zithromax and Staphylococcal-Infections

Few adequately designed clinical trials have addressed optimal treatment duration in lower respiratory tract infections. Drugs possessing favourable pharmacokinetic and pharmacodynamic profiles may obtain early bacterial eradication allowing shorter treatment duration. This may be associated with a number of advantages including reduced resistance induction, increased compliance, lesser adverse events, and cost containment. Recently, a novel 2.0 g single dose of azithromycin microspheres has been compared with 7-day levofloxacin 500 mg or extended release clarithromycin in over 400 patients with community-acquired pneumonia. Clinical cure and bacteriological eradication rates, hospitalizations, and deaths were similar between azithromycin and comparators. Azithromycin 2.0 g microspheres proved as effective as 7 days of levofloxacin 500 mg in acute exacerbation of chronic bronchitis patients across all degrees of obstruction severity. In both settings Azithromycin microspheres obtained clinical cure in most patients harbouring macrolide-resistant Streptococcus pneumoniae strains. The drug was well tolerated in clinical studies and in healthy volunteers with modest and transitory adverse events. An undoubted advantage of single-dose azithromycin administration is the facility in ensuring that patients complete their prescribed course of therapy. A further advantage of single-dose therapy is the potential for use as directly-observed therapy, which may be useful in specific clinical conditions.

Topics: Administration, Inhalation; Animals; Anti-Bacterial Agents; Azithromycin; Capsules; Clinical Trials as Topic; Drug Carriers; Humans; Microspheres; Respiratory Tract Infections; Staphylococcal Infections

Staphylococcus aureus is a major cause of serious illness and death in children, indicating the need to monitor prevalent strains, particularly in the vulnerable pediatric population. Nasal carriage of S. aureus is important as carriers have an increased risk of serious illness due to systemic invasion by this pathogen and can transmit the infection. Recent studies have demonstrated the effectiveness of azithromycin in reducing the prevalence of nasopharyngeal carrying of pneumococci, which are often implicated in respiratory infections in children. However, very few studies of the impact of azithromycin on staphylococci have been undertaken. During a clinical trial under taken in 2016, nasal swabs were collected from 778 children aged 3 to 59 months including 385 children who were swabbed before administration of azithromycin or placebo and 393 after administration of azithromycin or placebo. Azithromycin was given in a dose of 100 mg for three days, together with the antimalarials sulfadoxine-pyrimethamine and amodiaquine, on four occasions at monthly intervals during the malaria transmission season. These samples were cultured for S. aureus as well as for the pneumococcus. The S. aureus isolates were tested for their susceptibility to azithromycin (15 g), penicillin (10 IU), and cefoxitine (30 g) (Oxoid Ltd). S. aureus was isolated from 13.77% (53/385) swabs before administration of azithromycin and from 20.10% (79/393) six months after administration (PR = 1.46 [1.06; 2.01], p = 0.020). Azithromycin resistance found in isolates of S. aureus did not differ significantly before and after intervention (26.42% [14/53] vs 16.46% [13/79], (PR = 0.62 [0.32; 1.23], p = 0.172). Penicillin resistance was very pronounced, 88.68% and 96.20% in pre-intervention and in post-intervention isolates respectively, but very little Methicillin Resistance (MRSA) was detected (2 cases before and 2 cases after intervention). Monitoring antibiotic resistance in S. aureus and other bacteria is especially important in Burkina Faso due to unregulated consumption of antibiotics putting children and others at risk.

Topics: Anti-Bacterial Agents; Antimalarials; Azithromycin; Child, Preschool; Drug Resistance, Bacterial; Female; Humans; Infant; Malaria; Male; Nasopharynx; Prevalence; Staphylococcal Infections; Staphylococcus aureus

Oral azithromycin given during labour reduces carriage of bacteria responsible for neonatal sepsis, including Staphylococcus aureus. However, there is concern that this may promote drug resistance.. Here, we combine genomic and epidemiological data on S. aureus isolated from mothers and babies in a randomized intra-partum azithromycin trial (PregnAnZI) to describe bacterial population dynamics and resistance mechanisms.. Participants from both arms of the trial, who carried S. aureus in day 3 and day 28 samples post-intervention, were included. Sixty-six S. aureus isolates (from 7 mothers and 10 babies) underwent comparative genome analyses and the data were then combined with epidemiological data. Trial registration (main trial): ClinicalTrials.gov Identifier NCT01800942.. Seven S. aureus STs were identified, with ST5 dominant (n = 40, 61.0%), followed by ST15 (n = 11, 17.0%). ST5 predominated in the placebo arm (73.0% versus 49.0%, P = 0.039) and ST15 in the azithromycin arm (27.0% versus 6.0%, P = 0.022). In azithromycin-resistant isolates, msr(A) was the main macrolide resistance gene (n = 36, 80%). Ten study participants, from both trial arms, acquired azithromycin-resistant S. aureus after initially harbouring a susceptible isolate. In nine (90%) of these cases, the acquired clone was an msr(A)-containing ST5 S. aureus. Long-read sequencing demonstrated that in ST5, msr(A) was found on an MDR plasmid.. Our data reveal in this Gambian population the presence of a dominant clone of S. aureus harbouring plasmid-encoded azithromycin resistance, which was acquired by participants in both arms of the study. Understanding these resistance dynamics is crucial to defining the public health drug resistance impacts of azithromycin prophylaxis given during labour in Africa.

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Carrier State; Comparative Genomic Hybridization; Drug Resistance, Bacterial; Female; Gambia; Genome, Bacterial; Humans; Infant, Newborn; Labor, Obstetric; Microbial Sensitivity Tests; Middle Aged; Nasopharynx; Neonatal Sepsis; Pregnancy; Staphylococcal Infections; Staphylococcus aureus; Young Adult

Oral azithromycin given to women in labor decreases maternal and neonatal bacterial carriage but increases azithromycin-resistant bacteria during at least 4 weeks following the intervention. We assessed the prevalence of bacterial carriage and azithromycin resistance 12 months after treatment among study infants.. Nasopharyngeal swabs (NPSs) were collected between November 2014 and May 2015 from children aged 11-13 months whose mothers had received azithromycin or placebo during labor. Streptococcus pneumoniae and Staphylococcus aureus were isolated using conventional microbiological methods. Antibiotic susceptibility was determined by disk diffusion and confirmed by Etest or VITEK-2.. NPSs were collected from 461 children. The prevalence of S. pneumoniae and S. aureus was similar between children from the azithromycin and placebo arms (85.0% vs 82.1%; odds ratio [OR], 1.23 [95% confidence interval {CI}, .73-2.08] for S. pneumoniae and 21.7% vs 21.3%; OR, 1.02 [95% CI, .64-1.64] for S. aureus). Prevalence of azithromycin-resistant S. pneumoniae was similar in both arms (1.8% vs 0.9% in children from the azithromycin and placebo arms, respectively; OR, 2.10 [95% CI, .30-23.38]); resistance to other antibiotics was also similar between arms. For S. aureus, there was no difference in azithromycin resistance between children in the azithromycin (3.1%) and placebo (2.6%) arms (OR, 1.22 [95% CI, .35-4.47]) or resistance to any other antibiotics.. The higher prevalence of S. aureus azithromycin resistance observed among women treated during labor and their babies 4 weeks after treatment had waned 12 months after delivery. Azithromycin intervention did not induce other antibiotic resistance to S. pneumoniae or S. aureus.. NCT01800942.

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Azithromycin; Carrier State; Drug Resistance, Bacterial; Female; Follow-Up Studies; Gambia; Humans; Infant; Labor, Obstetric; Long Term Adverse Effects; Male; Maternal Exposure; Microbial Sensitivity Tests; Nasopharynx; Pregnancy; Prevalence; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae; Young Adult

We have recently completed a proof-of-concept trial showing that bacterial colonization decreased in women and newborns after the administration of azithromycin during labor. Here, we aim to assess the effect of the intervention on maternal and neonatal clinical infections.. This was a double-blind, placebo-controlled randomized trial. Gambian women in labor were given either an oral dose of azithromycin (2 g) or placebo. Follow-up was conducted for 8 weeks after delivery.. From April 2013 to April 2014, we recruited 829 mothers and their 830 newborns. Sixteen infants died during the follow-up period (8 per arm). No maternal deaths or serious adverse events related to the intervention were reported. Maternal infections were lower in the azithromycin group (3.6% vs 9.2%; relative risk [RR], 0.40; 95% confidence interval [CI], 0.22-0.71; P = .002), as was the prevalence of mastitis (1.4% vs 5.1%; RR, 0.29; 95% CI, 0.12-0.70; P = .005) and fever (1.9% vs 5.8%; RR, 0.33; 95% CI, 0.15-0.74; P = .006). Among newborns, the overall prevalence of infections was also lower in the azithromycin group (18.1% vs 23.8%; RR, 0.76; 95% CI, 0.58-0.99; P = .052) and there was a marked difference in prevalence of skin infections (3.1% vs 6.4%; RR, 0.49; 95% CI, 0.25-0.93; P = .034).. Azithromycin given to women in labor decreases infections in both women and newborns during the puerperal period. Larger studies designed to evaluate the effect of the intervention on severe morbidity and mortality are warranted.

Topics: Administration, Oral; Azithromycin; Bacterial Infections; Carrier State; Developing Countries; Double-Blind Method; Female; Fever of Unknown Origin; Gambia; Humans; Infant, Newborn; Infant, Newborn, Diseases; Mastitis; Pneumococcal Infections; Pregnancy; Puerperal Infection; Skin Diseases, Bacterial; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus agalactiae

To determine whether repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics promotes antimicrobial resistance in patients undergoing intravitreal injections for choroidal neovascularization (CNV).. Prospective, randomized, controlled, clinical trial.. Forty-eight eyes of 24 patients undergoing unilateral intravitreal injections for CNV.. Patients were assigned randomly to 1 of 4 ophthalmic antibiotics (azithromycin 1%, ofloxacin 0.3%, gatifloxacin 0.3%, moxifloxacin 0.5%) to be used after each injection in the treatment eye only. Bilateral conjunctival and unilateral nasopharyngeal cultures on the treatment side were obtained at baseline and were repeated at each subsequent visit for 1 year. All bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. Genetic analysis of bacteria strains was performed using pulse-field gel electrophoresis.. Changes in antibiotic susceptibility patterns of conjunctival and nasopharyngeal flora over time and emergence of resistant strains.. Eight subjects (33%) grew Staphylococcus aureus from the nasopharynx and 1 subject (13%) showed emergence of a resistant strain. Coagulase-negative staphylococci (CNS) cultured from eyes repeatedly exposed to fluoroquinolone antibiotics demonstrated significantly increased rates of resistance to third- and fourth-generation fluoroquinolones compared with untreated eyes. Resistance to ofloxacin and levofloxacin was roughly 85% (P = 0.003), and resistance to gatifloxacin and moxifloxacin approached 67% (P = 0.009) and 77% (P<0.001), respectively. In contrast, CNS isolated from eyes repeatedly exposed to azithromycin demonstrated significantly increased resistance (94%) to erythromycin and azithromycin when compared with control eyes (P = 0.009) and decreased resistance to third-generation (P<0.03) and fourth-generation (P<0.001) fluoroquinolones when compared with eyes exposed to fluoroquinolones.. Repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics selects for resistant strains.

