Effects of Combined Treatment with Sansanmycin and Macrolides on Pseudomonas aeruginosa and Formation of Biofilm

Objective To observe the effects of combined treatment with sansanmycin and macrolides on Pseudomonas aeruginosa and formation of biofilm. Methods Micro-dilution method was used to determine the minimal inhibitory concentrations （MICs） of sansanmycin, gentamycin, carbenicillin, polymyxin B, roxithromycin, piperacillin, and tazobactam. PAl and PA27853 biofilms were observed under optical microscope after staining and under SEM after treatment with sansanmycin at different dosages and combined treatment with sansanmycin and roxithromycin. Viable bacteria in PAl and PA27853 biofilms were counted after treatment with sansanmycin at different dosages or combined treatment with sansanmycin and roxithromycin. Results The MIC of sansanmycin was lower than that of gentamycin and polymyxin B, but was higher than that of carbenicillin. Roxithromycin enhanced the penetration of sansanmycin to PAl and PA27853 strains through biofilms. PAl and PA27853 biofilms were gradually cleared with the increased dosages of sansanmycin or with the combined sansanmycin and roxithromycin. Conclusion Sub-MIC levels of roxithromycin and sansanmycin substantially inhibit the generation of biofilms and proliferation of bacteria. Therefore, combined antibiotics can be used in treatment of intractable bacterial infection.

Preliminary Study on Drug Susceptibility Profile and Resistance Mechanisms to Macrolides of Clinical Isolates of Non-tuberculous Mycobacteria from China

Objective Macrolide susceptibility and drug resistance mechanisms of clinical non-tuberculous mycobacteria（NTM） isolates were preliminarily investigated for more accurate diagnosis and treatment of the infection in China. Methods Four macrolides, including clarithromycin（CLAR）, azithromycin（AZM）, roxithromycin（ROX）, and erythromycin（ERY）, were used to test the drug susceptibility of 310 clinical NTM isolates from six provinces of China with the broth microdilution method. Two resistance mechanisms, 23 S r RNA and erm, were analyzed with nucleotide sequence analysis. Results Varied effectiveness of macrolides and species-specific resistance patterns were observed. Most Mycobacterium abscessus subsp. massiliense were susceptible and all M. fortuitum were highly resistant to macrolides. All the drugs, except for erythromycin, exhibited excellent activities against slow-growing mycobacteria, and drug resistance rates were below 22.2%. Only four highly resistant strains harbored 2,058/2,059 substitutions on rrl and none of other mutations were related to macrolide resistance. G2191 A and T2221 C on rrl were specific for the M. abscessus complex（MABC）. Seven sites, G2140 A, G2210 C, C2217 G, T2238 C, T2322 C, T2404 C, and A2406 G, were specifically carried by M. avium and M. intracellulare. Three sites, A2192 G, T2358 G, and A2636 G, were observed only in M. fortuitum and one site G2152 A was specific for M. gordonae. The genes erm（39） and erm（41） were detected in M. fortuitum and M. abscessus and inducible resistance was observed in relevant sequevar. Conclusion The susceptibility profile of macrolides against NTM was demonstrated. The well-known macrolide resistance mechanisms, 23 S r RNA and erm, failed to account for all resistant NTM isolates, and further studies are warranted to investigate macrolide resistance mechanisms in various NTM species.

Acatulides A-G,neuroprotective macrolides from Acaulium album H-JQSF

Fungal symbionts co-evolve with hosts and microbial co-inhabitants to acquire an unpredictable potential for producing novel bioactive metabolites,but the knowledge about the topic remains patchy and superficial.Here we present the chemical characterization of acatulides A-G(1-7)as architecturally unprecedented macrolides from the solid-state culture of Acaulium album H-JQSF,an arthropod-associated fungus.The acatulide structures were elucidated by spectroscopic analysis,modified Mosher's method and single-crystal X-ray diffraction.The plausible biosynthetic pathways for compounds 1-4 are proposed.Interestingly,acatulides B-D(2-4)and G(7)were demonstrated to be neuroprotective against the 1-methyl-4-phenylpyridinium(MPP+)-induced damage to SH-SY5Y cells and nematode Caenorhabditis elegans(C.elegans).

