zithromax and Haemophilus-Infections

The first clinical indication of non-antibiotic benefits of macrolides was in the Far East, in adults with diffuse panbronchiolitis. This condition is characterised by chronic airway infection, often with Pseudomonas aeruginosa, airway inflammation, bronchiectasis and a high mortality. Low dose erythromycin, and subsequently other macrolides, led in many cases to complete remission of the condition, and abrogated the neutrophilic airway inflammation characteristic of the disease. This dramatic finding sparked a flurry of interest in the many hundreds of macrolides in nature, especially their anti-inflammatory and immunomodulatory effects. The biggest subsequent trials of azithromycin were in cystic fibrosis, which has obvious similarities to diffuse panbronchiolitis. There were unquestionable improvements in lung function and pulmonary exacerbations, but compared to diffuse panbronchiolitis, the results were disappointing. Case reports, case series and some randomised controlled trials followed in other conditions. Three trials of azithromycin in preschool wheeze gave contradictory results; a trial in pauci-inflammatory adult asthma, and a trial in non-cystic fibrosis bronchiectasis both showed a significant reduction in exacerbations, but none matched the dramatic results in diffuse panbronchiolitis. There is clearly a huge risk of antibacterial resistance if macrolides are used widely and uncritically in the community. In summary, Azithromycin is not the answer to anything in paediatric respiratory medicine; the paediatric respiratory community needs to refocus on the dramatic benefits of macrolides in diffuse panbronchiolitis, use modern - omics technologies to determine the endotypes of inflammatory diseases and discover in nature or synthesise designer macrolides to replicate the diffuse panbronchiolitis results. We must now find out how to do better!

Topics: Anti-Bacterial Agents; Asthma; Azithromycin; Bronchiectasis; Bronchiolitis; Bronchiolitis Obliterans; Bronchiolitis, Viral; Child; Child, Preschool; Ciliary Motility Disorders; Cystic Fibrosis; Disease Progression; Drug Resistance, Bacterial; Haemophilus Infections; Humans; Infant; Lung Diseases, Interstitial; Lung Transplantation; Macrolides; Respiratory Sounds; Stem Cell Transplantation

Diffuse panbronchiolitis (DPB) is a rare progressive and eventually fatal pulmonary disease first identified in Japan and initially seen predominantly in Southeast Asia. Macrolide antibiotics rapidly reverse symptoms and pathology, and their use increased the 5 and 10-year survival from 50 and 30 percent, respectively, to over 90%. Review of 181 case reports from previous publications found patients with DPB commonly had their pulmonary symptoms preceded by rhinosinusitis, frequently by many years. Long delays in diagnosis for many years were common. The review further identified DPB in all ethnic groups and multiple areas outside of Southeast Asia. Although diagnosis was most commonly made in adults, 13% of the diagnoses were made in children and nine of the adult cases described onset in childhood. Few cases of relapse were reported, but extended periods of monitoring after treatment were not generally present.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis; Haemophilus Infections; Humans; Prognosis

In 1984, the effectiveness of low-dose, long-term erythromycin treatment (macrolide therapy) for diffuse panbronchiolitis (DPB) was first reported in Japan. The 5-year survival rate for DPB improved from 62.9 to 91.4% after implementation of macrolide therapy. The usefulness of this treatment has since been demonstrated in patients with other chronic airway diseases, such as chronic bronchitis, cystic fibrosis, bronchiectasis, bronchial asthma, and chronic rhinosinusitis (CRS). The new 14-membered macrolides clarithromycin and roxithromycin and the 15-membered macrolide azithromycin are also effective for treating these inflammatory diseases. The mechanism of action of the 14- and 15-membered macrolides may involve anti-inflammatory rather than anti-bacterial activities. Macrolide therapy is now widely used for the treatment of CRS in Japan; it is particularly effective for treating neutrophil-associated CRS and is useful for suppressing mucus hypersecretion. However, macrolide therapy is not effective for eosinophil-predominant CRS, which is characterized by serum and tissue eosinophilia, high serum IgE levels, multiple polyposis, and bronchial asthma. Recent reports have described the clinical efficacy of macrolides in treating other inflammatory diseases and new biological activities (e.g., anti-viral). New macrolide derivatives exhibiting anti-inflammatory but not anti-bacterial activity thus have therapeutic potential as immunomodulatory drugs. The history, current state, and future perspectives of macrolide therapy for treating CRS in Japan will be discussed in this review.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis; Chronic Disease; Clarithromycin; Erythromycin; Haemophilus Infections; History, 20th Century; History, 21st Century; Humans; Japan; Macrolides; Nasal Polyps; Rhinitis; Sinusitis

Haemophilus influenzae is the most common bacterial pathogen associated with acute exacerbations of chronic bronchitis (AECB). This study determined the rate of bacterial eradication of H. influenzae during AECB treated with either macrolides or moxifloxacin. Adult AECB patients with H. influenzae were included in a pooled analysis of four double-blind, multicentre, randomised trials. Patients received either moxifloxacin (400 mg qd for 5-10 days) or macrolides (azithromycin 500 mg/250 mg qd for 5 days or clarithromycin 500 mg bid for 5-10 days). Bacterial eradication and clinical success were recorded at the test-of-cure visit (7-37 days post-therapy). Of 2555 patients in the intent-to-treat population, 910 were microbiologically valid and 292 (32%) had H. influenzae cultured at baseline. Bacterial eradication of H. influenzae was significantly higher with moxifloxacin vs. macrolide-treated patients (93.0% [133/143] vs. 73.2% [109/149], respectively, P = 0.001). Moxifloxacin also demonstrated higher eradication rates compared with azithromycin (96.8% vs. 84.6%, P = 0.019) and clarithromycin (90.1% vs. 64.2%, P = 0.001) analysed separately. Clinical success was 89.5% (128/143) for moxifloxacin vs. 85.2% (127/149) for the macrolide group (P = 0.278); similar results were found when moxifloxacin was compared individually with each macrolide. For patients with AECB due to H. influenzae, moxifloxacin provided superior bacterial eradication rates than macrolide therapy.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Aza Compounds; Azithromycin; Bronchitis, Chronic; Chronic Disease; Clarithromycin; Clinical Trials, Phase III as Topic; Double-Blind Method; Female; Fluoroquinolones; Haemophilus Infections; Haemophilus influenzae; Humans; Male; Middle Aged; Moxifloxacin; Multicenter Studies as Topic; Quinolines; Randomized Controlled Trials as Topic; Treatment Outcome

Haemophilus influenzae is an important cause of respiratory tract infections, particularly in elderly persons. It is the major bacterial pathogen in acute exacerbations of chronic bronchitis (AECB) and also causes otitis media and sinusitis. In many cases, treatment is empiric, and there is a lack of understanding of resistance issues with this bacterium. There is little understanding of the epidemiology of H. influenzae respiratory infections, although some strains may be replaced by new strains that cause more severe infections. There is almost no information on how these bacteria may spread in the community. Ampicillin resistance is significant (it may be >30%), and there are few oral agents capable of reducing organism burden. There is little understanding of the epidemiology of H. influenzae respiratory infections, and almost no information on how these bacteria may spread in the community. Recent evidence suggests that these bacteria may behave in a similar way to Streptococcus pneumoniae. If that proves correct, then it will be important to follow these organisms in the community to determine if resistance determinants may spread more widely than we have thus far believed. The implications for treatment, infection prevention and control, and public health should not be underestimated as it has been with other organisms such as S. pneumoniae and Staphylococcus aureus.

