inferior to macrolides for treating foals with subclinical pneumonia. Use of GaM might reduce pressure for macrolide-resistance in R. equi.
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There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 +/- 1.0 versus 1.0 +/- 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 +/- 0.1 versus 0.44 +/- 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 +/- 9 L/hr to 10 +/- 3 L/hr occurred after clarithromycin administration. Oral midazolam availability was significantly increased from 0.31 +/- 0.1 to 0.75 +/- 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability were significantly increased from 0.42 +/- 0.2 to 0.83 +/- 0.2 and from 0.74 +/- 0.1 to 0.90 +/- 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05).
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The study group comprised 17 H. pylori-positive patients who had failed to clear H. pylori infection after 1 week of treatment with usual doses of proton pump inhibitor, amoxicillin and clarithromycin. The sensitivity of H. pylori to clarithromycin and amoxicillin, and the CYP2C19 genotype status of each patient were determined and treatment with rabeprazole (10 mg qid) and amoxicillin (500 mg qid) for 2 weeks was started.
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Helicobacter pylori eradication usually fails when clarithromycin is used against resistant strains.
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To report the largest series to date of Haemophilus species bacteremia (HB) from a single center.