Advances in Medical Treatment of Primary Aldosteronism

Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.

Pathogenicity and Antimicrobial Resistance in Coagulase-Negative Staphylococci

The coagulase-negative staphylococci (CoNS) group was considered saprophytic or rarely pathogenic for many years. Since the first case of septicemia caused by CoNS, there has been a progressive increase in the prevalence of healthcare-associated infections caused by CoNS. The CoNS group has emerged as one of the main causes of nosocomial infections related to vascular catheters and prostheses, especially among immunocompromised patients. This gradual increase in infections is due to the change in the relationship between patients and procedures since CoNS are closely related to devices implanted in the human body. CoNS are successful in colonizing the host because they have several virulence mechanisms, such as biofilm formation and production of enzymes and toxins, in addition to several mechanisms of resistance to antimicrobials. Despite their great clinical relevance, few studies have focused on CoNS’s pathogenicity and resistance to antimicrobials, which reveals the current need to better understand the factors by which this group became pathogenic to humans and other animals. This review aims to synthesize the aspects related to the pathogenicity and antimicrobial resistance in CoNS.

高效液相色谱-串联质谱法对猪肉中四种大环内酯类药物残留量的测定

A simple and sensitive method was developed for the simultaneous determination of four macrolides in pork using high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).Homogenized sample was extracted with NaH2PO4 buffer and acetonitrile solution,and defatted with n-hexane.Further cleanup was performed on a Sep-Pakt C18 solid-phase extraction cartridge.The compounds were determined by LC-MS/MS operated in positive electrospray ionization mode.The limits of detection(LODs) were 0.5 μg/kg.The average recoveries at three spiked concentration levels of 1.0,5.0,10.0 μg/kg were in the range of 70%-110%,with the intra-day RSD of less than 12.9% and inter-day RSD of less than 13.4%.

液相色谱-质谱法同时检测畜禽肉中五种大环内酯类抗生素

大环内酯类抗生素(macrolide antibiotics,MALS)对革兰氏阳性菌和支原体有较强的抑制能力,支原体在畜禽中是感染面较广的多发病,因此这类抗生素在动物药品和饲料添加物中占有重要位置.然而,人们在获得经济利益的同时对抗生素的副作用也有了进一步的认识.……

Study of Serotypes, Susceptibility to Macrolide and Virulence and Resistance Molecular Profiles in Invasive Strains of <i>Streptococcus agalactiae</i>in Two Argentine Provinces

A study of invasive strains of Streptococcus agalactiae (GBS) from Cordoba and Misiones, Argentina;was conducted to determine serotypes, the susceptibility to macrolides and molecular profiles of virulence and resistance. We studied 17 strains, recovered from cerebrospinal fluid, blood and cellulite and, a strain of trophoblastic remnants from Misiones. The serotypes were determined by agglutination with sera and phenotypes of resistance to macrolide-lincosamide-streptogramin B (MLSB), were determined with the double-disk test (D-test). The confirmation was performed by E-test by ERI and CLI respectively that determined the minimum inhibitory concentration (MIC). Results were interpreted as recommended by the Clinical and Laboratory Standards Institute (CLSI) 2013. Resistance genes: ermB, ermTR and mefA and the virulence genes: bac, bca, rib, lmb, hylB, scpB, fbsA, fbsB and cylB were investigated by conventional PCR. Serotype III (50%) and Ia (50%) were detected in Cordoba. One strain showed cMLSB phenotype, confirmed by MIC. The same strains showed a resistance gene ermB. All studied virulence genes were detected in 100% of these strains. In Misiones, serotypes were III (72.7%), Ia (18.2%) and Ib (9.1%). All strains were susceptible to CLI and ERI by D-test, confirmed by MIC. None of the strains showed resistance genes. Virulence genes bca, rib, hylB, lmb, fbsA, fbsB and cylB were detected in 100% of the strains, bac in 81.8% and scpB in 90.9%. Our results are in accordance with international data, associating higher frequency of serotype III of invasive neonatal disease followed by Ia. The presence of serotype Ib could indicate a regional difference for Misiones. We highlight the macrolides susceptibility in strains of Misiones and consistency in the results for D-test, MIC and PCR for the single strain resistant phenotype cMLSB from Cordoba. The virulence genes studied were presented with high frequency as expected for invasive strains.