Topics: Azithromycin; beta-Lactams; Community-Acquired Infections; Drug Resistance, Bacterial; Fluoroquinolones; Haemophilus Infections; Haemophilus influenzae; Humans; Macrolides; Microbial Sensitivity Tests

Erythromycin, the prototypical macrolide, has been widely used since the 1950s in the management of pediatric infections. Erythromycin is the drug of choice for infants and children with Legionnaire's disease, pertussis, diphtheria, lower respiratory tract infections caused by Mycoplasma pneumoniae, Chlamydia pneumoniae and Chlamydia trachomatis and enteritis caused by Campylobacter jejuni. It is also indicated for treatment of syphilis; for streptococcal, staphylococcal and pneumococcal infections; genital infections caused by Ureaplasma urealyticum; and for the prevention of rheumatic fever and endocarditis in patients who are allergic to beta-lactam antibiotics. The new macrolides azithromycin and clarithromycin are also active against Borrelia burgdorferi, Helicobacter pylori, Mycobacterium avium-intracellulare complex, Cryptosporidium spp. and Toxoplasma gondii. Erythromycin is associated with a low risk of serious side effects, although gastric distress occurs in a significant proportion of patients. Drug interactions with theophylline, carbamazepine, warfarin, cyclosporine, terfenadine and digoxin limit erythromycin use. The newer macrolides azithromycin and clarithromycin are more stable, better absorbed and better tolerated than erythromycin. Azithromycin is more active than erythromycin against Haemophilus influenzae. Excellent tissue and intracellular penetration may contribute to their clinical efficacy. In children both azithromycin and clarithromycin are indicated for acute otitis media caused by Streptococcus pneumoniae, H. influenzae and Moraxella catarrhalis and for pharyngitis/tonsillitis caused by Streptococcus pyogenes. (As of December, 1996, azithromycin for oral suspension was approved for community-acquired pneumonia in children caused by C. pneumoniae, H. influenzae, M. pneumoniae and S. pneumoniae.) Claritromycin is also indicated for acute maxillary sinusitis, uncomplicated skin and skin structure infections, pneumonia and disseminated mycobacterial infections. Azithromycin and clarithromycin are associated with a lower incidence of gastrointestinal side effects, a low rate of drug discontinuation caused by side effects and a low potential for interaction with other drugs.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Child; Child, Preschool; Clarithromycin; Drug Interactions; Erythromycin; Haemophilus Infections; Haemophilus influenzae; History, 20th Century; Humans; Infant; Infant, Newborn; Microscopy, Electron; Phagocytes; Phagocytosis

Requirements for the antimicrobial activity of an antibiotic are: (1) binding of the drug to a specific site in the bacteria; (2) occupation of a critical number of binding sites; and (3) persistence at these binding sites for a sufficient time. With concentration-dependent antibiotics the ratio of the peak serum drug concentration to the MIC of a pathogen is the primary determinant of bacterial killing; with concentration-independent antibiotics it is the length of time serum concentration remains above the MIC, rather than the peak level. The pharmacokinetics of the new macrolides azithromycin and clarithromycin differ notably from those of conventional antibiotics in a more rapid and extensive distribution to body tissues. Because of these unique tissue pharmacokinetics, the pharmacodynamic models that apply to other classes of antibiotics may not explain the antimicrobial activity and clinical efficacy of azithromycin and clarithromycin.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Child; Child, Preschool; Clarithromycin; Ear, Middle; Haemophilus Infections; Humans; Infant; Infant, Newborn; Microbial Sensitivity Tests; Streptococcal Infections; Tissue Distribution

Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are the most frequently isolated pathogens in patients with acute otitis media (AOM). Other potential causative pathogens include Streptococcus pyogenes in older children and Chlamydia pneumoniae in younger children. The recent emergence of penicillin-resistant S. pneumoniae and the increasing frequency of beta-lactamase-producing strains of M. catarrhalis and H. influenzae are creating concerns regarding the use of amoxicillin as traditional first line empiric therapy for AOM in younger children. Both the in vitro antibiotic activity against these more resistant causative pathogens and the antibiotic concentrations achieved in middle ear fluid must be considered when selecting antibiotics for treatment of refractory AOM. The newer macrolides, azithromycin and clarithromycin, provide reasonable in vitro coverage against penicillin-resistant S. pneumoniae and beta-lactamase-producing H. influenzae, although azithromycin is more active against the latter. Both drugs also achieve notably higher, sustained concentrations in middle ear fluid than do beta-lactam antibiotics. Thus the newer macrolides represent important new rational alternatives for the management of AOM.

Topics: Anti-Bacterial Agents; Azithromycin; beta-Lactam Resistance; Child; Child, Preschool; Clarithromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Infant; Lactams; Moraxella catarrhalis; Neisseriaceae Infections; Otitis Media; Penicillin Resistance; Penicillins; Streptococcal Infections; Streptococcus pneumoniae

Azithromycin is a molecule of the macrolide family, belonging to the azalides class. Several of its characteristics allow for its use in the treatment of the community-acquired lower respiratory tract infections. Commonly isolated pathogens in bronchial infections are most frequently H. influenzae, S. pneumoniae, M. catarrhalis, C. pneumoniae and M. pneumoniae, and more rarely or in the context of a particular background, S. aureus, Gram negative bacteria and L. pneumophila. MIC90 of these germs is generally low or slightly elevated, displaying an inhibitory activity of the azithromycin on these bacteria. Nevertheless, the frequency of macrolide-resistant S. pneumoniae is not negligible and this germ must be considered as inconstantly susceptible to the macrolide family. Pharmacokinetics studies evidenced from high to very high azithromycin concentrations in the pulmonary tissues, reaching values well above MIC of pathogens commonly isolated. Given the long half-life, these concentrations persist a long time after oral administration. As azithromycin concentrates much in polymorphonuclear leucocytes, they release azithromycin after having migrated into the infectious site by chimiotactism, thus allowing to increase the antibiotic concentration at infection site. These requirements have been confirmed in vivo in animal models and in clinical studies. Two experimental models on macrolide susceptible S. pneumoniae, and H. influenzae evidenced a better activity of azithromycin in comparison to other macrolides tested against these two germs.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Azithromycin; Bronchitis; Chronic Disease; Community-Acquired Infections; Haemophilus Infections; Humans; Mice; Pneumonia, Bacterial; Pneumonia, Mycoplasma; Pneumonia, Pneumococcal