Topics: Adult; Aged; Aged, 80 and over; Anti-Infective Agents; Aza Compounds; Azithromycin; Conjunctiva; Drug Resistance, Bacterial; Fluoroquinolones; Gatifloxacin; Humans; Intravitreal Injections; Levofloxacin; Middle Aged; Moxifloxacin; Nasopharynx; Ofloxacin; Prospective Studies; Quinolines; Staphylococcal Infections

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Humans; Phenotype; Placebos; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Long-term administration of azithromycin (AZM) in children with cystic fibrosis (CF) has improved outcomes. However, the doses and schedule of administration are not very well studied in children with CF.. A randomized controlled trial was conducted to compare the effect of two doses of azithromycin (5mg/kg/day and 15mg/kg/day) on FEV(1) and pulmonary exacerbations in children with cystic fibrosis. Enrolled children were randomly allocated to receive daily azithromycin (5mg/kg/day or 15mg/kg/day) for 6months. Clinical assessment and FEV(1) measurement were performed monthly.. 56 children (28 in high dose group and 28 in low dose group) were enrolled. 47 (24 and 23 children in low and high dose groups) completed 12months of follow up. There was no difference in clinical scores, FEV(1), pulmonary exacerbation rates between two groups at baseline, 6months and at 12months. Per protocol analysis revealed that pulmonary exacerbation increased after discontinuing AZM and there was significantly more increase after 12months of enrolment in children getting high dose azithromycin. There was no improvement in FEV(1) in either group at the end of treatment period. Children tolerated daily low as well as high dose AZM well for 6months. There was no significant side effect of azithromycin.. In this randomized controlled trial, we did not find differences in the effect of 2 doses (5mg/kg/day or 15mg/kg/day) of AZM on change in percentage predicted FEV(1), clinical scores, Pseudomonas colonization rates, pulmonary exacerbations and need for antibiotics. There was increase in exacerbations after stopping azithromycin in both the groups. Our results also suggest that the decrease in the incidence of LRTI persists only till 6months after discontinuing azithromycin.

Topics: Anti-Bacterial Agents; Azithromycin; Body Weight; Candidiasis; Child; Child, Preschool; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Interleukin-8; Male; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Spirometry; Sputum; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pneumoniae; Treatment Outcome

Respiratory tract infection is a serious complication associated with bronchoscopic biopsy. This study attempted to examine its incidence and determine an efficacious therapy for preventing such infections.. Nine hundred and thirty patients who underwent bronchoscopic biopsy in Osaka City University Hospital outpatient clinic were enrolled in the study. All patients were randomly assigned to receive a 3-day course of azithromycin (500 mg/day), cefcapene pivoxil hydrochloride (300 mg/day) or no antibiotics. The primary outcome was the incidence of respiratory tract infection after bronchoscopic biopsy among the three groups.. In the no-treatment group, nine of the 310 patients (2.9%) had respiratory tract infection after bronchoscopic biopsy. All patients with infection had abnormal bronchoscopic findings. Of the patients with respiratory tract infection, 60% were in the no-treatment group, 26.7% in the cefcapene group and 13.3% in the azithromycin group. Although not statistically significant, the incidence in the azithromycin group (0.7%) was lower than in the no-treatment group (P = 0.06). Among the patients with abnormal bronchoscopic findings, the incidence in the azithromycin group was significantly lower than that in the no-treatment group (3.0% vs. 14.8%; P = 0.02). Moreover, maximum C-reactive protein values also appeared to be lower in the azithromycin group than in the no-treatment group and the cefcapene group.. A 3-day course of azithromycin administration is well tolerated and effective in preventing infection post bronchoscopy.

Topics: Adult; Aged; Anti-Bacterial Agents; Azithromycin; Biopsy; Bronchoscopy; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Respiratory Tract Infections; Retrospective Studies; Staphylococcal Infections; Treatment Outcome

In this multicenter, investigator-blind trial, we compared the efficacy and safety of azithromycin and cefadroxil for the treatment of uncomplicated skin and skin structure infections (SSSIs). A total of 296 patients were randomized to receive either azithromycin (500 mg on day 1, followed by 250 mg once a day on days 2 to 5) or cefadroxil (500 mg twice a day for 10 days). Outpatients, ranging in age from 18 to 75 years, with acute uncomplicated SSSIs were enrolled in the study. Clinical and bacteriologic response was assessed between days 10 and 13 (primary end point) and between days 28 and 32. In a modified intent-to-treat analysis, clinical success rates assessed between days 10 and 13 were 97% (111/114) for azithromycin and 96% (101/105) for cefadroxil (P = .717). For azithromycin and cefadroxil, corresponding rates of bacteriologic eradication for Staphylococcus aureus were 94% (64/68) and 86% (60/70), respectively, and for Streptococcus pyogenes, 80% (4/5) and 100% (6/6), respectively. Clinical success rates assessed between days 28 and 32 were 100% (82/82) for azithromycin compared with 90% (75/83) for cefadroxil (P = .007). Corresponding rates of eradication for S aureus were 100% (59/59) versus 89% (56/63), respectively; and for S pyogenes, 100% (4/4) versus 83% (5/6), respectively. The incidence of treatment-related adverse events was similar in the 2 treatment groups. However, 5 of the 139 patients (4%) in the cefadroxil group discontinued therapy because of treatment-related adverse events compared with none of the 152 patients in the azithromycin group (P = .02). Five-day therapy with azithromycin was as effective as 10-day therapy with cefadroxil for treating uncomplicated SSSIs.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Azithromycin; Cefadroxil; Female; Follow-Up Studies; Humans; Male; Middle Aged; Severity of Illness Index; Single-Blind Method; Staphylococcal Infections; Streptococcal Infections; Streptococcus pyogenes; Time Factors; Treatment Outcome; United States

During two separate periods a total of 654 patients were included in a clinical study relating preoperative bacterial colonization to occurrence of postoperative wound infection in plastic surgery. During the second period one half of the patients were randomized to receive prophylactic azithromycin. Bacteriological samples were collected from the nasal vestibulum during both periods, and additionally from the surgical field during the second period. All patients had preoperative chlorhexidine bathing. The bacteriological findings were categorized as either normal flora or potentially pathogenic bacteria, and as either having no growth. Surgical wounds were divided into four contamination classes. Postoperative follow-up was 30 days, and assessment of wound infection was based on a graded scale. We did not find any statistically significant relation between preoperative bacterial colonization and postoperative wound infection, regardless of place of sample collection, method of bacterial classification, class of contamination or use of prophylactic azithromycin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azithromycin; Carrier State; Child; Child, Preschool; Double-Blind Method; Humans; Infant; Infant, Newborn; Middle Aged; Nose; Premedication; Prospective Studies; Staphylococcal Infections; Staphylococcus aureus; Surgery, Plastic; Surgical Wound Infection

The efficacy and safety of azithromycin and clarithromycin were compared in an open multicentre study involving 380 adult patients with acute otitis media, acute sinusitis, or acute streptococcal pharyngitis or tonsillitis. Patients were assigned randomly to receive azithromycin as a single dose of 500 mg daily for three days, or clarithromycin 250 mg bid for ten days. Overall clinical efficacy was found to be similar in each treatment group at day 10-14, with a satisfactory outcome (cured or improved) in 95% of azithromycin and 96% of clarithromycin patients. Bacteriological efficacy was also similar, with eradication of the pathogen in 94% and 95% of isolates, respectively, in the azithromycin and clarithromycin groups. In otitis media, a satisfactory clinical response was seen in 97% of patients in each treatment group. Azithromycin therapy resulted in a clinical response rate of 93% in sinusitis patients, with bacteriological eradication in 93% of patients. Two patients (who were cured clinically) had persistent pathogens. Similarly, clarithromycin achieved clinical response and bacteriological eradication in 95% and 92% of sinusitis patients, respectively. Pathogens persisted in two patients with clinical cure, and in one case of clinical failure. In pharyngitis or tonsillitis, Streptococcus pyogenes was eradicated successfully in 95% of patients in both groups, and the clinical success rates were 96% and 97% for azithromycin and clarithromycin, respectively. No case of clinical failure was associated with persistence of S. pyogenes infection. At the follow-up assessment of this diagnosis group, reinfection had occurred in three (8%) azithromycin patients and one (3%) clarithromycin patient, and all but one patient remained asymptomatic. Both drugs were well-tolerated, with 8.4% of patients on azithromycin and 7.4% on clarithromycin reporting adverse events, mainly gastrointestinal. It was concluded that a three-day course of azithromycin was as effective and well-tolerated as a ten-day course of clarithromycin in adults with acute upper respiratory tract infections.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Azithromycin; Bacterial Infections; Child; Clarithromycin; Drug Administration Schedule; Erythromycin; Escherichia coli Infections; Female; Humans; Male; Middle Aged; Otitis Media; Pharyngitis; Respiratory Tract Infections; Sinusitis; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pyogenes; Tonsillitis

Seventy-eight patients participated in this multicenter, third-party-blinded study comparing a single daily dose of azithromycin for 5 days (500 mg on day 1 followed by 250 mg/day for days 2-5) with amoxicillin (500 mg three times daily) for 10 days in the treatment of acute bacterial maxillary sinusitis. A total of 38 evaluable patients contributed to the efficacy analysis. The overall clinical response rate was 100% for both antibiotics. The clinical cure rate, as determined by the investigator, was 73.9% for azithromycin and 73.3% for amoxicillin; improvement was seen in 26.1% and 26.7% of patients, respectively. The bacteriologic cure rate in these 38 patients was 100% in both groups. Both antibiotics were well tolerated; side effects were reported by 4.9% of patients in the azithromycin group compared with 8.1% in the amoxicillin group. Most of these side effects were gastrointestinal disturbances that were reported by four of five (three amoxicillin, one azithromycin) patients experiencing side effects. All side effects were mild, and in both groups only minor abnormalities in laboratory data were detected. No patient discontinued the study because of treatment-related side effects. In this study, a 5-day course (one dose per day) of azithromycin proved to have efficacy, safety, and tolerability that was equal to a 10-day course (three doses per day) of amoxicillin in the treatment of acute bacterial sinusitis.

Topics: Acute Disease; Adolescent; Adult; Aged; Amoxicillin; Azithromycin; Erythromycin; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Male; Maxillary Sinusitis; Middle Aged; Staphylococcal Infections; Streptococcal Infections

This was a randomized, third-party-blinded, multicenter study that compared once-daily azithromycin (500 mg on day 1, followed by 250 mg on days 2-5) to cefaclor (500 mg three times daily for 10 days) in the treatment of patients with acute bronchitis or pneumonia. A total of 546 patients were entered into the study and 272 patients were evaluable for efficacy analysis. Of these, 249 (176 azithromycin, 73 cefaclor) had bronchitis and 23 (15 azithromycin, 8 cefaclor) had pneumonia. The combined clinical cure and improvement rate, as determined by the investigator, was 96% for azithromycin and 94% for cefaclor, with 88% bacteriologic eradication in both treatment groups. The elimination of Haemophilus influenzae was significantly better with azithromycin (94.5%) than with cefaclor (61.1%) (p less than 0.001; Fisher's exact two-tail test). The two antibiotics were well tolerated during this study; the incidence of side effects reported was similar for azithromycin and cefaclor. Approximately two thirds of the side effects were mild. Only minor abnormalities in the screening laboratory tests were noted. This study shows that a 5-day course of once-daily azithromycin is as effective as a 10-day three times daily course of cefaclor in the treatment of patients with acute lower respiratory tract infections.