Macrolide-Clarithromycin Task-Force for the Treatment and Prophylaxis of Covid-19 as a Single Agent

SARS-CoV-2 is a novel RNA coronavirus responsible of a deadly pandemic: the clinical illness COVID-19. With only one authorized drug for emergency use in critically ill patients: Remdesivir, there is not any other approved drug or vaccine yet with proven potential to overcome this infection. We exposed here many scientific evidences to support our novel idea that a macrolide, basically Clarithromycin, could be effective as a single agent for treatment and prophylaxis of COVID-19. Clarithromycin could change the history of this pandemic. It could reduce the costs of treatment and the potential adverse effects when combining more than one drug such as with Hydroxychloroquine. Clarithromycin treatment and prophylaxis as a single agent could be much more simple, safe and cheaper as giving Chloroquine or Hydroxychloroquine alone or in combination with Azithromycin as well as other therapeutic options.

Immune system as a new therapeutic target for antibiotics

Since the discovery of penicillin by Fleming in 1928, the knowledge of the antibiotics’ spectrum and mechanism of action has been steadily increasing. Antibiotics became an effective tool in the fight against many pathogens, changing the prognosis of outcome for many serious diseases. It is already known that antibiotics not only have the antibacterial activity, but many of them—e.g. macrolides, sulphonamides and tetracyclines—have immunomodulating effect, affecting functions of lymphocytes, macrophages and costimulatory molecules, macrophage migration and phagocytosis, as well as proinflammatory cytokine secretion. The expanding knowledge of the effects of antibiotics on the immune system has brought with it new applications of antibiotics in organ transplantation, invasive cardiology and treatment of autoimmune diseases such as rheumatoid arthritis or asthma.

Investigation on the Veterinary Antibiotics Contamination in Groundwater with SPE-LC/MS/MS

[Objective]The aim is to provide data support for the prevention and control of pollution of exogenous chemical in pig breeding industry.[Methods]Solid-phase extraction（SPE）and tandem mass（LC-MS/MS）were used for determining four classes（tetracyclines,quinolones,macrolides and sulfonamides）of 10 common veterinary antibiotics in groundwater of an important pig breeding base in the Yangtze River Delta region of China.[Results]Results revealed the total concentration of the ten antibiotics in urban rivers ranged from 20.1 ng /L to 61.2 ng /L.The highest proportion was taken by tetracyclines,account for 95%,the concentration was up to 44.0 ng /L.Quinolones shared the second largest proportion of total concentration,about 29%,the concentration was up to 21.6 ng /L,while concentration of sulfonamides and macrolides were respectively below 2.7 ng /L and 6.3 ng /L.The highest total concentration of the ten antibiotics in rural rivers was up to 467 ng /L,60% of which was shared by tetracyclines,the highest concentration of tetracyclines was 253 ng /L.Sulfonamides share 20% of the total concentration,the highest concentration of it was 165 ng /L.The highest concentration of macrolides and quinolones was 14.6 ng /L and 14.5 ng /L,respectively.[Conclusion] Antibiotics＇ pollution in town rivers is more serious than urban rivers＇ pollution caused by antibiotics.