Lacking protective antibodies, patients with primary antibody deficiencies (PADs) experience frequent respiratory tract infections, leading to chronic pulmonary damage. Macrolide prophylaxis has proved effective in patients with chronic respiratory diseases.. We aimed to test the efficacy and safety of orally administered low-dose azithromycin prophylaxis in patients with PADs.. We designed a 3-year, double-blind, placebo-controlled, randomized clinical trial to test whether oral azithromycin (250 mg administered once daily 3 times a week for 2 years) would reduce respiratory exacerbations in patients with PADs and chronic infection-related pulmonary diseases. The primary end point was the number of annual respiratory exacerbations. Secondary end points included time to first exacerbation, additional antibiotic courses, number of hospitalizations, and safety.. Eighty-nine patients received azithromycin (n = 44) or placebo (n = 45). The number of exacerbations was 3.6 (95% CI, 2.5-4.7) per patient-year in the azithromycin arm and 5.2 (95% CI, 4.1-6.4) per patient-year in the placebo arm (P = .02). In the azithromycin group the hazard risk for having an acute exacerbation was 0.5 (95% CI, 0.3-0.9; P = .03), and the hazard risk for hospitalization was 0.5 (95% CI, 0.2-1.1; P = .04). The rate of additional antibiotic treatment per patient-year was 2.3 (95% CI, 2.1-3.4) in the intervention group and 3.6 (95% CI, 2.9-4.3) in the placebo group (P = .004). Haemophilus influenzae and Streptococcus pneumoniae were the prevalent isolates, and they were not susceptible to macrolides in 25% of patients of both arms. Azithromycin's safety profile was comparable with that of placebo.. The study reached the main outcome centered on the reduction of exacerbation episodes per patient-year, with a consequent reduction in additional courses of antibiotics and risk of hospitalization.

Topics: Adult; Azithromycin; Dose-Response Relationship, Drug; Double-Blind Method; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Male; Middle Aged; Pneumonia, Pneumococcal; Primary Immunodeficiency Diseases; Streptococcus pneumoniae

We conducted a multicenter, unblinded, non-comparative, phase 3 trial of azithromycin-intravenous therapy followed by oral administration in Japanese adults to evaluate clinical efficacy and safety against community-acquired pneumonia in order to obtain regulatory approval for the intravenous formulation in Japan. Azithromycin (500 mg, once daily) was intravenously administered for 2-5 days followed by oral 500 mg once daily administration to complete a total of 7-10 days treatment in 102 adults with moderate-to-severe community-acquired pneumonia. The efficacy rate in the Clinical Per Protocol Set overall was 84.5% (60/71 subjects) on Day 15 (primary analysis). The most common causative pathogen was Haemophilus influenzae (17 strains), followed by Streptococcus pneumoniae (14 strains), Moraxella catarrhalis (5 strains) and Mycoplasma pneumoniae (5 strains). Eleven of 14 S. pneumoniae isolates were resistant to azithromycin (MIC ≥2.0 μg/ml), of which 5 strains with a relatively low MIC of <32 μg/ml had only mef A gene and 6 strains with a high MIC of >64 μg/ml had only the erm B gene except for 2 isolates having both the mef A and erm B genes. Despite dominance of macrolide-resistant strains in Japan, clinical efficacy and bacterial eradication were achieved in 10 of 11 patients (90.9%). Intravenous-to-oral azithromycin therapy demonstrated excellent clinical and bacteriological effects on moderate-to-severe pneumococcal pneumonia despite a high MIC and resistance gene development. This discrepancy is referred to as the "in vivo-in vitro paradox". The current study results provide an insight into this paradox.. NCT00809328.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; Community-Acquired Infections; Drug Resistance, Bacterial; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Male; Middle Aged; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Treatment Outcome; Young Adult

The growing problem of drug resistance among respiratory pathogens in community-acquired pneumonia (CAP), particularly Streptococcus pneumoniae, (S. pneumoniae) has complicated initial empiric therapy of CAP. This study was undertaken to evaluate the efficacy and tolerability of a 3-day course of azithromycin in adults with mild to moderately severe CAP, and to determine whether in vitro macrolide resistance among strains of S. pneumoniae is related to clinical efficacy/failure.. An open-label, non-comparative study was undertaken at 3 university-affiliated hospitals in Japan. Patients were eligible if they were 18 years or older and had mild or moderately severe CAP. All patients received azithromycin 500 mg/day for three days, and clinical and microbiological responses were evaluated 1 and 2 weeks after initiating therapy.. A total of 78 patients received the study medication, 59 of whom had sufficient data available for efficacy analysis. Overall, a good clinical response with azithromycin was achieved in 49 patients (83.1%) and a microbiological response was achieved in 78.3%. Azithromycin resistance, based on CLSI criteria, was demonstrated in 85.7% (12/14) of S. pneumoniae isolates, and the presence of ermB genes was found in 50.0% (7/14). However, among patients in whom S. pneumoniae was isolated (n=17), a good clinical response was achieved in 76.5% (13/17), and the microbiological response rate was 64.3% (9/14). Furthermore, 6 of 7 patients in whom high-level resistance was documented (MICs >256 microg/mL and carrying ermB genes) exhibited good clinical responses. Azithromycin was well tolerated; adverse events, mainly of a gastrointestinal nature, were recorded in 6 patients (7.7%).. Most patients responed well to azithromycin, indicating that azithromycin might be clinically effective for the treatment of CAP with macrolide-resistant S. pneumoniae. However, a larger study is necessary to prove the efficacy against macrolide-resistant S. pneumoniae.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; Community-Acquired Infections; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Female; Haemophilus Infections; Hospitals, University; Humans; Japan; Macrolides; Male; Middle Aged; Pneumonia, Bacterial; Pneumonia, Mycoplasma; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Young Adult

High dose amoxicillin is recommended for the initial treatment of children with acute otitis media (AOM), particularly patients at risk for having drug-resistant Streptococcus pneumoniae. Single dose azithromycin (30 mg/kg) is considered an alternative agent for the treatment of AOM.. To compare the clinical efficacy and safety of single dose azithromycin with that of high dose amoxicillin among children with uncomplicated AOM.. This was a double blind, double dummy, multinational, clinical trial in which children (6-30 months of age) with AOM were randomized to treatment with single dose azithromycin (30 mg/kg) or high dose amoxicillin (90 mg/kg/d, in 2 divided doses) for 10 days. Tympanocentesis was performed at baseline and clinical responses were assessed at days 12-14 (end of therapy) and at days 25-28 (end of study).. The study enrolled 313 patients, and 83% of the patients were < or =2 years of age. A total of 158 patients in the azithromycin group and 154 in the amoxicillin group were considered clinical modified intent-to-treat patients. A middle ear pathogen was detected for 212 patients (68%). Haemophilus influenzae was the most common pathogen (isolated for 96 patients), followed by S. pneumoniae (92 patients), Moraxella catarrhalis (23 patients) and Streptococcus pyogenes (23 patients). beta-Lactamase production was observed for 17% of H. influenzae isolates and 100% of M. catarrhalis isolates. Thirty-five (38%) S. pneumoniae isolates were penicillin-nonsusceptible and 24 (26%) isolates were macrolide-resistant. At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84 and 84%, respectively) and for children < or =2 years of age (82 and 82%, respectively). At the end of therapy and end of study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of treatment-related adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (P = 0.064). Diarrhea was more common in the amoxicillin group than in the azithromycin group (17.5 and 8.2%, respectively) (P = 0.017). Compliance, defined as completion of > or =80% of the study medication, was higher in the azithromycin group (100%) than in the amoxicillin group (90%) (P = 0.001).. In this study, single dose azithromycin was as effective as high dose amoxicillin for the treatment of children with AOM, whereas rates of adverse events were lower and compliance improved with the simplified single dose regimen.