Topics: Azithromycin; Bronchitis; Cefaclor; Erythromycin; Haemophilus Infections; Humans; Klebsiella Infections; Moraxella catarrhalis; Neisseriaceae Infections; Pneumonia; Prospective Studies; Sputum; Staphylococcal Infections; Streptococcal Infections

This randomized, third-party-blinded study compared short-course therapy of once-daily azithromycin (500 mg on day 1, followed by 250 mg/day on days 2-5) with cephalexin (500 mg twice daily for 10 days) in the treatment of patients with skin and skin structure infections. At 25 centers, a total of 361 patients were entered into the study and 148 were evaluable for efficacy. The main causative pathogens, Staphylococcus aureus and Streptococcus pyogenes, were responsible for approximately two thirds of the infections in the two treatment groups. Clinical cure and improvement rates for the two treatments were comparable; 99% with azithromycin and 96% with cephalexin. On completion of therapy, both treatments had eradicated approximately 98% of pathogens. In general, both agents were well-tolerated. The results of this study show that a 5-day course of once-daily treatment with azithromycin is as effective as a 10-day course of twice-daily treatment with cephalexin in the management of skin and skin structure infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azithromycin; Cephalexin; Drug Administration Schedule; Erythromycin; Humans; Middle Aged; Skin Diseases, Infectious; Staphylococcal Infections; Streptococcal Infections

Bacterial infection is still one of the diseases that threaten human health, and bacterial drug resistance is widespread worldwide. As a result, their eradication now largely relies on antibacterial drug discovery. Here, we reveal a novel approach to the development of 14-membered macrolide antibiotics by describing the design, synthesis, and evaluation of novel clarithromycin derivatives incorporating 1,2,3-triazole moieties at the 4''- and 11-OH positions. Using chemical synthesis, 35 clarithromycin derivatives were prepared, and their antibacterial properties were profiled. We found that compounds 8e-8h, 8l-8o, 8v, and 19d were as potent as azithromycin against Enterococcus faecalis ATCC29212. Furthermore, compounds 8c, 8d, 8n, and 8o showed slightly improved antibacterial activity (2-fold) against Acinetobacter baumannii ATCC19606 when compared with azithromycin and clarithromycin. In addition, compounds 8e, 8f, 8h, 8l, and 8v exhibited excellent antibacterial activity against Staphylococcus aureus ATCC43300, Staphylococcus aureus PR, and Streptococcus pneumoniae ER-2. These compounds were generally 64- to 128-fold more active than azithromycin, and 32- to 128-fold more active than clarithromycin. The results of molecular docking indicated that compound 8f may bind to the nucleotide residue A752 through hydrogen-bonding, hydrophobic, electrostatic, or π-π stacking interactions. The predicted ClogP data suggested that higher values of ClogP (>6.65) enhanced the antibacterial activity of compounds such as 8e, 8f, 8h, 8l, and 8v. The determination of the minimum bactericidal concentration showed that most of the tested compounds were bacteriostatic agents. From this study of bactericidal kinetics, we can conclude that compound 8f had a concentration- and time-dependent effect on the proliferation of Staphylococcus aureus ATCC43300. Finally, the results of the cytotoxicity assay showed that compound 8f exhibited no toxicity at the effective antibacterial concentration.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Triazoles

Cell Surface hydrophobicity is one of the determinant biophysical parameters of bacterial aggregation for being networked to form a biofilm. Phytoconstituent, like vitexin, has long been in use for their antibacterial effect. The present work demonstrates the role of vitexin in modulating Staphylococcus aureus surface hydrophobicity while aggregating to form biofilm and pathogenesis in a host. In planktonic form, vitexin shows minimum inhibitory concentration at 252 µg/ml against S. aureus. Sub-MIC doses of vitexin and antibiotics (26 µg/ml of vitexin, 55 µg/ml of azithromycin, and 2.5 µg/ml of gentamicin) were selected to treat S. aureus. Dead cell counts after treatment were studied through flow cytometry. As dead cell counts were minimal (<5 %), these doses were considered for all subsequent experiments. While studying aggregating cells, it was observed that vitexin reduces S. aureus surface hydrophobicity and membrane permeability at the sub-MIC dose of 26 µg/ml. The in silico binding analysis showed a higher binding affinity of vitexin with surface proteins (IcaA, DltA, and SasG) of S. aureus. Down-regulation of dltA and icaAB expression, along with the reduction in membrane potential with a sub-MIC dose of vitexin, explains reduced S. aureus surface hydrophobicity. Vitexin was found to interfere with S. aureus biofilm-associated protein biomass, EPS production, and swarming movement. Subsequently, the suppression of proteases production and down-regulation of icaAB and agrAC gene expression with a sub-MIC dose of vitexin explained the inhibition of S. aureus virulence in vitro. Besides, vitexin was also found to potentiate the antibiofilm activity of sub-MIC doses of gentamicin and azithromycin. Treatment with vitexin exhibits a protective response in S. aureus infected macrophages through modulation of expression of cytokines like IL-10 and IL-12p40 at protein and mRNA levels. Furthermore, CFU count and histological examination of infected mouse tissue (liver and spleen) justify the in vivo protective effect of vitexin from S. aureus biofilm-associated infection. From this study, it can be inferred that vitexin can reduce S. aureus surface hydrophobicity, leading to interference with aggregation at the time of biofilm formation and subsequent pathogenesis in a host.

Topics: Animals; Anti-Bacterial Agents; Apigenin; Azithromycin; Biofilms; Gentamicins; Hydrophobic and Hydrophilic Interactions; Mice; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

A critical point in dentistry is the empiric prescription of broad-spectrum antibiotics that could increase the levels of antimicrobial resistance. Alveolar osteitis is one of the most common post-op- erative complications in which antibiotic use is controversial. A 35-year-old female, with pain in the right mandibular region and treated with cefixime, was diagnosed with cracked tooth syndrome and pulpitis. The tooth was extracted and a massive purulent bleeding drainage was observed. Irrigation of the socket and a new therapy with azithromycin were done. Bacteriological analysis, a specific mecA gene PCR for the methicillin resistance, and the antimicrobial susceptibility test were per- formed on the bacterial isolate. A Staphylococcus epidermidis isolate was methicillin-resistant and showed resistance to erythromycin, azithromycin, clarithromycin, and sulfamethoxazole + trimeth- oprim. After 7 days, intraoral examination showed a complete resolution. The aim of this report is to suggest that systemic antibiotics may provide insufficient efficacy during alveolar osteitis, especially when caused by a multidrug-resistant organism.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Dry Socket; Female; Humans; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus epidermidis

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Lipase; Methicillin-Resistant Staphylococcus aureus; Methylene Blue; Mice; Microbial Sensitivity Tests; Nanoparticles; Peptides; Photochemotherapy; Photosensitizing Agents; Silicon Dioxide; Singlet Oxygen; Staphylococcal Infections

Antibiotic resistance is a major problem, with methicillin-resistant Staphylococcus aureus (MRSA) being a prototypical example in surgical and community-acquired infections. S. aureus, like many pathogens, is immune evasive and able to multiply within host immune cells. Consequently, compounds that aid host immunity (e.g., by stimulating the host-mediated killing of pathogens) are appealing alternatives or adjuncts to classical antibiotics. Azithromycin is both an antibacterial and an immunomodulatory drug that accumulates in immune cells. We set out to improve the immunomodulatory properties of azithromycin by coupling the immune activators, nitric oxide and acetate, to its core structure. This new compound, designated CSY5669, enhanced the intracellular killing of MRSA by 45% ± 20% in monocyte-derived macrophages and by 55% ± 15% in peripheral blood leukocytes, compared with untreated controls. CSY5669-treated peripheral blood leukocytes produced fewer proinflammatory cytokines, while in both monocyte-derived macrophages and peripheral blood leukocytes, phagocytosis, ROS production, and degranulation were unaffected. In mice with MRSA pneumonia, CSY5669 treatment reduced inflammation, lung pathology and vascular leakage with doses as low as 0.01 μmol/kg p.o. CSY5669 had diminished direct

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Cytokines; Inflammation; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Nitric Oxide; Pneumonia, Staphylococcal; Prodrugs; Reactive Oxygen Species; Staphylococcal Infections; Staphylococcus aureus

Osteomyelitis is bacterial infection of bone, commonly caused by Staphylococcus aureus. This work aims to study the potential of azithromycin and kaempferol against chronic osteomyelitis induced by azithromycin-resistant Staphylococcus aureus (ARSA). It was noticed that rats tolerated the treatments with no diarrhoea or weight loss; also, no deaths were observed in rats. The treatment by azithromycin alone failed to inhibit bacterial growth and also had no effect on the infection condition of bone, although the treatment decreased the levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), but did not improve the oxidative stress levels. Kaempferol monotherapy slightly inhibited bacterial growth and bone infection; the treatment also inhibited the levels of IL-6 and (TNF-α). The treatment also improved the antioxidant status. However, the combined treatment of azithromycin and kaempferol significantly suppressed bacterial growth and bone infection and modulated oxidative stress. In vitro, the combined treatment inhibited the levels of IL-6 and TNF-α, and also suppressed the phosphorylation of ERK1/2 and stress-activated protein kinase (SAPK). The combined treatment also showed anti-biofilm activity in ARSA. The combination attenuates ARSA-induced osteomyelitis in rats compared with their treatments alone by reducing oxidative stress, inhibiting the phosphorylation of ERK1/2 and SAPK and inhibiting biofilm formation.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Biofilms; Cytokines; Disease Management; Disease Models, Animal; Disease Susceptibility; Drug Therapy, Combination; Kaempferols; MAP Kinase Signaling System; Osteomyelitis; Phosphorylation; Rats; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

Topics: Acinetobacter Infections; Aged; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Azithromycin; Bacteremia; Candidemia; COVID-19 Drug Treatment; Enzyme Inhibitors; Female; Gram-Negative Bacterial Infections; Humans; Hydroxychloroquine; Italy; Klebsiella Infections; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Pneumonia, Ventilator-Associated; Protective Factors; Pseudomonas Infections; Respiration, Artificial; SARS-CoV-2; Staphylococcal Infections; Superinfection; Teicoplanin

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. Bacterial co-infections are associated with unfavourable outcomes in respiratory viral infections; however, microbiological and antibiotic data related to COVID-19 are sparse. Adequate use of antibiotics in line with antibiotic stewardship (ABS) principles is warranted during the pandemic. We performed a retrospective study of clinical and microbiological characteristics of 140 COVID-19 patients admitted between February and April 2020 to a German University hospital, with a focus on bacterial co-infections and antimicrobial therapy. The final date of follow-up was 6 May 2020. Clinical data of 140 COVID-19 patients were recorded: The median age was 63.5 (range 17-99) years; 64% were males. According to the implemented local ABS guidelines, the most commonly used antibiotic regimen was ampicillin/sulbactam (41.5%) with a median duration of 6 (range 1-13) days. Urinary antigen tests for Legionella pneumophila and Streptococcus peumoniae were negative in all cases. In critically ill patients admitted to intensive care units (n = 50), co-infections with Enterobacterales (34.0%) and Aspergillus fumigatus (18.0%) were detected. Blood cultures collected at admission showed a diagnostic yield of 4.2%. Bacterial and fungal co-infections are rare in COVID-19 patients and are mainly prevalent in critically ill patients. Further studies are needed to assess the impact of antimicrobial therapy on therapeutic outcome in COVID-19 patients to prevent antimicrobial overuse. ABS guidelines could help in optimising the management of COVID-19. Investigation of microbial patterns of infectious complications in critically ill COVID-19 patients is also required.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ampicillin; Anti-Bacterial Agents; Antifungal Agents; Antimicrobial Stewardship; Aspergillosis; Azithromycin; Bacterial Infections; Cohort Studies; Coinfection; COVID-19; Enterobacteriaceae Infections; Escherichia coli Infections; Female; Germany; Humans; Klebsiella Infections; Linezolid; Male; Meropenem; Middle Aged; Piperacillin, Tazobactam Drug Combination; Practice Patterns, Physicians'; Retrospective Studies; SARS-CoV-2; Staphylococcal Infections; Streptococcal Infections; Sulbactam; Vancomycin; Young Adult