Mycoplasma pneumoniae Macrolide Resistance and MLVA Typing in Children in Beijing,China,in 2016:Is It Relevant?

Objective The aim of this study is to investigate the macrolide resistance rate and molecular type with multiple-locus variable-number tandem-repeat analysis(MLVA)of Mycoplasma pneumoniae of Beijing in 2016 in pediatric patients.Methods Real-time quantitative polymerase chain reaction(PCR)was used to identify M.pneumoniae,and MLVA was performed.The domain V of the 23 S rRNA was sequenced to detect macrolide-resistant point mutations.We also investigated the activities of antibiotics against M.pneumoniae isolates in vitro.Results The PCR detection rate of M.pneumoniae in children in Beijing was 40%,and the macrolide resistance rate was 66%.The A2063 G mutation in the 23 S rRNA V region is the dominant mutation(137/146,93.84%),whereas the A2064 G mutation is rare(9/146,6.16%).Seventy-three samples were typed successfully by MLVA typing,including 86.3%(63/73)were MLVA type 4-5-7-2,and 13.7%(10/73)were MLVA type 3-5-6-2.No other types were found.No strains were resistant to levofloxacin or tetracycline.Conclusion In 2016,a specific decrease in the macrolide resistance rate occurred in Beijing.The detection rate and macrolide resistance rate of outpatients are lower than those of inpatients.The A2063 G mutants M.pneumoniae have high levels of resistance to erythromycin and azithromycin.The primary MLVA type is 4-5-7-2,followed by 3-5-6-2.No other MLVA types were detected.No strains resistant to tetracycline or levofloxacin were found in vitro.

Synthesis of novel 15-membered macrolide derivatives

In order to develop new antibiotics effective against resistant bacteria,a series of novel 15-membered macrolide derivatives were designed and synthesized by the modification of hydroxyl groups at C-11,C-12 and C-4＂ positions.Their structures were confirmed by MS,IR,^1H NMR or ^13C NMR.

Synthesis of derivatives of imidazo[4,5-b]pyridine:Novel sulfur contained side chains for macrolide antibiotics

Two series of novel derivatives of imidazo[4,5-b]pyridine were synthesized. These compounds could be used as side chains of semisynthesised ketolide antibiotics. The side chains have free amine group which can attached to ketolide core. Macrolides with this kind of side chains will show obvious activities against erythromycin-resistant strains. The structure of the side chains was confirmed by ^1H, ^13C NMR, MS, HMBC spectra. 2007 Ping Sheng Lei. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Antifungalmycin,an antifungal macrolide from Streptomyces padanus 702

Two polyene macrolide antibiotics:antifungalmycin(1)and fungichromin(2)were isolated from the culture mycelia of Streptomyces padanus 702 via bioactivity-guided fractionation using various chromatographic procedures.Their structures were elucidated on the basis of spectral analysis,and 1 is a new polyene macrolide.Compounds 1 and 2 showed significant inhibition against Gibberella zeae with EC_(50)values of 26.71 and 2.21μg/mL,Fusicoccum sp.(plantain head blight)with EC_(50)values of 23.4 and 3.17μg/mL,Mucor ssp.8894 with EC_(50)values of 28.80 and 2.11μg/mL,Ustilaginoidea virens with EC_(50)values of 26.72 and 0.21μg/mL,respectively.This shows that the microbial secondary metabolites 1 and 2 have the potential to be developed as agricultural fungicides for use against G.zeae,Fusicoccum sp.,Mucor ssp.8894,and U.virens.