Topics: Amoxicillin; Anti-Bacterial Agents; Azithromycin; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Bacterial; Haemophilus Infections; Haemophilus influenzae; Humans; Infant; Moraxellaceae Infections; Otitis Media; Patient Compliance; Pneumococcal Infections; Streptococcal Infections; Streptococcus pyogenes

We compared the outcomes of two different regimens--azithromycin and pseudoephedrine hydrochloride (PHCl)--for the treatment of otitis media with effusion (OME) in children. In a double-blind randomized clinical study, a total of 90 children aged between 2 and 13 years with persistent OME were randomly assigned to one of 3 treatment groups. The first group received azithromycin at a dose of 10 mg/kg once daily for 3 days and this regimen was repeated weekly for up to 12 weeks according to the results of tympanometry and pneumatic otoscopy. The second group received azithromycin at a dose of 10 mg/kg once daily for 3 days for the first week, and this regimen was repeated for 1 day a week for the following 11 weeks. The third group received PHCl, 4 mg/kg, 3 times daily for up to 12 weeks. Each patient underwent pneumatic otoscopic and tympanometric investigations at baseline and at Weeks 4, 8 and 12. The outcomes in the azithromycin-treated groups were superior to that in the decongestant group. However, the difference between the outcomes in the azithromycin groups according to the treatment protocol was not statistically significant. Azithromycin therapy, particularly a once-weekly regimen, helps patients to comply with treatment and also helps us to achieve good results with minimal therapy.

Topics: Acoustic Impedance Tests; Adolescent; Adrenergic Agents; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Ephedrine; Female; Follow-Up Studies; Haemophilus Infections; Humans; Male; Neisseriaceae Infections; Otitis Media with Effusion; Retrospective Studies

The effect of antibiotic therapy on nasopharyngeal colonization by Streptococcus pneumoniae and Haemophilus influenzae was evaluated in children diagnosed with acute otitis media. Children were randomly assigned to receive either amoxicillin/clavulanate or azithromycin therapy, and nasopharyngeal swabs were obtained for culture before and after starting therapy. Amoxicillin/clavulanate therapy eradicated or suppressed all strains of S. pneumoniae susceptible to penicillin, 75% of strains with intermediate resistance, and 40% of strains resistant to penicillin. Azithromycin therapy cleared two-thirds of azithromycin-susceptible strains of S. pneumoniae but none of azithromycin-nonsusceptible strains. Selection for antibiotic-resistant strains in individual children was not observed in children who received amoxicillin/clavulanate therapy but was observed in 2 children who received azithromycin therapy. Carriage of H. influenzae was also reduced by antimicrobial therapy but more so by amoxicillin/clavulanate. Antibiotic therapy does not directly increase the number of resistant strains in the population but, by eradicating susceptible strains, allows greater opportunity for carriage and spread of resistant strains.

Topics: Acute Disease; Amoxicillin; Anti-Bacterial Agents; Azithromycin; Carrier State; Child; Child, Preschool; Clavulanic Acid; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Infant; Male; Nasopharynx; Otitis Media; Pneumococcal Infections; Streptococcus pneumoniae

In this multicenter, open label trial the investigators evaluated the efficacy and safety of azithromycin suspension administered once daily for 5 days for the treatment of clinically and bacteriologically established acute otitis media.. Two hundred eligible children with acute otitis media from 10 US centers were treated with 10 mg/kg of azithromycin oral suspension on Day 1, followed by 5 mg/kg once daily for the next 4 days. Tympanocentesis and subsequent culture of middle ear effusion were performed at baseline. Clinical efficacy was evaluated on Days 6, 11 and 30.. Analysis of clinical efficacy in evaluable patients 11 days after the initiation of therapy showed that the rate of satisfactory responses (cured or improved) ranged from 79.6 to 82.4% in patients infected with Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. Satisfactory clinical response at Day 30 was reported in 70% of evaluable patients, and eradication of S. pneumoniae, H. influenzae and M. catarrhalis was presumed in 64 to 73%. Relapses occurred in 14% of the evaluable patients. Among the treated patients 8.5% reported mild or moderate side effects.. Azithromycin is an effective, safe and well-tolerated treatment for children with acute otitis media.

Topics: Acute Disease; Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Drug Administration Schedule; Female; Haemophilus Infections; Humans; Male; Moraxella catarrhalis; Neisseriaceae Infections; Otitis Media; Pneumococcal Infections

Topics: Azithromycin; Carrier State; Child, Preschool; Haemophilus Infections; Haemophilus influenzae; Humans; Infant; Pharynx; Pneumococcal Infections; Streptococcus pneumoniae; Tetracycline; Trachoma

The efficacy and safety of a three-day regimen of azithromycin (500 mg od) and a ten-day regimen of co-amoxiclav (625 mg tid) were compared in a single-blind study in 99 patients with acute lower respiratory tract infections. Of these, 70 (71%) suffered an infective exacerbation of their chronic obstructive pulmonary disease. Nine patients had pneumonia and 19 purulent bronchitis. Treatment success, defined as cure or improvement, occurred in 43 of 48 (90%) patients in the azithromycin group, compared with 45 of 51 (88%) patients in the co-amoxiclav group. The most common isolated pathogens were Haemophilus influenzae (25 cases; MIC range of azithromycin (A) < or = 0.06-4 mg/L; for co-amoxiclav (CA) 0.25-4 mg/L; Streptococcus pneumoniae (10 cases; A: < or = 0.06- > 128; CA: < or = 0.06); and Moraxella catarrhalis (four cases; A: < or = 0.06; CA: < or = 0.06-0.25). Microbiological response rates were comparable in the two groups. In 5% of patients, serological evidence for virus or atypical pathogens was found. Thirteen (26%) patients treated with co-amoxiclav had gastrointestinal complaints (seven with diarrhoea), compared with five (10%) treated with azithromycin (P = 0.09). Additional complaints occurred in three patients treated with co-amoxiclav and in one patient treated with azithromycin. It was concluded that a three-day regimen of azithromycin was as effective, clinically and microbiologically, as a ten-day regimen of co-amoxiclav in the treatment of acute lower respiratory tract infections.

Topics: Adult; Aged; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Azithromycin; Bronchitis; Clavulanic Acids; Drug Administration Schedule; Drug Combinations; Erythromycin; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Male; Middle Aged; Moraxella catarrhalis; Neisseriaceae Infections; Pneumococcal Infections; Respiratory Tract Infections; Single-Blind Method; Streptococcus pneumoniae

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

Non-typeable Haemophilus influenzae (NTHi) has become the major cause of invasive H. influenzae diseases in the post-H. influenzae type b vaccine era. The emergence of multidrug-resistant (MDR) NTHi is a growing public health problem. Herein, we investigated the molecular basis of MDR in NTHi. The isolated NTHi were subjected to antimicrobial susceptibility testing for 12 agents. Whole genome and plasmid sequencing were conducted and analyzed to identify significant genetic variations and plasmid-encoded genes conferred antibiotic resistance.. This study clarified the molecular epidemiology of MDR in NTHi. This can benefit the monitoring of drug resistance trends in NTHi and the adequate medical management of patients with NTHi infection.