We aimed to demonstrate the contribution of anti-inflammatory and anti-virulence effects of azithromycin (AZM) in ocular surface infection treatment.. Staphylococcus aureus was injected into the corneal stroma of rabbits to induce keratitis. AZM at concentrations of 0.01, 0.1, and 1% was instilled into the eye twice daily. The eyes were examined using a slit lamp and scored. The viable bacteria in the cornea were counted at 48 h post infection. To evaluate the anti-inflammatory efficacy of AZM, S. aureus culture supernatant-induced anterior ocular inflammation in rabbit was examined using a slit lamp and scored. To evaluate the inhibitory effect of AZM on bacterial toxin production, S. aureus was cultured with AZM and hemolytic reaction in the culture supernatant was determined.. In the bacterial keratitis model, AZM dose-dependently inhibited the increase in the clinical score. The viable bacterial count in the cornea treated with 1% AZM significantly decreased compared with that of the vehicle, whereas bacterial count in 0.01 and 0.1% AZM-treated corneas was similar to that of the vehicle. In the anterior ocular inflammation model, 0.1 and 1% AZM inhibited the increase in the clinical score. AZM inhibited hemolytic reaction at concentrations that did not inhibit bacterial growth.. The results demonstrated that AZM has not only anti-bacterial, but also anti-inflammatory effects, and inhibits bacterial toxin production leading to ocular surface damage in bacterial infection. Thus, the therapeutic effect of AZM against ocular infections is expected to be higher than that which could be assumed if it only had anti-bacterial activity.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Colony Count, Microbial; Cornea; Disease Models, Animal; Eye Infections, Bacterial; Keratitis; Male; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Virulence

Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; Azithromycin; Humans; Inappropriate Prescribing; Length of Stay; Methicillin-Resistant Staphylococcus aureus; Oseltamivir; Retrospective Studies; Seasons; Staphylococcal Infections

The management of ocular infections is challenging due to poor drug bioavailability and vehicle related adverse effects associated with current antibiotic eye drops. Semifluorinated alkanes (SFAs) are reportedly well-tolerated on the ocular surface and can enhance ocular drug bioavailability. Therefore, an SFA-based azithromycin suspension (SFA-AZM) was prepared and its antibacterial efficacy was compared to that of marketed azithromycin eye drops by monitoring the growth of bioluminescent Staphylococcus aureus in ex vivo ocular tissues. Corneal and conjunctival distribution of hydrophobic fluorescent dye particles from an SFA suspension (SFA-BODIPY) resulted in preferential dye localisation in the epithelial layers of both tissues. However, corneal dye absorption was significantly lower than conjunctival absorption, likely due to limited adhesion of suspended dye particles to the corneal compared to the conjunctival epithelium. In line with the dye distribution results, bacterial colonisation in the conjunctiva reduced significantly upon application of SFA-AZM with the efficacy being greater than or at least equal to the marketed azithromycin eye drops. In the cornea, all tested azithromycin eye drops reduced the rate of bacterial growth with similar efficacy. Overall, the SFA-AZM suspension tested here may provide a safe and effective alternative for the management of ocular infections by enhancing conjunctival drug absorption and thus drug efficacy.

Topics: Alkanes; Animals; Anti-Bacterial Agents; Azithromycin; Biological Availability; Conjunctiva; Cornea; Drug Carriers; Eye Infections; Hydrophobic and Hydrophilic Interactions; Ophthalmic Solutions; Staphylococcal Infections; Staphylococcus aureus; Suspensions; Swine

Azithromycin has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis. Concerns remain, however, regarding the potential emergence of treatment-related respiratory pathogens.. To determine whether chronic azithromycin use (defined as three-times weekly administration) is associated with increased rates of detection of eight specific respiratory pathogens.. We performed a new-user, propensity score-matched retrospective cohort study utilizing data from the Cystic Fibrosis Foundation Patient Registry. Incident azithromycin users were propensity score matched 1:1 with contemporaneous nonusers. Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate the association between chronic azithromycin use and incident respiratory pathogen detection. Analyses were performed separately for each pathogen, limited to patients among whom that pathogen had not been isolated in the 2 years before cohort entry.. After propensity score matching, the mean age of the cohorts was approximately 12 years. Chronic azithromycin users had a significantly lower risk of detection of new methicillin-resistant Staphylococcus aureus, nontuberculous mycobacteria, and Burkholderia cepacia complex compared with nonusers. The risk of acquiring the remaining five pathogens was not significantly different between users and nonusers.. Using an innovative new-user, propensity score-matched study design to minimize indication and selection biases, we found in a predominantly pediatric cohort that chronic azithromycin users had a lower risk of acquiring several cystic fibrosis-related respiratory pathogens. These results may ease concerns that chronic azithromycin exposure increases the risk of acquiring new respiratory pathogens among pediatric patients with cystic fibrosis.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Follow-Up Studies; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Propensity Score; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Staphylococcal Infections; Young Adult

We describe the first case of chancroid seen in the Czech Republic, diagnosed in a 40-year-old heterosexual HIV-positive man. Despite genital localization of the ulcer, the transmission of Haemophilus ducreyi infection in our patient remains unclear, as he denied having sexual intercourse and he did not travel outside the Czech Republic for several months before the ulcer appeared. The correct diagnosis has been revealed by a multiplex nucleic acid amplification test. Physicians in countries in the eastern and central Europe region should be aware that chancroid can occur in their patients.

Topics: Adult; Azithromycin; Chancroid; Haemophilus ducreyi; HIV Seropositivity; Humans; Lymphadenopathy; Male; Methicillin-Resistant Staphylococcus aureus; Multiplex Polymerase Chain Reaction; Staphylococcal Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Ulcer

Antibiotic delivery via liposomal encapsulation represents a promising approach for the efficient topical treatment of skin infections. The present study aimed to investigate the potential of using different types of azithromycin (AZT)-loaded liposomes to locally treat skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains. Conventional liposomes (CLs), deformable liposomes (DLs), propylene glycol-containing liposomes (PGLs) and cationic liposomes (CATLs) encapsulating AZT were prepared, and their physical characteristics, drug release profiles, ex vivo skin penetration/deposition abilities, in vitro anti-MRSA activities (planktonic bacteria and biofilm) and cell biocompatibilities were assessed. The (phospho)lipid composition and presence of surfactant or propylene glycol affected the physical characteristics of the liposomes, the release profile of AZT, its deposition inside the skin, as well as in vitro antibacterial efficacy and tolerability with the skin cells. All the liposomes retained AZT inside the skin more efficiently than did the control and were biocompatible with keratinocytes and fibroblasts. CATLs, DLs and PGLs efficiently inhibited MRSA strain growth and were superior to free AZT in preventing biofilm formation, exhibiting minimal inhibitory concentrations and minimal biofilm inhibitory concentrations up to 32-fold lower than those of AZT solution, thus confirming their potential for improved topical treatment of MRSA-caused skin infections.

Topics: Administration, Cutaneous; Animals; Anti-Bacterial Agents; Azithromycin; Biofilms; Cell Line; Chemistry, Pharmaceutical; Drug Delivery Systems; Drug Liberation; Humans; Liposomes; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Propylene Glycol; Skin Absorption; Skin Diseases, Bacterial; Staphylococcal Infections; Swine

Mass drug administration (MDA) with azithromycin is a corner-stone of trachoma control however it may drive the emergence of antimicrobial resistance. In a cluster-randomized trial (Clinical trial gov NCT00792922), we compared the reduction in the prevalence of active trachoma in communities that received three annual rounds of MDA to that in communities that received a single treatment round. We used the framework of this trial to carry out an opportunistic study to investigate if the increased rounds of treatment resulted in increased prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus. Three cross-sectional surveys were conducted in two villages receiving three annual rounds of MDA (3 × treatment arm). Surveys were conducted immediately before the third round of MDA (CSS-1) and at one (CSS-2) and six (CSS-3) months after MDA. The final survey also included six villages that had received only one round of MDA 30 months previously (1 × treatment arm).. In the 3 × treatment arm, a short-term increase in prevalence of S. aureus carriage was seen following MDA from 24.6% at CSS-1 to 38.6% at CSS-2 (p < 0.001). Prevalence fell to 8.8% at CSS-3 (p < 0.001). A transient increase was also seen in prevalence of carriage of azithromycin resistant (Azm. Three annual rounds of MDA with azithromycin were associated with a short-term increase in both the prevalence of nasopharyngeal carriage of S. aureus and prevalence of carriage of Azm. This study was ancillary to the Partnership for the Rapid Elimination of Trachoma, ClinicalTrials.gov NCT00792922 , registration date November 17, 2008.

Topics: Administration, Oral; Adolescent; Anti-Bacterial Agents; Azithromycin; Carrier State; Child; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Gambia; Humans; Immunization Programs; Macrolides; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Nasopharyngitis; Nasopharynx; Prevalence; Risk Factors; Specimen Handling; Staphylococcal Infections; Streptococcus pneumoniae; Trachoma

The ribosome is the primary protein synthesis machine in the cell and is a target for treatment of a variety of diseases including bacterial infection and cancer. The ribosomal peptide exit tunnel, the route of egress for the nascent peptide, is an inviting site for drug design. Toward a rational engagement of the nascent peptide components for the design of small molecule inhibitors of ribosome function, we designed and disclosed herein a set of N-10 indole functionalized azithromycin analogs. The indole moiety of these compounds is designed to mimic the translation stalling interaction of SecM W155 side-chain with the prokaryotic (Escherichia coli) ribosome A751 residue. Many of these N-10 functionalized compounds have enhanced translation inhibition activities against E. coli ribosome relative to azithromycin while a subset inhibited the growth of representative susceptible bacteria strains to about the same extent as azithromycin. Moreover, the inclusion of bovine serum in the bacterial growth media enhanced the anti-bacterial potency of the N-10 functionalized azithromycin analogs by as high as 10-fold.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Azithromycin; Drug Design; Escherichia coli; Escherichia coli Infections; Humans; Indoles; Models, Molecular; Molecular Sequence Data; Peptides; Protein Biosynthesis; Ribosomes; Staphylococcal Infections; Staphylococcus aureus