Selective Association between Cephalosporin, Quinolone, Macrolide, and Penicillin Antibiotic Consumption and Childhood Obesity in Europe

The accelerated weight gain in productive animals as a result of feeding antibiotic enriched fodder has been well known for decades. The better energy harvest is the result of modified gut microbiota as a consequence of applied antibiotics. Similar mechanisms might result obesity in humans as well. Objectives: Finding associations between global antibiotic consumption of different classes in EU countries and obesity data in adults and children prove that antibiotics might play a significant role in the development of obesity “epidemics” and related illnesses. Methods: Antibiotic consumption data were compared with obesity figures in adults and children in European countries and statistically analyzed for significance. Results: Significant correlation was found between the average yearly consumption of cephalosporins (p = 0.007), quinolones (p = 0.031), macrolides (p = 0.000083) and childhood obesity data, but no significant association was observed with the average penicillin consumption. No association was observed between adult obesity and any of the antibiotic classes studied. Conclusions: Our results support the hypothesis that different types of antibiotics might influence the development of obesity among children, and this finding can serve as a unified explanation for the development of obesity “epidemics”, similarly to the obesity and gut flora alteration-related diseases (type 2 diabetes mellitus, autism, etc.).

Synthesis of novel 15-membered macrolide dimers

A series of novel dimers of 15-membered macrolides was synthesized and evaluated. The dimers exhibited excellent activity against erythromycin-susceptible S. pneumonia, but did not show any improved activity against erythromycin-resistant S. pneumoniae encoded by erm gene. ？2009 Shu Tao Ma. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All fights reserved.

Synthesis of 12-alkoxycarbonylmethylene-1,15-pentadecanolides

Six novel 12-alkoxycarbonylmethylene-1,15-pentadecanolides （3） were synthesized from 2-nitrocyclo-dodecanone by the Michael addition with acrolein followed by ring enlargement, Nef reaction and Wittig-Homer reaction. Their structures were confirmed bv 1H NMR, IR and elemental analysis. The preliminary bioassay showed that they have some fungicidal activity.

Pharmacokinetics of Milbemycin Oxime in Dogs Following Its Intravenous and Oral Administration

The pharmacokinetics of milbemycin oxime was investigated in dogs following oral(per os, PO) and intravenous(IV) administration. Three groups of dogs received milbemycin oxime tablets as a single PO dose equal to 0.25, 0.5 and 1.0 mg · kg-1 of milbemycin oxime, respectively, another group received a single IV dose of 0.5 mg · kg-1. Blood samples were collected at predetermined times after drug administration and the milbemycin oxime concentrations in plasma were determined by LC-MS/MS. The drug protein binding in dog plasma in vitro was determined by equilibrium dialysis at concentrations spanning the range of values observed in vivo in dog plasma. After PO administration at doses of 0.25, 0.5 and 1.0 mg · kg-1, milbemycin oxime was slowly absorbed and eliminated, the time to reach the maximum plasma concentration(Tmax) was 4.14±0.20, 4.27±0.14 and 4.06±0.13 h, the mean absorption time(MAT) was 19.06, 13.67 and 11.77 h, the terminal rate half-life(t1/2λz) was 15.06±0.37, 11.09±0.54 and 9.76±0.89 h and the total body clearance(Cl) was 1.15±0.05, 1.18±0.03 and 1.17±0.07 m L · min-1 · kg-1, respectively. The maximum plasma concentration(Cmax, 36.50±1.40, 76.11±2.77 and 182.05±7.20 ng · m L-1, respectively) and the area under the first-moment curve(AUC-10→∞, 985.83±49.46, 1 663.12±51.42 and 3 558.04±197.88 mg · h · L, respectively) increased accordingly to the administered dose rates; the oral bioavailabilities were estimated to be 88.61%, 74.75% and 79.96%, respectively. The values of fu were 0.12%, 0.14% and 0.13% in dog plasma, respectively. In conclusion, the pharmacokinetics of milbemycin oxime in dogs following oral administration revealed its higher oral bioavailability and advantageous pharmacokinetic properties, such as its lower total body clearance and longer elimination half-life, and indicated that the single oral dose of 0.50 mg · kg-1 of milbemycin oxime which was recommended in all the parasitological efficacy studies allowed an adequate concentration of the drug.