High Concentrations Of Azithromycin Research Articles

Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study

The increasing incidence of syphilis and the limitations of first-line treatment with penicillin, particularly in neurosyphilis, neonatal syphilis, and pregnancy, highlight the need to expand the therapeutic repertoire for effective management of this disease. We assessed the in-vitro efficacy of 18 antibiotics from several classes on Treponema pallidum subspecies pallidum (T pallidum), the syphilis bacteria. Using the in-vitro culture system for T pallidum, we exposed the pathogen to a concentration range of each tested antibiotic. After a 7-day incubation, the treponemal burden was evaluated by quantitative PCR targeting the T pallidum tp0574 gene. The primary outcome was the minimum inhibitory concentration (MIC) at which the quantitative PCR values were not significantly higher than the inoculum wells. We also investigated the susceptibility of macrolide-resistant strains to high concentrations of azithromycin, and the possibility of developing resistance to linezolid, a proposed candidate for syphilis treatment. Amoxicillin, ceftriaxone, several oral cephalosporins, tedizolid, and dalbavancin exhibited anti-treponemal activity at concentrations achievable in human plasma following regular dosing regimens. The experiments revealed a MIC for amoxicillin at 0·02 mg/L, ceftriaxone at 0·0025 mg/L, cephalexin at 0·25 mg/L, cefetamet and cefixime at 0·0313 mg/L, cefuroxime at 0·0156 mg/L, tedizolid at 0·0625 mg/L, spectinomycin at 0·1 mg/L, and dalbavancin at 0·125 mg/L. The MIC for zoliflodacin and balofloxacin was 2 mg/L. Ertapenem, isoniazid, pyrazinamide, and metronidazole had either a poor or no effect. Azithromycin concentrations up to 2 mg/L (64 times the MIC) were ineffective against strains carrying mutations associated to macrolide resistance. Exposure to subtherapeutic doses of linezolid for 10 weeks did not induce phenotypic or genotypic resistance. Cephalosporins and oxazolidinones are potential candidates for expanding the current therapeutic repertoire for syphilis. Our findings warrant testing efficacy in animal models and, if successful, clinical assessment of efficacy. European Research Council.

Degradation of high concentrations of azithromycin when present in a high organic content wastewater by using a continuously fed laboratory-scale UASB bioreactor

As the presence of emergent contaminants in wastewater, such as antibiotics, has become a threat for public health, the evaluation of strategies to treat them has been gaining importance. A critical example of this situation can be found in wastewaters coming from the pharmaceutical industry, where high concentrations of antibiotics are sometimes accompanied by high organic contents. Even the agroindustry can be affected by a similar problem when cattle infections are treated with antibiotics and part of the antibiotic-contaminated milk has to be wasted. With these situations in mind, in the present study we evaluated a progressive acclimation strategy for a granular sludge in a UASB reactor treating a high organic-content synthetic wastewater contaminated with azithromycin. In parallel, we tested a previously reported low-cost method for azithromycin determination by spectrophotometry, obtaining results comparable with liquid chromatography coupled to mass spectrometry. Although azithromycin has been reported as recalcitrant and resistant to biological degradation, the antibiotic was removed with efficiencies over 50% for wastewater with 10 mg L−1 of azithromycin and a COD of more than 4000 mgO2 L−1. Furthermore, efficiencies over 40% were achieved for wastewater with higher azithromycin concentrations (80 mg L−1) and a COD of 20,000 mgO2 L−1. A careful acclimation strategy permitted the partial removal of azithromycin from wastewater when treating concentrations comparable and higher than what would be expected for domestic and hospital wastewaters, even when its chemical oxygen demand is considerably higher than the average maximum of around 1000 mgO2 L−1.

Adsorptive removal of azithromycin from aqueous solutions using raw and saponin-modified nano diatomite.