We hypothesized that if internalization of Staphylococcus aureus could be blocked by using cytochalasin D (an inhibitor of phagocytosis and phagolysosome fusion), then the intracellular entry and survival of the pathogen in host's phagocytic cells recruited to the inflammatory site can be restricted. At the same time, if we use antimicrobial agents (e.g., ciprofloxacin and azithromycin) having potent intracellular and extracellular microbicidal activity against the bacterium that have not entered into the phagosome and remains adhered to the phagocytic cell membrane, then they can be eradicated from the site of infection without compromising the host cell. To validate this, role of ciprofloxacin (CIP) and azithromycin (AZM) in eliminating S. aureus by suppressing the phagocytic activity of macrophages with cytochalasin D before infection was investigated. CIP and AZM were used either alone or in combination with cytochalasin D. Supernatant and lysate obtained from the culture of macrophages were used for quantification of reactive oxygen species, lysozymes, antioxidant enzymes, and cytokines produced. Azithromycin was better than ciprofloxacin in combination with cytochalasin D for eradicating S. aureus and regulating cytokine release. Further studies are required for ensuring proper delivery of this combination at the site of infection.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Azithromycin; Ciprofloxacin; Cytochalasin D; Drug Therapy, Combination; Glutathione; Hydrogen Peroxide; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-6; Macrophages; Male; Mice; Microbial Sensitivity Tests; Muramidase; Phagocytosis; Staphylococcal Infections; Staphylococcus aureus; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Staphylococcus aureus is one of the most frequent pathogens infecting the respiratory tract of patients with cystic fibrosis (CF). This study was the first to examine S. aureus isolates from CF patients in the Czech Republic. Among 100 S. aureus isolates from 92 of 107 observed patients, we found a high prevalence of resistance to macrolide-lincosamide-streptogramin B (MLS(B)) antibiotics (56%). More than half of the resistant strains (29 of 56) carried a mutation in the MLS(B) target site. The emergence of MLS(B) resistance and mutations conferring resistance to MLS(B) antibiotics was associated with azithromycin treatment (p=0.000000184 and p=0.000681, respectively). Methicillin resistance was only detected in 3% of isolates and the rate of resistance to other antibiotics did not exceed 12%. The prevalence of small-colony variant (SCV) strains was relatively low (9%) and eight of nine isolates with the SCV phenotype were thymidine dependent. The study population of S. aureus was heterogeneous in structure and both the most prevalent community-associated and hospital-acquired clonal lineages were represented. Of the virulence genes, enterotoxin genes seg (n=52), sei (n=49), and sec (n=16) were the most frequently detected among the isolates. The PVL genes (lukS-PV and lukF-PV) have not been revealed in any of the isolates.

Topics: Anti-Bacterial Agents; Azithromycin; Cross Infection; Cystic Fibrosis; Czech Republic; Drug Resistance, Bacterial; Humans; Long-Term Care; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mutation; Ribosomes; Staphylococcal Infections; Staphylococcus aureus; Thymidine

The aim of the present study was to assess the prevalence and resistance of commensal S. aureus in the nasal microbiota of community-dwelling persons in Austria, as well as to identify possible associations with socio-demographic factors. Multi-drug resistance in this population was additionally studied.. This cross-sectional study was conducted within the context of the European APRES project. In nine European countries, nasal swabs were collected from 32,206 general practice patients who received care for non-infectious reasons. In Austria, 20 GPs attempted to recruit 200 consecutive patients without infectious diseases, with each patient completing demographic questionnaires as well as providing a nose swab sample. Isolation, identification, and resistance testing of S. aureus were performed. Statistical analyses included subgroup analyses and logistic regression models.. 3309 nose swabs and corresponding questionnaires from Austrian subjects were analyzed. S. aureus was identified in 16.6 % (n = 549) of nose swabs, of which 70.1 % were resistant against one or more antibiotics, mainly penicillin. S. aureus carrier status was significantly associated with male sex (OR 1.6; 1.3-2.0), younger age (OR 1.3; 1.0-1.8), living in a rural area (OR 1.4; 1.1-1.7) and working in the healthcare sector (OR 1.5; 1.0-2.1). Multi-drug resistances were identified in 13.7 % (n = 75) of the S. aureus carriers and 1.5 % (n = 8) tested positive for MRSA. The highest resistance rate was observed against penicillin (64.8 %), followed by azithromycin (13.5 %) and erythromycin with 13.3 %.. This study describes the prevalence and resistance patterns of commensal S. aureus in community-dwelling persons in Austria and shows that differences exist between socio-demographic groups. Demographic associations have been found for S. aureus carriers but not for carriers of resistant S. aureus strains. Only two thirds of S. aureus strains were found to be resistant against small spectrum penicillin. As it is recognized that one of the corner stones for the containment of antibiotic resistance is the appropriate prescription of antibiotics in the outpatient sector, this finding lends support to the avoidance of prescription of broad-spectrum antibiotics to treat S. aureus infections in the community.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antibiotics, Antitubercular; Austria; Azithromycin; Child; Child, Preschool; Cross-Sectional Studies; Demography; Drug Resistance, Multiple, Bacterial; Erythromycin; Female; Humans; Logistic Models; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Nasal Cavity; Odds Ratio; Penicillins; Prevalence; Primary Health Care; Staphylococcal Infections; Staphylococcus aureus; Surveys and Questionnaires; Young Adult

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

Topics: Adenosine Triphosphatases; Amides; Animals; Anti-Bacterial Agents; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Mice; Mice, Knockout; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pyrroles; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Thiazoles; Topoisomerase II Inhibitors

Recurrent staphylococcal skin and soft tissue infections may recur despite decontamination and multiple courses of antibiotic therapy and may dramatically impair the patient's quality of life. We report successful use of long-term azithromycin prophylaxis in a recurrent laryngitis and a scalp folliculitis due to methicillin-susceptible Staphylococcus aureus.

Topics: Aged; Anti-Bacterial Agents; Antibiotic Prophylaxis; Azithromycin; Folliculitis; Humans; Laryngitis; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Recurrence; Staphylococcal Infections

Staphylococcus biofilm exhibits high antibiotic resistance and therapeutic doses of antibiotics are often sub-inhibitory. Whereas data are available on the effect of sub-inhibitory antibiotics on matrix formation, little is known on their influence on biofilm population. Here, using BioTimer Assay (BTA), a method developed to quantify biofilm population, the influence of sub-inhibitory gentamicin, ofloxacin and azithromycin on Staphylococcus aureus ATCC 6538 biofilm population in flow with respect to static condition was assessed. Antibiotics and flow condition increased biofilm population even if at different extent, depending on the antibiotic molecule. The greatest bacterial population was found in biofilm developed under flow condition in the presence of azithromycin. A significant increase in biofilm matrix was recorded for biofilm developed in the presence of antibiotics in flow with respect to static condition. The growth rates (GRs) of 24-h biofilm developed under the influence of antibiotics and flow condition were also evaluated using BTA and a specific mathematical model. Antibiotics and flow condition affected the GRs of 24-h biofilm even if at different extent. The lowest GR value was recorded for biofilm developed under flow condition in the presence of ofloxacin. Although further studies are needed, our data indicate that antibiotics and flow condition influenced biofilm development by increasing both bacterial population and matrix formation and affected the GRs of the developed biofilm. To the best of our knowledge, BTA is unique in allowing the calculation of the GRs of biofilm and it may be considered to be a useful study model to evaluate the activity of antibiofilm molecules.

Topics: Anti-Bacterial Agents; Azithromycin; Biofilms; Gentamicins; Microbial Sensitivity Tests; Models, Theoretical; Ofloxacin; Staphylococcal Infections; Staphylococcus aureus

Information about the prevalence of Staphylococcus aureus resistance to antimicrobial drugs has mainly been obtained from invasive strains, although the commensal microbiota is thought to be an important reservoir of resistance. We aimed to compare the prevalence of nasal S aureus carriage and antibiotic resistance, including meticillin-resistant S aureus (MRSA), in healthy patients across nine European countries.. In this cross-sectional study, nasal swabs were obtained from 32,206 patients recruited by family doctors participating in existing nationwide family doctor networks in Austria, Belgium, Croatia, France, Hungary, Spain, Sweden, the Netherlands, and the UK. Eligible patients were aged 4 years or older (≥ 18 years in the UK) and presented with a non-infectious disorder. Swabs were sent to national microbiological laboratories for identification and isolation of S aureus. Antibiotic resistance testing was done at one central microbiological laboratory. We established the genotypic structure of the isolated MRSA strains with the spa typing method.. S aureus was isolated from 6956 (21 · 6%) of 32,206 patients swabbed. The adjusted S aureus prevalence for patients older than 18 years ranged from 12 · 1% (Hungary) to 29 · 4% (Sweden). Except for penicillin, the highest recorded resistance rate was to azithromycin (from 1 · 6% in Sweden to 16 · 9% in France). In total, 91 MRSA strains were isolated, and the highest MRSA prevalence was reported in Belgium (2 · 1%). 53 different spa types were detected-the most prevalent were t002 (n = 9) and t008 (n = 8).. The prevalence of S aureus nasal carriage differed across the nine European countries assessed, even after correction for age, sex, and family doctor. Generally, the prevalence of resistance, including that of MRSA, was low. The MRSA strains recorded showed genotypic heterogeneity, both within and between countries.. European Commission, 7th Framework Programme(grant agreement 223083).

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Azithromycin; Bacterial Typing Techniques; Carrier State; Child; Child, Preschool; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Europe; Female; Humans; Logistic Models; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Prevalence; Staphylococcal Infections; Young Adult

To determine alternate therapeutic measures to combat Staphylococcus aureus induced arthritis. Thus, azithromycin was combined with riboflavin, which may combat the ROS production and inflammation.. An in vivo model of S. aureus infection-induced arthritis was set up by infecting mice with 5 × 10⁶ bacterial cell/mouse. S. aureus was administered intravenously. Azithromycin and riboflavin was injected intraperitoneally at a single dose of 100 and 20 mg/kg body, respectively. The mice were sacrificed at 3, 9, 15 days post infection (dpi). TNF-α, IFN-γ, IL-6 and IL-10 from serum and SOD, catalase and reduced glutathione concentration were observed in hepatic, cardiac, renal and splenic tissue.. CFU was found very prominent in spleen and joints and reduced in blood at 3 and 9 dpi. However, treatment with azithromycin and riboflavin completely eradicated the bacteria from blood and spleen. TNF-α, IFN-γ, IL-6, and MCP-1 were induced due to infection which were downregulated by treatment with azithromycin and riboflavin. Infected mice were also found to have altered antioxidant status, measured in terms of reduced glutathione and anti-oxidant enzymes such as SOD and catalase.. These changes were found to be ameliorated when the animals were co-treated with azithromycin and riboflavin.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Arthritis, Infectious; Azithromycin; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Free Radicals; Male; Mice; Reactive Oxygen Species; Riboflavin; Severity of Illness Index; Staphylococcal Infections; Staphylococcus aureus; Survival Rate; Treatment Outcome

The study aims to test the effect of transdermal application of azithromycin in the prevention of skin flap infection in experimental rats. The accumulative penetration quantities of azithromycin through excised rat skin and the azithromycin quantities in flap tissues from rats given 1%, 2%, and 3% azithromycin gels were assayed by UV spectrophotometer. Staphylococcus aureus and pathogenic Escherichia coli were inoculated to the underneath of the random ischemic rat flaps to induce bacterial infection. The azithromycin gels were applied on the flaps daily for 7 days. The survival areas of flaps were measured by planimetry. The accumulative penetration quantities of azithromycin and the azithromycin quantities in flap tissues increased in a time-dependent manner (P < 0.05). Azithromycin gels decreased the inflammatory reaction and enhanced the survival area of flaps (P < 0.05). We concluded that 1% azithromycin gel could penetrate into the flap tissues and significantly increase survival area of infected flaps.