Topics: Amoxicillin-Potassium Clavulanate Combination; Ampicillin; Anti-Bacterial Agents; Azithromycin; beta-Lactamases; Cefuroxime; Ciprofloxacin; Haemophilus Infections; Haemophilus influenzae; Humans; Levofloxacin; Microbial Sensitivity Tests; Tetracycline; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Anti-Bacterial Agents; Azithromycin; Common Variable Immunodeficiency; Dihydropteroate Synthase; Haemophilus Infections; Haemophilus influenzae; Humans; Microbial Sensitivity Tests; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Anti-Bacterial Agents; Asthma; Azithromycin; Clarithromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Microbial Sensitivity Tests

Azithromycin (AZM), that is a macrolide antibiotic, has been found to treat diffuse panbronchiolitis (DPB) effectively. However, the mechanism of action underlying the therapeutic effects remains unclear. We selected 64 patients with DPB from 305 patients who were diagnosed with DPB at the outpatient clinic in Shanghai Pulmonary Hospital from Jan 2010 to Oct 2014. The primary PBLs, CD4 + T cells, and Jurkat T cells were treated with AZM or erythromycin (EM), and the effects of AZM and EM on IL-17A and CXCL-2 production, proliferation, apoptosis and autophagy were evaluated. AZM and EM significantly inhibited IL-17A and CXCL-2 production in patients' PBLs (all P < 0.05). AZM significantly inhibited proliferation and promoted apoptosis of T cells from DPB patients. AZM can enhance autophagosome formation of T cells by suppressing S6RP phosphorylation, which is a downstream target of mTOR pathway (all P < 0.05). AZM and EM significantly decreased secreted IL-17A levels (P < 0.05) in the primary CD4 + T cells of patients with DPB. AZM may treat DPB patients by targeting cytokine production, proliferation, apoptosis and autophagy of T cell. The mechanism of therapeutic effects of AZM on DPB may be associated with a specific inhibition of mTOR pathway in the T lymphocytes.

Topics: Adult; Aged; Anti-Bacterial Agents; Azithromycin; Bronchiolitis; Dose-Response Relationship, Drug; Female; Haemophilus Infections; Humans; Jurkat Cells; Male; Middle Aged; Signal Transduction; T-Lymphocytes; TOR Serine-Threonine Kinases

Topics: Anti-Bacterial Agents; Azithromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory System

To determine antibiotic susceptibility of isolates of Streptococcus pneumoniae (n = 573) and Haemophilus influenzae (n = 345) collected in 2014-16 from Bulgaria, Romania, Serbia and Croatia.. MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.. Among S. pneumoniae, susceptibility was generally lowest in Romania and Serbia and highest in Bulgaria. Rates of susceptibility to penicillin (CLSI oral or EUCAST) were 22.3% and 21.8% in Romania and Serbia respectively, 57% in Croatia and 86.6% in Bulgaria. Similarly, macrolide susceptibility using CLSI/EUCAST breakpoints was low in Romania and Serbia (∼28% and 34.5%, respectively), higher in Croatia (55.9%) and highest in Bulgaria (∼75%). Only fluoroquinolones were active against all isolates in all four countries. Susceptibility was higher and variability across countries less pronounced for H. influenzae. Susceptibility by CLSI criteria to amoxicillin/clavulanic acid, azithromycin, cefuroxime, ceftriaxone and fluoroquinolones was ≥98% in all countries. Ampicillin susceptibility ranged from 85.3% in Romania to 100% in Bulgaria. Much greater variability was seen across breakpoints. Susceptibility to azithromycin and cefuroxime using CLSI criteria was ≥98% in all four countries, but was 0%-1% by EUCAST criteria.. The variability in antimicrobial susceptibility using different breakpoints makes it difficult for clinicians to interpret antimicrobial resistance data, and efforts should be made to harmonize breakpoints. The variability found across the four neighbouring countries demonstrates the need to monitor and publish national and local resistance patterns. These findings provide information critical for the selection of appropriate antimicrobial agents for the treatment of S. pneumoniae and H. influenzae.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Azithromycin; Bulgaria; Child; Community-Acquired Infections; Croatia; Drug Resistance, Multiple, Bacterial; Epidemiological Monitoring; Haemophilus Infections; Haemophilus influenzae; Humans; Macrolides; Microbial Sensitivity Tests; Middle Aged; Pneumococcal Infections; Respiratory Tract Infections; Romania; Serbia; Streptococcus pneumoniae; Surveys and Questionnaires; Young Adult

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis; Erythromycin; Haemophilus Infections; Humans; Japan; Macrolides; Male; Middle Aged; Prognosis; Sputum; Suppuration

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiectasis; Bronchiolitis; Bronchiolitis Obliterans; Haemophilus Infections; Humans; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Clarithromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Membrane Transport Proteins; Microbial Sensitivity Tests

This study was performed in children with adenotonsillar hypertrophy to evaluate the effect of azithromycin (AZT) on the presence of NTHi in monocyte/macrophages (CD14(+) cells) of adenoids/tonsils and the persistence of NTHi after adenotonsillectomy. A total of 36 pediatric patients participated in the study: 20 children were treated with AZT before adenotonsillectomy, and 16 children did not receive the antibiotic prior to surgery. NTHi were identified by culture and PCR in swabs and tissue samples. NTHi was detected in the lysates of CD14(+) cells by fluorescence in situ hybridization (FISH) and by culture. The molecular typing was used to cluster NTHi isolates from each child. The intracellular NTHi was found in 10 (62.5%) untreated patients and was identified in three (15%) azithromycin-treated patients (P = 0.003). The proportion of the persistent NTHi strains was similar in both groups. AZT treatment followed by adenotonsillectomy did not completely eliminate NTHi from pharynges; however, it significantly reduced the risk of carriage of Haemophilus influenzae inside the CD14(+) cells.

Topics: Anti-Bacterial Agents; Azithromycin; Carrier State; Child; Child, Preschool; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Hypertrophy; Lymph Nodes; Male; Molecular Typing; Palatine Tonsil; Pharynx; Prospective Studies

Acute otitis media, inflammation of the middle ear, is the most common bacterial infection in children and, as a consequence, is the most common reason for antimicrobial prescription to this age group. There is currently no effective vaccine for the principal pathogen involved, non-typeable Haemophilus influenzae (NTHi). The most frequently used and widely accepted experimental animal model of middle ear infection is in chinchillas, but mice and gerbils have also been used. We have established a robust model of middle ear infection by NTHi in the Junbo mouse, a mutant mouse line that spontaneously develops chronic middle ear inflammation in specific pathogen-free conditions. The heterozygote Junbo mouse (Jbo/+) bears a mutation in a gene (Evi1, also known as Mecom) that plays a role in host innate immune regulation; pre-existing middle ear inflammation promotes NTHi middle ear infection. A single intranasal inoculation with NTHi produces high rates (up to 90%) of middle ear infection and bacterial titres (10(4)-10(5) colony-forming units/µl) in bulla fluids. Bacteria are cleared from the majority of middle ears between day 21 and 35 post-inoculation but remain in approximately 20% of middle ears at least up to day 56 post-infection. The expression of Toll-like receptor-dependent response cytokine genes is elevated in the middle ear of the Jbo/+ mouse following NTHi infection. The translational potential of the Junbo model for studying antimicrobial intervention regimens was shown using a 3 day course of azithromycin to clear NTHi infection, and its potential use in vaccine development studies was shown by demonstrating protection in mice immunized with killed homologous, but not heterologous, NTHi bacteria.