This study aims to investigate the performance and mechanism of raw (R-ND) and saponin-modified nano diatomite (M-ND) in the removal of azithromycin from aqueous solutions. Adsorbent characterization was performed using X-ray fluorescence, Brunauer-Emmett-Teller (BET), scanning electron spectroscopy, dynamic light scattering and energy-dispersive X-ray analyses. It was shown that the specific surface area of R-ND was 119.5 m2/g, 14-fold higher than that for raw diatomite, and for M-ND it was 90.1 m2/g. Various adsorption conditions, i.e. adsorbent dosage, pH, initial concentration and contact time were investigated. According to the results, despite reducing the specific surface area by 25%, modification of nano diatomite by saponin markedly enhanced its performance in the removal of azithromycin. The maximum adsorption capacity of R-ND and M-ND in the removal of azithromycin was 68 and 91.7 mg/g, respectively. Fourier transform infrared spectroscopy results revealed that azithromycin was adsorbed by O-H groups on the diatomite surface. Weber-Morris intra-particle diffusion (IPD) model suggested that while IPD is not the rate-controlling step in high concentrations of azithromycin, it is the only step that controls the rate of adsorption in low concentrations. In comparison to R-ND, M-ND showed a higher efficiency in the removal of azithromycin and, therefore, it can be used as a promising low-cost adsorbent to remove azithromycin from aqueous solutions.

Biotransformation of macrolide antibiotics using enriched activated sludge culture: Kinetics, transformation routes and ecotoxicological evaluation

The biotransformation of three prominent macrolide antibiotics (azithromycin, clarithromycin and erythromycin) by an activated sludge culture, which was adapted to high concentrations of azithromycin (10 mg/L) was investigated. The study included determination of removal kinetics of the parent compounds, identification of their major biotransformation products (TPs) and assessment of ecotoxicological effects of biotransformation. The chemical analyses were performed by ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry, which enabled a tentative identification of TPs formed during the experiments. The ecotoxicological evaluation included two end-points, residual antibiotic activity and toxicity to freshwater algae. The enriched activated sludge culture was capable of degrading all studied macrolide compounds with high removal efficiencies (>99%) of the parent compounds at elevated concentrations (10 mg/L). The elimination of all three macrolide antibiotics was associated with the formation of different TPs, including several novel compounds previously unreported in the literature. Some of the TPs were rather abundant and contributed significantly to the overall mass balance at the end of the biodegradation experiments. Biodegradation of all investigated macrolides was associated with a pronounced reduction of the residual antibiotic activity and algal toxicity, indicating a rather positive ecotoxicological outcome of the biotransformation processes achieved by the enriched sludge culture.

P08.33 Azithromycin pharmacokinetics and implications for extended doses forchlamydia trachomatisand other sexually transmitted infections

Introduction Chlamydia treatment failure remains concerning with high repeat positive diagnoses of up to 14% in women and 22% for rectal infections in men. Meta-analysis estimates of rectal chlamydia treatment efficacy suggests azithromycin may be 20% less efficacious than doxycycline, but this is based on observational data only – with no RCTs evaluating rectal chlamydia treatment nor any pharmacokinetic data for azithromycin in rectal mucosa. This systematic review will examine the dose-related pharmacokinetics of azithromycin in blood and tissues with discussions on possible considerations of extended regimens to improve efficacy for anorectal infections should a 1 g dose prove suboptimal from RCTs. Methods Medline and Embase were searched from 1946 to February 2015. Inclusion criteria were: English language, adults and reported pharmacokinetics after any oral dose of azithromycin. Studies of urogenital and rectal tissue were the primary focus but other tissues (excluding eyes) were included. Dose administered and pharmacokinetic parameters such as peak concentration and area under the concentration-time curve (AUC) were extracted. Results Studies reported high concentrations of azithromycin in cervical, urological, gynaecological, pulmonary, prostatic and oral tissue/fluid after total doses of 500 mg to >2 g. No studies of rectal tissue were reported, however studies of gastric tissue/fluid (a proxy for rectal tissue) showed high concentrations being rapidly attained and sustained for >7 days. Increasing doses results in greater tissue concentrations, which are sustained longer above chlamydia minimum inhibitory concentration (MIC) but with only modest increases in peak blood levels between high and low doses. Similar tissue concentrations were obtained whether the total dose was given over short versus longer duration, suggesting regimens beyond (e.g. >3 days) do not have absorption advantages. Conclusion Azithromycin concentrations above the MIC are rapidly attained and sustained following treatment. While no data are available in rectal tissue, studies in gastric tissue/fluid suggest adequate rectal concentrations should be obtained. Azithromycin pharmacokinetics also suggest that total doses >1 g given over a few days can be effective in delivering high concentrations to tissues susceptible to chlamydia infections. Disclosure of interest statement None.