Topics: Administration, Cutaneous; Animals; Anti-Bacterial Agents; Azithromycin; Dose-Response Relationship, Drug; Drug Administration Schedule; Escherichia coli Infections; Gels; Random Allocation; Rats; Rats, Wistar; Spectrophotometry, Ultraviolet; Staphylococcal Infections; Surgical Flaps; Surgical Wound Infection; Treatment Outcome

A series of novel alkylides, possessing 3-O-arylalkyl group instead of 3-O-cladinose, were designed, synthesized and evaluated for in vitro antibacterial activities. The increased potency clearly ranked by the order of 3-O-(3-aryl-2-propargyl), 3-O-(3-aryl-E-prop-2-enyl), 3-O-(3-aryl-propyl), and 3-O-(3-aryl-Z-prop-1-enyl) groups. Some alkylides, exemplified by 7a, 10a, 21, 22, 26, 27 and 33, showed improved activities against inducible MLS(B) resistance and efflux resistance compared to the second-generation macrolides. Among them, 26 possessed comparable activities against erythromycin-susceptible Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes (MICs of 0.016-0.5 μg/mL). Moreover, 26 displayed dramatically enhanced potency against both efflux resistant and inducibly MLS(B) resistant strains (MICs of 0.125-0.5 μg/mL) resistant to clarithromycin and azithromycin (MICs of 1- >254 μg/mL), independent of methicillin-susceptible and methicillin-resistant phenotypes.

Topics: Anti-Bacterial Agents; Clarithromycin; Drug Resistance, Multiple, Bacterial; Humans; Macrolides; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Streptococcal Infections; Streptococcus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure-Activity Relationship

Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide derivatives with activities against resistant pathogens is urgently needed. A series of novel 6-O-(heteroaryl-isoxazolyl)propynyl 2-fluoro ketolides has been synthesized from erythromycin A. These compounds have shown very promising in vitro and in vivo antibacterial activities against key respiratory pathogens including erythromycin-susceptible/resistant strains.

Topics: Anti-Bacterial Agents; Crystallography, X-Ray; Drug Resistance, Bacterial; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Halogenation; Humans; Ketolides; Microbial Sensitivity Tests; Models, Molecular; Respiratory Tract Infections; Staphylococcal Infections; Staphylococcus

In vivo effectiveness of topical antibiotics may depend on their ability to associate with epithelial cells to provide continued protection, but this contribution is not measured by standard antibiotic susceptibility tests. We report a new in vitro method that measures the ability of test antibiotics azithromycin (AZM), erythromycin (ERY), tetracycline (TET), and bacitracin (BAC) to associate with mammalian cells and to protect these cells from destruction by bacteria. Mammalian cell lines were grown to confluence using antibiotic-free medium and then incubated in medium containing a single antibiotic (0 to 512 μg/ml). After incubation, the cells were challenged with Staphylococcus aureus ocular isolates, without antibiotics added to the culture medium. Epithelial cell layer integrity was assessed by gentian violet staining, and the minimum cell layer protective concentration (MCPC) of an antibiotic sufficient to protect the mammalian cells from S. aureus was determined. Staining was also quantified and analyzed. Bacterial viability was determined by culture turbidity and growth on agar plates. Preincubation of Chang and human corneal limbal epithelial cells with AZM, ERY, and TET at ≥64 μg/ml provided protection against AZM-susceptible S. aureus strains, with increasing protection at higher concentrations. TET toxicity was demonstrated at >64 μg/ml, whereas AZM displayed toxicity to one cell line at 512 μg/ml. BAC failed to show consistent protection at any dose, despite bacterial susceptibility to BAC as determined by traditional antibiotic susceptibility testing. A range of antibiotic effectiveness was displayed in this cell association assay, providing data that may be considered in addition to traditional testing when determining therapeutic dosing regimens.

Topics: Anti-Bacterial Agents; Azithromycin; Bacitracin; Cell Line; Conjunctiva; Epithelial Cells; Erythromycin; Humans; Microbial Sensitivity Tests; Protein Binding; Staphylococcal Infections; Staphylococcus aureus; Tetracycline

Biofilm formation in Staphylococcus epidermidis is mediated by icaADBC-dependent and -independent pathways. Subinhibitory concentrations of erythromycin, azithromycin, and clarithromycin enhanced, in a dose-dependent manner, the level of biofilm formation by 20% (21/105 isolates) by macrolide-resistant ica-positive and -negative isolates tested in vitro. The presence of ica, however, apparently produced an enhanced effect on biofilm formation. The levels of expression of the biofilm-related genes icaA, atlE, fruA, pyrR, sarA, and sigB were increased in response to erythromycin. The results likely underscore the potential clinical relevance of macrolide-induced biofilm growth.

Topics: Anti-Bacterial Agents; Base Sequence; Biofilms; DNA Primers; Dose-Response Relationship, Drug; Erythromycin; Gene Expression; Genes, Bacterial; Humans; In Vitro Techniques; Macrolides; Microscopy, Electron, Scanning; Reverse Transcriptase Polymerase Chain Reaction; Staphylococcal Infections; Staphylococcus epidermidis

Azithromycin is a time-dependent antimicrobial with long persistence. The main characteristics of azithromycin suggest that it could be useful for treating bovine mastitis caused by Staphylococcus aureus. To investigate this possibility, its pharmacokinetic (PK) behavior was studied. Six Holstein lactating cows with subclinical mastitis were administered two 10 mg/kg intramuscular (i.m.) doses of azithromycin, with a 48-h interval. Milk and plasma concentrations were measured by microbiological assay. The MIC(90) was determined in 51 S. aureus isolations to calculate pharmacokinetic/pharmacodynamic (PK/PD) parameters. Milk maximal concentration (C(max)) was 7.76 +/- 1.76 microg/mL (16.67 h post-first administration) and 7.82 +/- 2.18 microg/mL (14 h post-2(nd) administration). In plasma C(max) was 0.18 +/- 0.03 microg/mL (2 h post-1(rst) administration) and 0.11 +/- 0.03 microg/mL (14 h post-2(nd) administration). Azithromycin was eliminated from the milk with a half-life (T(1/2)lambda) of 158.26 +/- 137.7 h after 2(nd) administration, meanwhile plasma T(1/2)lambda resulted shorter(13.97 +/- 11.1 h). The mean area under the concentration vs. time curve from 0 to 24 h (AUC(0-24h)) was 153.82 +/- 34.66 microg.h/mL in milk secretion and 2.61 +/- 0.59 microgxh/mL in plasma. Infection presence in the quarters had a significant effect (P < 0.05) on the area under the concentration vs. time curve from 0 to infinity (AUC(0-infinity)) and clearance from the mammary gland (Cl(mam)/F). Moreover, it had influence on milk bioavailability (F(milk)), T(1/2)lambda, AUC(0-infinity) and mean residence time (MRT) in milk, which values resulted increased in mastitic quarters. In this study, it was determined that the production level and the mammary health status have an influence on PK parameters of azithromycin treatments in bovine mastitis.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Azithromycin; Cattle; Drug Residues; Female; Half-Life; Lactation; Mammary Glands, Animal; Mastitis, Bovine; Microbial Sensitivity Tests; Milk; Staphylococcal Infections; Staphylococcus aureus

Antibiotic treatment of Staphylococcus aureus infections is often problematic due to the slow response to therapy and the high frequency of infection recurrence. The intracellular persistence of staphylococci has been recognized and could offer a good explanation for these treatment difficulties. Knowledge of the interplay between intracellular antibiotic activity and the overall outcome of infection is therefore important. Several intracellular in vitro models have been developed, but few experimental animal models have been published. The mouse peritonitis/sepsis model was used as the basic in vivo model exploring a quantitative ex vivo extra- and intracellular differentiation assay. The intracellular presence of S. aureus was documented by electron microscopy. Five antibiotics, dicloxacillin, cefuroxime, gentamicin, azithromycin, and rifampin (rifampicin), were tested in the new in vivo model; and the model was able to distinguish between their extra- and intracellular effects. The intracellular effects of the five antibiotics could be ranked as follows as the mean change in the log(10) number of CFU/ml (Delta log(10) CFU/ml) between treated and untreated mice after 4 h of treatment: dicloxacillin (3.70 Delta log(10) CFU/ml) > cefuroxime (3.56 Delta log(10) CFU/ml) > rifampin (1.86 Delta log(10) CFU/ml) > gentamicin (0.61 Delta log(10) CFU/ml) > azithromycin (0.21 Delta log(10) CFU/ml). We could also show that the important factors during testing of intracellular activity in vivo are the size, number, and frequency of doses; the time of exposure; and the timing between the start of infection and treatment. A poor correlation between the intracellular accumulation of the antibiotics and the actual intracellular effect was found. This stresses the importance of performing experimental studies, like those with the new in vivo model described here, to measure actual intracellular activity instead of making predictions based on cellular pharmacokinetic and MICs.

Topics: Animals; Animals, Outbred Strains; Anti-Bacterial Agents; Colony Count, Microbial; Dicloxacillin; Dose-Response Relationship, Drug; Female; Humans; Mice; Microbial Sensitivity Tests; Peritoneum; Peritonitis; Rifampin; Sepsis; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

4''-Carbamate, 11,12-cyclic carbonate-4''-carbamate and 11,4''-di-O-arylcarbamoyl analogs of azithromycin were designed, synthesized and evaluated. The 4''-carbamate analogs retained excellent activity against erythromycin-susceptible Staphylococcus pneumoniae and showed improved activity against erythromycin-resistant Staphylococcus pneumoniae. Compared with 4''-carbamate analogs, 11,12-cyclic carbonate-4''-carbamate analogs exhibited improved activity against erythromycin-resistant Staphylococcus pneumoniae encoded by the mef gene or the erm and mef genes, and 11,4''-di-O-arylalkylcarbamoyl analogs showed greatly improved activity (0.25-0.5 microg/mL) against erythromycin-resistant Staphylococcus pneumoniae encoded by the erm gene. Among them, the novel series of 11,4''-di-O-arylalkylcarbamoyl analogs 7a-k exhibited potent and balanced activity against susceptible and resistant bacteria. In particular, compounds 7f and 7k were the most effective against susceptible bacteria and resistant bacteria encoded by the erm gene or the mef gene.