Topics: Animals; Azithromycin; Disease Models, Animal; Haemophilus Infections; Haemophilus influenzae; Heterozygote; Immunity, Innate; Inflammation; Mice; Mice, Inbred C3H; Mice, Mutant Strains; Microspheres; Mutation; Otitis Media; Signal Transduction; Stem Cells

The bacteria Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib) are leading causes of childhood pneumonia and meningitis and are major contributors to worldwide mortality in children younger than 5 years of age. Asymptomatic nasopharyngeal carriage of pneumococcus and Hib was determined for healthy children in Shanghai in 2009.. Children from 5 immunization clinics were enrolled in this study. Specimens from the nasopharynx were collected and cultured in Columbia and chocolate agar to identify pneumococcal and Hib carriage. Pneumococcal specimens were serotyped with the Neufeld test, and antibiotic resistance for pneumococcal and Hib specimens used the E-test method. Significance of risk factors for carriage was assessed through chi-square tests.. Among 614 children, 16.6% had pneumococcal carriage and 8.0% Hib carriage. The predominant serotype of pneumococcus that was isolated was 19 F (52.9%); serotype coverage was 68.6% for both 7-valent pneumococcal conjugate vaccine (PCV) and PCV-10, and 82.3% for PCV-13. Household residency and father's education were both significantly related to pneumococcal and Hib carriage. The majority of S. pneumoniae isolates were sensitive to most antimicrobials but there were high levels of resistance to azithromycin (51.0 %) and erythromycin (51.0%). Haemophilus influenzae isolates were sensitive to almost all antimicrobials tested although 12.2% of isolates were resistant to ampicillin.. The pneumococcal and Hib vaccines require payment, and the children with the highest burden of disease may not be receiving these vaccines. Moreover, the presence of high antibiotic susceptibility towards pneumococcus, and to a lesser extent towards Hib, underscores the need for preventive protection against these diseases. Public funding of pneumococcal and Hib vaccines would be one mechanism to increase uptake of these vaccines.

Topics: Anti-Infective Agents; Azithromycin; China; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Female; Haemophilus Infections; Haemophilus influenzae type b; Humans; Infant; Male; Microbial Sensitivity Tests; Nasopharynx; Odds Ratio; Pneumococcal Infections; Streptococcus pneumoniae

Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti-inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection.

Topics: Animals; Azithromycin; Cell Line; Epithelial Cells; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Macrophages, Alveolar; Mice; Respiratory Tract Infections

Diffuse panbronchiolitis is a progressive fatal respiratory disease of unknown cause seen predominantly in Southeast Asian adults. We report this condition in a 10-year-old child of Korean birth because of the uncommon presentation at this age and the favorable outcome associated with early diagnosis. Our objective was also to demonstrate the gradual but complete resolution of the disease and sustained remission from early institution of azithromycin.

Topics: Anti-Bacterial Agents; Asian People; Azithromycin; Bronchiolitis; Child; Haemophilus Infections; Humans; Male

Topics: Amoxicillin; Animals; Anti-Bacterial Agents; Asthma; Azithromycin; Bronchiolitis Obliterans; Chlamydophila Infections; Clarithromycin; Female; Haemophilus Infections; Humans; Lung Transplantation; Male

Glucocorticosteroids are used as a main treatment to reduce airway inflammation in people with asthma who suffer from neutrophilic airway inflammation, a condition frequently associated with Haemophilus influenzae colonization. Here we show that glucocorticosteroids have a direct influence on the behavior of H. influenzae that may account for associated difficulties with therapy. Using a mouse model of infection, we show that corticosteroid treatment promotes H. influenzae persistence. Transcriptomic analysis of bacteria either isolated from infected mouse airway or grown in laboratory medium identified a number of genes encoding regulatory factors whose expression responded to the presence of glucocorticosteroids. Importantly, a number of these corticosteroid-responsive genes also showed elevated expression in H. influenzae within sputum from asthma patients undergoing steroid treatment. Addition of corticosteroid to H. influenzae led to alteration in biofilm formation and enhanced resistance to azithromycin, and promoted azithromycin resistance in an animal model of respiratory infection. Taken together, these data strongly suggest that H. influenzae can respond directly to corticosteroid treatment in the airway potentially influencing biofilm formation, persistence and the efficacy of antibiotic treatment.

Topics: Animals; Anti-Bacterial Agents; Asthma; Azithromycin; Biofilms; Disease Models, Animal; Drug Resistance, Bacterial; Gene Expression Profiling; Glucocorticoids; Haemophilus Infections; Haemophilus influenzae; Humans; Mice; Sputum

Macrolide antibiotics, like erythromycin, clarithromycin, and azithromycin, possess anti-inflammatory properties. These properties are considered fundamental to the efficacy of these three macrolides in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, long-term treatment with macrolide antibiotics presents a considerable risk for promotion of bacterial resistance. We have examined antibacterial and anti-inflammatory effects of a novel macrolide class: N'-substituted 2'-O,3'-N-carbonimidoyl bridged erythromycin-derived 14- and 15-membered macrolides. A small focused library was prepared, and compounds without antimicrobial activity, which inhibited IL-6 production, were selected. Data analysis led to a statistical model that could be used for the design of novel anti-inflammatory macrolides. The most promising compound from this library retained the anti-inflammatory activity observed with azithromycin in lipopolysaccharide-induced pulmonary neutrophilia in vivo. Importantly, this study strongly suggests that antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, which raises development plausibility of novel anti-inflammatory therapeutics.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Azithromycin; Bronchiolitis; Bronchoalveolar Lavage Fluid; Cell Line; Clarithromycin; Cystic Fibrosis; Drug Interactions; Drug Resistance, Bacterial; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Interleukin-6; Lipopolysaccharides; Lung; Macrolides; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Moraxella catarrhalis; Neutrophils; Rats; Rats, Sprague-Dawley; Streptococcus

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

A 67-year-old never-smoker was diagnosed with diffuse panbronchiolitis (DPB) and was started on 250 mg azithromycin twice weekly. Over a 16-month observation period, lung function was assessed monthly, including a dedicated small airways test, the multiple breath nitrogen washout (MBW) with indices S(cond) and S(acin) of ventilation heterogeneity at the level of the conductive and acinar air spaces, respectively. Baseline measurements indicated moderate airway obstruction, air trapping and considerable dysfunction of the small airways around the acinar entrance. Treatment resulted in excellent symptomatic improvement paralleled by marked improvements in FEV(1), FVC, RV/TLC, S(cond) and S(acin); by contrast, there were no consistent changes in FEF(75) or TL(CO). While improvements were such that S(cond) fell within normal limits after 5 months, S(acin) remained abnormal even after 16 months of treatment. This suggests a distinct acinar structural abnormality in DPB that cannot be reversed by azithromycin.