Pharmacokinetics of azithromycin and concentration in body fluids and bronchoalveolar cells in foals.

To determine the pharmacokinetics of azithromycin and its concentration in body fluids and bronchoalveolar lavage cells in foals. 6 healthy 6- to 10-week-old foals. Azithromycin (10 mg/kg of body weight) was administered to each foal via i.v. and intragastric (i.g.) routes in a crossover design. After the first i.g. dose, 4 additional i.g. doses were administered at 24-hour intervals. A microbiologic assay was used to measure azithromycin concentrations in serum, peritoneal fluid, synovial fluid, pulmonary epithelial lining fluid (PELF), and bronchoalveolar (BAL) cells. Azithromycin elimination half-life was 20.3 hours, body clearance was 10.4 ml/min x kg, and apparent volume of distribution at steady state was 18.6 L/kg. After i.g. administration, time to peak serum concentration was 1.8 hours and bioavailability was 56%. After repeated i.g. administration, peak serum concentration was 0.63 +/- 0.10 microg/ml. Peritoneal and synovial fluid concentrations were similar to serum concentrations. Bronchoalveolar cell and PELF concentrations were 15- to 170-fold and 1- to 16-fold higher than concurrent serum concentrations, respectively. No adverse reactions were detected after repeated i.g. administration. On the basis of pharmacokinetic values, minimum inhibitory concentrations of Rhodococcus equi isolates, and drug concentrations in PELF and bronchoalveolar cells, a single daily oral dose of 10 mg/kg may be appropriate for treatment of R. equi infections in foals. Persistence of high azithromycin concentrations in PELF and bronchoalveolar cells 48 hours after discontinuation of administration suggests that after 5 daily doses, oral administration at 48-hour intervals may be adequate.

Ocular levels of azithromycin.

To assess azithromycin levels in human serum, aqueous humor, tear fluid, and conjunctival tissue specimens after administration of a single 1-g oral dose of azithromycin. Sixty patients undergoing cataract surgery were included in this analysis. Serum, aqueous, and tear specimens were collected 3, 6, and 12 hours and 1, 2, 3, and 4 days after azithromycin administration. Conjunctival tissue biopsy specimens were collected 1, 2, 3, 4, 6, 8, 10, 12, and 14 days after azithromycin administration. All specimens were subjected to analysis by high-performance liquid chromatography-mass spectrometry. Azithromycin concentration ranges during the specified sampling times were as follows: serum, 21 to 974 ng/mL; tear, 82 to 2892 ng/mL; aqueous, 10 to 69 ng/mL; and conjunctival, 0.7 to 32 micrograms/g. Levels above the 90% minimal inhibitory concentration (MIC90) for Chlamydia trachomatis were detected after 4 days in all tear samples and after 14 days in all conjunctival tissue specimens following oral azithromycin administration. We demonstrated prolonged high levels of azithromycin in drug-targeted ocular tissue. Prolonged high concentrations of azithromycin in conjunctival tissue make this drug suitable for treatment of conjunctivitis caused by chlamydiae and other susceptible organisms.