Topics: Anti-Bacterial Agents; Azithromycin; Carbamates; Carbonates; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus; Streptococcal Infections; Streptococcus pneumoniae

Maintenance azithromycin therapy may improve pulmonary function in patients with cystic fibrosis (CF) with Pseudomonas aeruginosa infection because of its antiinflammatory properties. However, azithromycin therapy might increase macrolide resistance in Staphylococcus aureus cultured from respiratory secretions. We studied the emergence of macrolide resistance in S. aureus and correlated this to pulmonary function decline in pediatric patients with CF on daily azithromycin therapy.. Respiratory cultures of 100 patients with CF were analyzed for S. aureus colonization and its resistance pattern before and during 3 years after initiation of azithromycin maintenance therapy. Mean annual change in forced expiratory volume as percent of predicted (FEV1 %) was calculated to compare pulmonary function before and after azithromycin therapy.. Staphylococcal colonization did not significantly decrease after initiation of azithromycin (50% versus 48%). Before start of therapy, 10% of patients with staphylococcal colonization had macrolide-resistant strains. Staphylococcal resistance increased to 83% in the first year; 97% in the second and 100% in the third year after initiation of azithromycin therapy (P < 0.001). Half of macrolide-resistant S. aureus comprised the macrolide-lincosamide-streptogramin phenotype. Percent forced expiratory volume in 1 second improved in the first year after initiation of azithromycin (mean annual change: -4.75% before versus +3.09% after initiation; P < 0.01) but decreased during the second and third years after initiation (-5.15% and -3.65%, respectively). Emergence of macrolide-resistant S. aureus was not related to pulmonary function decline.. Maintenance azithromycin therapy in patients with CF leads to macrolide resistance in nearly all S. aureus carriers. Pulmonary function improvement after initiation of azithromycin therapy seems to be temporary and appears not to be related to macrolide resistance of S. aureus.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cystic Fibrosis; Drug Resistance; Drug Resistance, Microbial; Humans; Infant; Lung; Macrolides; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Staphylococcus aureus

A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and evaluated. These compounds have significant potent antibacterial activity against not only Gram-positive pathogens, including inducibly macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens, such as H. influenzae. 6,9:11,12-dicarbonate acylide 47 (FMA0122) was twice as active against H. influenzae than azithromycin, whereas it showed only moderate in vivo efficacy in mouse protection tests. However, the 11,12-carbamate acylide 19 (TEA0929), which showed potent antibacterial activity against almost all of the main causative pathogens of community-acquired pneumonia tested, exhibited excellent in vivo efficacy comparable to those of second-generation macrolides.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Area Under Curve; Drug Resistance, Multiple, Bacterial; Erythromycin; Haemophilus influenzae; Macrolides; Mice; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Streptococcal Infections; Streptococcus pneumoniae; Structure-Activity Relationship

Antibiotic efflux pumps expressed in eukaryotic cells can decrease the intracellular accumulation of the corresponding drugs and therefore impair their activity against intracellular bacteria. We have investigated whether verapamil (an inhibitor of P-glycoprotein) and gemfibrozil (an inhibitor of multidrug resistance proteins (MRP) and other organic anion transporters), can modulate the intracellular activity of azithromycin and ciprofloxacin against Listeria monocytogenes and Staphylococcus aureus in J774 macrophages. In parallel, we have measured the cell accumulation and subcellular distribution of both drugs. Antibiotics were used at equipotent extracellular concentrations (from 0.5 x to 10 x MIC) to allow for pharmacological comparisons. Azithromycin was bacteriostatic against L. monocytogenes and slightly bactericidal against S. aureus. Verapamil did not improve the maximal activity of azithromycin but allowed it to reach a similar effect at extracellular concentrations about seven-fold lower in both models. Azithromycin was predominantly localized in cell granules (66%), the remainder being in the cytosol and in the 'nuclei/unbroken cells' fraction. Verapamil increased the cellular accumulation of azithromycin by almost 2.4-fold without modifying its subcellular distribution. Ciprofloxacin displayed a strong concentration-dependent bactericidal activity in both models. Gemfibrozil increased ciprofloxacin activity almost 2.5-fold against L. monocytogenes, but not against S. aureus. Ciprofloxacin was predominantly (65%) distributed in the cytosol. Gemfibrozil increased ciprofloxacin total accumulation by approximately 2.4-fold, but the excess was only found in the cytosol. Inhibition of efflux pumps may be a useful strategy to improve antibiotic efficacy against intracellular bacteria when increased accumulation can be obtained in the compartment where bacteria sojourn.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azithromycin; Ciprofloxacin; Gemfibrozil; Humans; In Vitro Techniques; Listeriosis; Macrophages; Staphylococcal Infections; Subcellular Fractions; Verapamil

Using J774 macrophages, the intracellular activities of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) against Staphylococcus aureus (strain ATCC 25923) have been quantitatively assessed in a 24-h model. S. aureus was positively localized in phagolysosomes by confocal and electron microscopy, and extracellular growth was prevented with 0.5 mg of gentamicin/liter (1x MIC) in controls. When tested at extracellular concentrations equivalent to their maximum concentrations in human serum, all antibiotics except azithromycin caused a significant reduction of the postphagocytosis inoculum within 24 h, albeit to markedly different extents (telithromycin [2 mg/liter], 0.60 log; ciprofloxacin [4.3 mg/liter], 0.81 log; gentamicin [18 mg/liter], 1.21 log; moxifloxacin [4 mg/liter], 1.51 log; oritavancin [25 mg/liter], 3.49 log). Intracellular activities were not systematically related to drug accumulation (apparent cellular-to-extracellular concentration ratios in infected cells: ciprofloxacin, 3.2; gentamicin, 6.8; telithromycin, 8.7; moxifloxacin, 13.4; azithromycin, 50; oritavancin, 348). Intracellular activity was not directly correlated to extracellular activity as measured in broth. Conditions of pH 5 (i.e., mimicking that of phagolysosomes) markedly reduced the activity of gentamicin, azithromycin, and telithromycin (>or=32 x) and fairly extensively reduced that of ciprofloxacin and moxifloxacin (>or=4 x) but did not affect oritavancin activity. We conclude that the cellular accumulation of antibiotics is not the only parameter to take into account for intracellular activity but that local environmental conditions (such as pH) and other factors can also prove critical.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Aza Compounds; Azithromycin; Ciprofloxacin; Fluoroquinolones; Gentamicins; Glycopeptides; Lipoglycopeptides; Lymphoma, Large B-Cell, Diffuse; Macrophages; Mice; Microbial Sensitivity Tests; Microscopy, Electron; Moxifloxacin; Quinolines; Staphylococcal Infections; Staphylococcus aureus; Tumor Cells, Cultured

Six strains of Staphylococcus aureus isolated from cystic fibrosis patients after treatment with azithromycin were cross-resistant to azithromycin and erythromycin. None of the isolates contained erm or msr(A) genes, but they all carried either A2058G/U or A2059G mutations within the rrl genes, with a majority of the rRNA copies bearing the mutation. One strain displayed an additional mutation in the rplV gene, encoding the L22 ribosomal protein.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Cystic Fibrosis; DNA, Bacterial; Drug Resistance; Erythromycin; Genes, Bacterial; Humans; Membrane Transport Proteins; Methyltransferases; Microbial Sensitivity Tests; Mutation; Oligonucleotide Probes; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Staphylococcal Infections; Staphylococcus aureus

Topics: Animals; Anti-Bacterial Agents; Drug Design; Drug Resistance, Microbial; Haemophilus influenzae; Lung; Lung Diseases; Macrolides; Mice; Models, Molecular; Rats; Respiratory Tract Infections; Staphylococcal Infections; Staphylococcus; Streptococcal Infections; Streptococcus; Structure-Activity Relationship

Azithromycin and ampicillin protected 94 and 72% of animals challenged with Streptococcus oralis, respectively (P = 0.177), while azithromycin and vancomycin protected 59 and 94% of the methicillin-resistant Staphylococcus aureus (MRSA)-challenged animals, respectively (P = 0.018). Azithromycin is effective in preventing experimental streptococcal endocarditis, but against MRSA it is less effective than vancomycin.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Aortic Valve; Azithromycin; Endocarditis, Bacterial; Female; Rabbits; Staphylococcal Infections; Streptococcal Infections

A rabbit model for Staphylococcus aureus osteomyelitis was used to compare 28-day combination antibiotic therapy using oral rifampin (40 mg/kg, twice daily) plus oral azithromycin (50 mg/kg, once per day), oral clarithromycin (80 mg/kg, twice daily), or parenteral nafcillin (30 mg/kg, four times daily). The left tibial metaphysis of New Zealand White rabbits was infected with Staphylococcus aureus. Grades 3 to 4 osteomyelitis (according to the Cierny-Mader classification system) development in the rabbits was confirmed radiographically. After antibiotic therapy regimens of 28 days, all tibias from controls that were infected but left untreated (n = 10) revealed positive cultures for Staphylococcus aureus at a mean concentration of 2.8 x 10(4) colony forming units/g bone. The rifampin plus clarithromycin (n = 15) and rifampin plus azithromycin (n = 15) groups showed significantly lower percentages of positive Staphylococcus aureus infection (20% and 13.3%, respectively) and bacterial concentrations (3.5 x 10(1) and 1.75 x 10(1) colony forming units/g bone, respectively). The osteomyelitic tibias of the nafcillin plus rifampin treated group (n = 7) showed no detectable Staphylococcus aureus infection (significantly lower than controls). The differences observed for bone bacterial concentrations and sterilization percentages between the antibiotic treated groups were not statistically significant. Although fluoroquinolones (including ofloxacin and ciprofloxacin) are the agents usually prescribed with rifampin, increasing resistance has been observed. Although macrolides traditionally are not used in the treatment of osteomyelitis, the results of this study indicate that azithromycin and clarithromycin may be attractive partners for rifampin for the treatment of Staphylococcus aureus osteomyelitis in humans.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Azithromycin; Biological Availability; Clarithromycin; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Nafcillin; Osteomyelitis; Rabbits; Rifampin; Staphylococcal Infections; Tibia; Treatment Outcome

In the search for new antibiotics active against macrolide-resistant pneumococci and Haemophilus influenzae, we synthesized a new class of 3-oxo-6-O-methylerythromycin derivatives, so-called "ketolides". A keto function was introduced in position 3 after removal of L-cladinose, a sugar which has long been thought essential. Further modifications of the macrolactone backbone allowed us to obtain three different series of 9-oxime, 11,12-carbamate, and 11, 12-hydrazonocarbamate ketolides. These compounds were found to be very active against penicillin/erythromycin-resistant pneumococci and noninducers of MLSB resistance. The 11,12-substituted ketolide 61 (HMR 3004) demonstrated a potent activity against multiresistant pneumococci associated with a well-balanced activity against all bacteria involved in respiratory infections including H. influenzae, Mycoplasma catarrhalis, group A streptococci, and atypical bacteria. In addition HMR 3004 displayed high therapeutic activity in animals infected by all major strains, irrespective of their resistance phenotype.

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Crystallography, X-Ray; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Drug Resistance, Multiple; Enterococcus; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Ketolides; Macrolides; Male; Mice; Models, Molecular; Molecular Conformation; Respiratory Tract Infections; Staphylococcal Infections; Staphylococcus; Streptococcus; Streptococcus pneumoniae

Topics: Animals; Anti-Bacterial Agents; Autoradiography; Azithromycin; Male; Mice; Mice, Inbred ICR; Staphylococcal Infections

The ability of azithromycin, erythromycin, clarithromycin, or cefuroxime to modify the course of group A streptococcus (GAS) or Staphylococcus aureus soft-tissue infection was compared in a mouse model. In GAS-infected mice given azithromycin, fewer demonstrated dermonecrosis (P = 0.0004); the average weight gain was greater (P < 0.05) and the latency to sustained weight gain was shorter (P < 0.05) than for animals given other antibiotics. All antibiotics were effective against S. aureus infections, with no significant differences among treatments in parameters evaluated. The effectiveness of azithromycin in GAS-infected mice may be related to the high and sustained tissue concentrations achieved with this antibiotic.