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Breath Tests; Bronchiolitis; Haemophilus Infections; Humans; Male; Nitrogen; Spirometry; Treatment Outcome

to determine the mechanism(s) of macrolide resistance in Haemophilus influenzae isolated from cystic fibrosis (CF) patients participating in a randomized placebo-controlled trial of azithromycin.. macrolide susceptibility, mutations and carriage of the macrolide resistance genes erm(A), erm(B), erm(C), erm(F) and mef(A) were determined using PCR assays and sequencing or hybridization of the PCR products. H. influenzae isolates were used as donors in conjugation studies with H. influenzae and Enterococcus faecalis recipients. Transconjugant susceptibility and the macrolide resistance genes carried were determined.. of the 106 H. influenzae isolates, 27 were resistant and 78 intermediate resistant to azithromycin and/or erythromycin. All isolates carried one or more macrolide resistance gene(s), with the mef(A), erm(B) and erm(F) genes found in 74%, 31% and 29% of the isolates, respectively. None of the selected isolates had L4 or L22 mutations. Twenty-five donors, with various macrolide MICs, transferred macrolide resistance genes to H. influenzae Rd (3.5 × 10(-7)-1 × 10(-10)) and/or E. faecalis (1 × 10(-7)-1 × 10(-8)) recipients. The H. influenzae transconjugants were phenotypically resistant or intermediate to both macrolides while E. faecalis transconjugants were erythromycin resistant.. this is the first identification of erm(A), erm(C) and erm(F) genes in H. influenzae or bacteria from CF patients and the first characterization of macrolide gene transfer from H. influenzae donors. The high level of H. influenzae macrolide gene carriage suggests that the use of azithromycin in the CF population may ultimately reduce the effectiveness of continued or repeated macrolide therapy.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Conjugation, Genetic; Cystic Fibrosis; DNA, Bacterial; Drug Resistance, Bacterial; Gene Transfer, Horizontal; Genes, Bacterial; Haemophilus Infections; Haemophilus influenzae; Humans; Macrolides; Microbial Sensitivity Tests; Nucleic Acid Hybridization; Polymerase Chain Reaction; Prevalence; Randomized Controlled Trials as Topic; Sequence Analysis, DNA

Patients with diffuse panbronchiolitis (DPB) are routinely treated with erythromycin, clarithromycin, and roxithromycin. The clinical effect of azithromycin on DPB has not been confirmed in a large cohort.. The present study was undertaken to investigate the clinical effects of azithromycin on patients with DPB.. Fifty-one patients with DPB treated with azithromycin in Shanghai Pulmonary Hospital, China, from July 2001 to April 2007 were analyzed retrospectively. Azithromycin (500 mg a day) was administrated intravenously in the first 1-2 weeks, taken orally (500 mg, once a day) for 3 months, and tapered to 3 times a week for 6-12 months. The patients were followed up until September 1, 2009. The therapeutic effect, according to their clinical and radiological findings, arterial gas analysis, lung function, and sputum bacterium before and after the therapy, was categorized into the following five grades: 1) cured; 2) improved; 3) no response; 4) aggravation, and 5) relapse.. With azithromycin therapy, 14 (27.5%) patients with DPB were completely cured. The symptoms were eliminated to certain degrees for the other 36 cases (70.6%) of DPB. Five-year survival in this cohort was 94.1%.. Azithromycin is effective and well tolerated for patients with diffuse panbronchiolitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asian People; Azithromycin; Bronchiolitis; Child; Cohort Studies; Female; Follow-Up Studies; Haemophilus Infections; Humans; Male; Middle Aged; Retrospective Studies; Young Adult

The aim of this study is to examine the internalization of nontypeable Haemophilus influenzae (NTHi) into human epithelial cells.. Bactericidal assay was applied to examine the effects of antibiotics against cell-adherent NTHi using HEp-2 cells. A trans-well chamber assay was applied to examine the internalization and penetration of NTHi using Detroit562 cells.. The adherence of NTHi to HEp-2 cells was noted after 2h of incubation. Azithromycin had a strong bactericidal effect against both cell-associated and non-adherent NTHi, while ceftriaxone did not show bactericidal effects on NTHi adhered to the HEp-2 cells. Three (60.0%) out of five NTHi isolates from the nasopharynx of children with intractable acute otitis media (AOM) internalized into and subsequently penetrated through the epithelial cells at various degrees. Azithromycin had a strong bactericidal effect against the cell-internalized NTHi, while ceftriaxone was bactericidal only against extracellular NTHi.. The potential of NTHi as the intracellular pathogen may contribute to the persistent existence of this pathogen that result in the prolonged and intractable clinical course of AOM. Azithromycin may be a therapeutically significant antibiotic for patients with prolonged respiratory tract infections due to NTHi.

Topics: Acute Disease; Anti-Bacterial Agents; Azithromycin; Bacterial Adhesion; Bacterial Physiological Phenomena; Ceftriaxone; Cell Line; Child; Dose-Response Relationship, Drug; Epithelial Cells; Gentamicins; Haemophilus Infections; Haemophilus influenzae; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Microbial Viability; Otitis Media with Effusion

Nontypeable Haemophilus influenzae (NTHi) is one of the most common pathogens in chronic airway infections and exacerbation. The hallmark of chronic respiratory diseases, including cystic fibrosis, diffuse panbronchiolitis and chronic obstructive pulmonary disease, is mucin overproduction. Prolonged macrolide antibiotic therapy at low doses is known to improve clinical outcome in patients with chronic respiratory diseases via anti-inflammatory effects. In this study, we investigated the effects of macrolide therapy on NTHi-induction of the MUC5AC mucin in human airway epithelial cells. A 15-membered macrolide, azithromycin, but not a 14-membered macrolide, clarithromycin, inhibited NTHi-induction of MUC5AC at both the mRNA and protein levels through selective suppression of activation of the transcription factor activator protein-1. Our findings suggest that each macrolide affects MUC5AC production in different ways and that azithromycin is more suitable for the treatment of NTHi-induced respiratory infection.

Topics: Anti-Bacterial Agents; Azithromycin; Cell Line, Tumor; Clarithromycin; Epithelial Cells; Haemophilus Infections; Haemophilus influenzae; Humans; Mucin 5AC; RNA, Messenger; Transcription Factor AP-1