Azithromycin Clinical Pharmacokinetics

Azalide antibiotics, of which azithromycin is the first demonstrated, have different pharmacokinetics from other antibiotics currently used. The bioavailability of the drug is approximately 37%. Extensive and rapid distribution from serum into the intracellular compartments is followed by rapid distribution to the tissues. Tissue concentrations exceed serum concentrations by up to 100-fold following a single azithromycin 500mg dose. Concentration of the drug within phagocytes aids in its ability to combat infections. High concentrations of azithromycin are found in the tonsil, lung, prostate, lymph nodes and liver, with only small concentrations found in fat and muscle. A 500mg dose on day 1, followed by 250mg daily on days 2 to 5, has been demonstrated to maintain azithromycin concentrations at sites of infection and continues to be effective for several days after administration has ceased. The pharmacokinetics of azithromycin make it a drug with diverse therapeutic applications.

Gynaecological tissue levels of azithromycin

In an open study the concentrations of azithromycin in plasma, urine, peritoneal fluid and gynaecological tissue in 20 patients undergoing elective gynaecological surgery were compared. Patients were allocated to one of four groups and all patients received a single 500 mg oral dose of azithromycin prior to surgery. In Group I, the dose was administered 24 h before surgery. In Groups II, III and IV it was administered 48, 72 and 96 h, respectively, prior to surgery. A total of 19 patients completed the study; one patient had peri-operative complications and did not proceed to surgery. High concentrations of azithromycin were found in gynaecological tissue up to 96 h after administration. The mean maximum observed concentration 24 h after administration was 1.44 +/- 0.22 micrograms/g. Using all data, the depletion rate constant was 0.0104 h-1, equivalent to a half-life of approximately 67 h. The mean concentration of drug in peritoneal fluid was approximately 9% of the mean concentration in gynaecological tissue. Tissue and peritoneal fluid azithromycin concentrations were much higher than plasma levels at the time of surgery. Detectable plasma levels were only found in four patients from Groups I and II. Six percent of the total dose was excreted in the urine during the seven-day period after drug administration. The single dose of azithromycin was well tolerated by all the patients in this study and no treatment-related side effects or laboratory test abnormalities were seen. It is concluded that a single 500 mg oral dose of azithromycin produces high and sustained levels in gynaecological tissue up to 96 h after administration.

Concentrations of azithromycin in human tonsillar tissue.

Patients scheduled to undergo tonsillectomy were administered 500 mg oral azithromycin as two 250 mg capsules given 12 h apart. Between 9 h and one week after the second dose, tonsil samples were taken during surgery and assayed for azithromycin. Mean concentrations in tonsillar tissue, 12 and 24 h after the second of the two 250 mg doses given 12 h apart, were 4.5 and 3.9 micrograms/g, respectively. Concurrent mean serum concentrations were approximately 0.03 and 0.01 micrograms/g, respectively. The mean concentration in tonsillar tissue 7.5 days after the last dose was 0.93 micrograms/g. The apparent half-life of drug in the tissue was 76 h. The ratio of mean concentration in tissue to that in serum was greater than 150-fold for all time intervals. The presence of high azithromycin concentrations in tonsillar tissue suggests that a once-daily regimen over five days or less may be effective in treating tonsillo-pharyngitis.

Tissue-directed pharmacokinetics

Azalide antibiotics demonstrate pharmacokinetics distinct from all antibacterial agents in common use. Following oral absorption, conventional oral antibiotics diffuse through serum and interstitial compartments and are eliminated rapidly. A minimal to moderate degree of intracellular penetration may be observed. The pharmacokinetics of azithromycin, the first azalide, are characterized by a rapid and extensive movement of the drug from the serum into intracellular compartments. A dynamic equilibrium exists between the intracellular, interstitial, and serum compartments, with predominant flux into tissue sites. Azithromycin is concentrated to a high degree within phagocytes and transported by chemotactic mechanisms to the site of infection. High concentrations of azithromycin are found in pulmonary, genital, and lymphatic tissues. Azithromycin's serum levels decline in a polyphasic manner with a terminal half-life of approximately 60 hours. These kinetics allow azithromycin to be administered once daily. It is predicted that after drug administration for 5 days, therapeutic levels of azithromycin will be maintained at the tissue sites of infection for an additional 4–7 days. Consideration of the extravascular pharmacodynamics of azithromycin is necessary when making predictions regarding its therapeutic application.