Topics: Analysis of Variance; Animals; Anti-Bacterial Agents; Azithromycin; Cefuroxime; Clarithromycin; Disease Models, Animal; Erythromycin; Fasciitis, Necrotizing; Mice; Mice, Hairless; Skin Diseases; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pyogenes

The direct effect of clarithromycin and azithromycin on human polymorphonuclear leukocyte (PMN) functions and their intracellular activity against Staphylococcus aureus, phagocytosed by human monocytes, were studied. The presence of both antibiotics, in the range of concentrations from 0.25 to 20 micrograms/ml, did not affect chemotaxis, opsonized-zymosan phagocytosis, respiratory burst measured by nitroblue tetrazolium reduction and phorbol myristate acetate-induced superoxide production, or the microbicidal activity of human PMNs against Candida albicans. Both macrolides were bactericidal against staphylococci in the monocyte system, while bacteriostatic activity was found in cell free system. At concentrations equal to the minimum inhibitory concentrations (MICs) (0.75 and 0.1 respectively for azithromycin and clarithromycin) more than 99% of intraphagocytic S. aureus were killed after 24 h incubation. Increasing the concentrations of each drug above the MICs (5 and 10 MICs) did not alter the killing rate of intracellular bacteria. Moreover, no differences between the intracellular bioactivity of these antibiotics were demonstrated, despite their different uptake kinetics.

Topics: Azithromycin; Cell-Free System; Clarithromycin; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Monocytes; Neutrophils; Phagocytosis; Staphylococcal Infections; Staphylococcus aureus

Azithromycin has been shown to preferentially distribute to infection loci. Due to the potential contribution of phagocytes as transporters of drug to these sites, there has been some concern that immunosuppression of the cellular arm of the host defence system would greatly reduce the delivery of azithromycin to sites of infection and hence impair efficacy. Therefore, we evaluated the pharmacokinetics and pharmacodynamics of azithromycin in a Staphylococcus aureus intramuscular infection model in normal and immunosuppressed mice, employing therapeutic and prophylactic regimens. Immunosuppression was induced by daily doses of cyclophosphamide that culminated in leucopenia with an underlying granulocytopenic condition, with circulating peripheral granulocytes numbering from < or = 0.1-0.3 x 10(9)/L. Azithromycin tissue levels were not reduced in infection loci in granulocytopenic mice but moderate increases in Cmax and AUC values were observed, relative to similar tissues from normal mice. The tissue half-life of azithromycin in infected tissues in a therapeutic mode (75 h) was three-fold longer than in a prophylactic mode (25 h); this correlated with the degree of inflammation (therapy was withheld until inflammation was evident; i.e., prophylaxis reduced inflammation). Histological examination of infected tissues from normal and leucopenic mice was indistinguishable despite a 70%-85% reduction in circulating granulocytes. Compared with untreated infected controls, bactericidal activity was noted following prophylaxis with azithromycin and bacteraemia was suppressed in mice receiving azithromycin therapeutically. In summary, these data indicate that azithromycin delivery and efficacy in a moderately immunosuppressed animal model are unimpaired.

Topics: Agranulocytosis; Animals; Anti-Bacterial Agents; Area Under Curve; Azithromycin; Bacteremia; Colony Count, Microbial; Cyclophosphamide; Half-Life; Immunosuppression Therapy; Immunosuppressive Agents; Leukocyte Count; Leukopenia; Male; Mice; Muscle, Skeletal; Staphylococcal Infections; Staphylococcus aureus

L-701,677, L-708,299 and L-708,365 are novel azalide derivatives of erythromycin that exhibit improved acid stability over erythromycin, azithromycin and clarithromycin. The half-life in aqueous solution at pH = 2.1 of these compounds ranged from 0.3 hour for erythromycin to 16.2 hours for L-708,299. The rank order of half-life in acid solution from most to least stable was L-708,299 > L-701,677 > L-708,365 > azithromycin = clarithromycin > erythromycin. In a disseminated Streptococcus pyogenes mouse infection model, azithromycin and L-708,365 were slightly more efficacious than clarithromycin, L-701,677 and L-708,299; all 5 compounds being more active than erythromycin. In a Klebsiella pneumoniae pulmonary challenge mouse model, azithromycin, L-701,677, L-708,299 and L-708,365 were all equal in efficacy and at least four-fold more active than clarithromycin and erythromycin. Clarithromycin, L-708,365 and interestingly erythromycin, showed greater bacterial clearance than azithromycin, L-701,677 and L-708,299 in a localized infection model that measured clearance of Staphylococcus aureus from mouse thigh tissues. Our results indicate that L-701,677, L-708,299 and L-708,365 exhibit improved acid stability and were at least equally efficacious as presently marketed macrolide/azalide antibiotics.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Clarithromycin; Drug Evaluation, Preclinical; Drug Stability; Erythromycin; Female; Half-Life; Klebsiella Infections; Macrolides; Mice; Mice, Inbred DBA; Molecular Structure; Staphylococcal Infections; Streptococcal Infections

We studied the efficacy and pharmacokinetics of azithromycin in a rabbit tissue-cage Staphylococcus aureus abscess model. A dosage of 15 mg/kg/day azithromycin was administered to rabbits with 24 h or 2 week old infected tissue cages and to uninfected controls. Concentrations of azithromycin were higher in the infected compared with the uninfected tissue cages. Azithromycin was effective in reducing the bacterial concentrations in both groups of infected tissue cages by approximately 3 log10 cfu/mL compared with untreated controls after 8 days of therapy. Fifty percent of the 24 h and 29% of the 2 week infected tissue cages became culture-negative.

Topics: Abscess; Animals; Azithromycin; Diffusion Chambers, Culture; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Time Factors

High throughput chemical file screening with an enzymatic assay to detect inhibitors of the ErmC methyltransferase enzyme from macrolide-lincosamide-streptogramin B (MLSB) resistant pathogenic bacteria identified low molecular weight compounds that had IC50S (50% inhibitory concentration) in the nMolar to microMolar range. These same inhibitors were assessed in vitro for their capacity to inhibit the liver enzyme, cathechol-O-methyltransferase and the prokaryotic enzyme, EcoRI methylase. Selective inhibitors of the ErmC methyltransferase were tested in tertiary assays to determine their minimal inhibitory concentrations (MICs), as single agents and in combination with the macrolide, azithromycin, against strains of pathogenic bacteria expressing MLSB-resistance. Compounds that were active in vitro, alone or in combination with azithromycin, against strains of macrolide-resistant pathogens were tested in a mouse model of infection using an MLSB-resistant strain of Staphylococcus aureus or a macrolide-susceptible strain of Streptococcus pyogenes.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Drug Resistance, Microbial; Drug Therapy, Combination; Enzyme Inhibitors; Lincosamides; Macrolides; Methyltransferases; Mice; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pyogenes; Virginiamycin

During the process of abscess formation, a myriad of changes are observed histologically that impede the penetration of antimicrobial agents into infection loci. A Staphylococcus aureus foreign body abscess, developed in rats, was employed to evaluate the penetration kinetics of azithromycin, roxithromycin and cephalexin at various stages of abscess development; the progressive patho-histological changes of abscess formation were also characterized in this model. In an early abscess (18 h post-challenge), azithromycin penetration into inflammatory fluid was enhanced (AUC of 351 vs 130 mg.h/kg) and residence prolonged relative to an inflammation control (half-life of 88 vs 27 h). In contrast, roxithromycin and cephalexin penetration into, and residence in, inflammatory fluid were unaltered in the early abscess. However, penetration into, and egress from, a mature abscess (ten days post-challenge) were impeded for all three antimicrobials (P < or = 0.03). The penetration kinetics of azithromycin into inflammatory fluid in an early abscess were independent of the dose regimen, but dependent on the total dose. The persistently high concentrations of azithromycin in inflammatory fluid within abscess were associated with the infiltration of phagocytic cells and encapsulation by fibrous tissue. These data are consistent with a phagocytic delivery mechanism for azithromycin, whereby the presence of high concentrations of azithromycin in inflammatory fluid are a consequence of augmented drug distribution via the release of accumulated intracellular drug from the infiltrating phagocytic cells and fibroblasts associated with abscess formation.

Topics: Abscess; Animals; Azithromycin; Cephalexin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythromycin; Male; Mice; Mice, Inbred Strains; Rats; Roxithromycin; Skin Diseases, Bacterial; Staphylococcal Infections; Staphylococcus aureus; Time Factors

The possibility of augmentation of azithromycin delivery to infection loci was evaluated by the use of Staphylococcus aureus thigh infection models with CD-1 mice. The intramuscular infections that developed were characterized by rapid growth of bacteria and induction of a localized oedema that was assessed gravimetrically. Microscopic examination of infected thighs showed massive infiltration of polymorphonuclear leucocytes (viable and degranulated), when compared to saline-injected thighs, from 24 to > or = 72 h after infection. Azithromycin concentrations were enhanced significantly (P < or = 0.02) in infected thigh tissues compared with contralateral non-infected tissues, and correlated with oedema from 24-72 h after challenge and dosing. The azithromycin levels in infected tissue after a 5 mg/kg dose were sufficient to cause a significant reduction in the number of cfu. If azithromycin administration was delayed until inflammation was more severe, the result was an even greater preferential concentration of azithromycin into the infected thigh. Preferential concentration of azithromycin was not observed when extensive oedema was produced by injection of histamine. However, this oedema was not associated with a significant influx of polymorphonuclear leucocytes. In comparative studies, macrolide antibiotics known to be concentrated in phagocytes, such as erythromycin, roxithromycin, and clarithromycin, were not concentrated preferentially in infected tissues under the experimental conditions used; tissue levels were above or at the in-vitro MIC level for < or = 24 h. The data indicate that delivery of biologically available azithromycin to infected tissues is enhanced by cellular inflammatory processes.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Erythromycin; Histamine; Inflammation; Male; Mice; Mice, Inbred Strains; Staphylococcal Infections; Staphylococcus aureus; Thigh

We examined the effect of azithromycin (CP-62,993), a new oral macrolide-like antibiotic, alone and in combination with rifampin, as treatment for experimental staphylococcal osteomyelitis. Clindamycin was used as a comparison drug. Rats (n = 10 to 15 per group) were infected by direct instillation of Staphylococcus aureus into the tibial medullary cavity. After 10 days, 21-day treatments with azithromycin (50 mg/kg of body weight, once daily, by the oral route), rifampin (20 mg/kg, once daily, subcutaneously), or clindamycin (90 mg/kg, three times daily, by the oral route) were started. The drugs were used singly or in combination (azithromycin plus rifampin or clindamycin plus rifampin). Peak azithromycin concentrations in bone were > 30 times higher than levels in serum, but the drug had little effect on final bacterial titers (5.13 +/- 0.46 log10 CFU/g of bone; for controls, 6.54 +/- 0.28 log10 CFU/g). Clindamycin was more active than azithromycin (3.26 +/- 2.14 log10 CFU/g of bone; 20% of sterilized bones), but rifampin was the most active single drug (1.5 +/- 1.92 log10 CFU/g; 53% of sterilized bones). Therapy with rifampin or clindamycin alone was associated with the emergence of resistance. Rifampin plus azithromycin (0.51 +/- 1.08 log10 CFU/g of bone; 80% of sterilized bones) and rifampin plus clindamycin (0.87 +/- 1.34 log10 CFU/g of bone; 66% of sterilized bones) were the most active regimens. Thus, azithromycin is ineffective as a single drug for the treatment of experimental staphylococcal osteomyelitis, despite high levels in bone that markedly exceeded the MIC, but it may be an attractive partner drug for rifampin.

Topics: Animals; Azithromycin; Bone and Bones; Clindamycin; Drug Resistance, Microbial; Drug Therapy, Combination; Erythromycin; Male; Osteomyelitis; Rats; Rifampin; Staphylococcal Infections