Haemophilus influenzae is one of the main aetiological agents of community-acquired respiratory tract infections. The primary aim of this study was to evaluate the antibacterial activity of telithromycin against H. influenzae clinical isolates showing different pattern of resistance in comparison with azithromycin and clarithromycin at 1/4 x, 1/2 x, 1 x, 2 x, 4 x minimum inhibitory concentration (MIC) and to peak concentrations in epithelial lining fluid (ELF). The secondary aim was to determine the influence of CO2 enriched atmosphere on bacterial susceptibility.. Telithromycin showed high activity against H. influenzae, including strains susceptible to beta-lactams (n = 200), beta-lactamase producer (n = 50) and beta-lactamase negative ampicillin resistant (BLNAR) (n = 10), with MIC from < or =0.03 to 4 mg/L, and MIC50/MIC90 of 1/2 mg/L with susceptibility rate of 100%, and minimum bactericidal concentrations (MBC) from 2 to 4-fold higher than the MIC. Azithromycin was the most active tested macrolide (range: 0.25 - 4 mg/L; MIC50/MIC90: 1/2 mg/L), comparable to telithromycin, while clarithromycin showed the highest MICs and MBCs (range: 0.25 - 8 mg/L; MIC50/MIC90: 2/8 mg/L). In time-kill studies, telithromycin showed a bactericidal activity at the higher concentrations (4 - 2 x MIC and ELF) against all the strains, being complete after 12 - 24 hours from drug exposition. At MIC concentrations, at ambient air, bactericidal activity of telithromycin and azithromycin was quite similar at 12 hours, and better than that of clarithromycin. Besides, telithromycin and clarithromycin at ELF concentrations were bactericidal after 12 hours of incubation for most strains, while 24 hours were needed to azithromycin to be bactericidal. Incubation in CO2 significantly influenced the MICs and MBCs, and only slightly the in vitro killing curves.. Telithromycin showed an in-vitro potency against H. influenzae comparable to azithromycin, with an in-vitro killing rate more rapid and superior to clarithromycin at 2X-MIC against beta-lactamase producers and BLNAR strains, and to azithromycin at ELF concentrations against beta-lactamase negative strains. Against all strains, MICs and MBCs were lower in the absence of CO2 for the tested antibiotics, showing an adverse effect of incubation in a CO2 environment. The in-vitro potency together with the tissue concentrations of the antimicrobial, should be considered in predicting efficacy.

Topics: Anti-Bacterial Agents; Azithromycin; beta-Lactamases; Carbon Dioxide; Clarithromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Microbial Sensitivity Tests; Respiratory Tract Infections; Time Factors

The bacterial time-kill curves of azithromycin against four bacterial strains (Streptococcus pneumoniae/penicillin-intermediate, S. pneumoniae/penicillin-sensitive, Haemophilus influenzae and Moraxella catarrhalis) were determined by in vitro infection models. Eighteen different pharmacokinetic/pharmacodynamic models were fitted to the time-kill data using non-linear regression and compared for best fit. A simple, widely used E(max) model was not sufficient to describe the pharmacodynamic effects for the four bacterial strains. Appropriate models that gave good curve fits included additional terms for saturation of the number of bacteria (N(max)), delay in the initial bacterial growth phase and/or the onset of anti-infective activity (1-exp(-zt)) as well as a Hill factor (h) that captures the steepness of the concentration-response profile. Azithromycin was highly effective against S. pneumoniae strains and M. catarrhalis while the efficacy against H. influenzae was poor. Applications of these pharmacokinetic/pharmacodynamic models will eventually provide a tool for rational antibiotic dosing regimen decisions.

Topics: Anti-Bacterial Agents; Azithromycin; Bacteria; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Models, Biological; Moraxella catarrhalis; Moraxellaceae Infections; Penicillin Resistance; Pneumococcal Infections; Streptococcus pneumoniae

This study investigated the presence of telithromycin and azithromycin efflux in 58 clinical strains of Haemophilus influenzae with various susceptibilities to macrolides, azalides, and ketolides. Efflux pumps were studied by measuring accumulation of radioactive [3H]telithromycin and [N-methyl-3H]azithromycin in the presence and absence of carbonyl m-chlorophenylhydrazone (CCCP), a protonophore. In 17 strains for which the telithromycin MICs were 0.06 to 0.5 microg/ml (azithromycin MICs, < or = 0.06 to 0.125 microg/ml; clarithromycin MICs, < or = 0.06 to 2 microg/ml), telithromycin and azithromycin accumulations were high without CCCP and not affected by its addition, which indicates absence of efflux. In 22 strains for which the telithromycin MICs were 0.25 to 4 microg/ml (azithromycin MICs, 0.25 to 1 microg/ml; clarithromycin MICs, 1 to 8 microg/ml), initially low levels of telithromycin accumulation became higher after addition of CCCP, indicating a functioning efflux pump. Nineteen strains for which the telithromycin MICs were > or = 2 microg/ml had efflux as well as various mutations in ribosomal proteins L4, L22, and/or 23S rRNA (domains II and V). Of these 19 strains, the telithromycin MICs (> or = 8 microg/ml) for 17 of them were significantly raised (azithromycin, MICs 4 to >32 microg/ml; clarithromycin MICs, 8 to >32 microg/ml). From these results we conclude that telithromycin efflux with or without additional ribosomal alterations is present in all H. influenzae strains, except for those for which the telithromycin MICs were very low.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Drug Resistance, Microbial; Haemophilus Infections; Haemophilus influenzae; Ketolides; Macrolides; Microbial Sensitivity Tests; Time Factors

As a result of the prolonged half-life and unique pharmacokinetic and pharmacodynamic (PK-PD) characteristics of azithromycin, shorter dosing regimens are being evaluated for the treatment of community-acquired infections. To provide further support for a shorter dosing regimen, the efficacy of azithromycin was determined in preclinical infection models comparing single- versus multi-dose regimens.. The efficacy of single versus multi-dose regimens of azithromycin was compared in mouse pneumonia, acute peritonitis, and neutropenic thigh infection models and in a gerbil model of Haemophilus influenzae acute otitis media. Azithromycin was administered as a single oral dose on the first treatment day, or as two divided doses over 2 treatment days, or as three divided doses over 3 treatment days. The pharmacokinetics of azithromycin was profiled following single and multi-dose regimens with the single dose data fit to an Emax model to characterize the PK-PD of azithromycin.. In the mouse efficacy models, administration of single-dose azithromycin produced superior rates of survival and bacterial clearance compared with the same total dose divided over 2 or 3 days. In the gerbil model, a single dose sterilized the middle ear and more rapidly cleared H. influenzae. The pharmacokinetic evaluation confirmed similar total exposure (AUC) in serum and pulmonary tissue for the three regimens. Correlation of PK-PD parameters and antimicrobial efficacy confirmed a concentration-dependent and dosing-independent relationship for azithromycin.. These data are consistent with data reported from clinical studies and indicate that a single-dose regimen would be at least as effective as the same dose administered over several days.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Azithromycin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Enterococcus faecalis; Female; Gerbillinae; Gram-Positive Bacterial Infections; Haemophilus Infections; Haemophilus influenzae; Metabolic Clearance Rate; Mice; Mice, Inbred DBA; Streptococcus pneumoniae; Streptococcus pyogenes

Topics: Adult; Azithromycin; Community-Acquired Infections; Delayed-Action Preparations; Drug Interactions; Haemophilus Infections; Humans; Pneumonia; Sinusitis

This study investigated macrolide resistance mechanisms in clinical Haemophilus influenzae strains with different levels of susceptibility to macrolides. A total of 6,382 isolates were collected during the Alexander Project from 1997 to 2000. For 96.9% of these isolates, the azithromycin MICs were 0.25 to 4 micro g/ml, and these were defined as baseline strains. For 1.8% of the isolates, the azithromycin MICs were lower (<0.25 micro g/ml), and for 1.3% of the isolates, the MICs were higher (>4 micro g/ml). These isolates were defined as hypersusceptible and high-level macrolide-resistant strains, respectively. To identify the mechanisms associated with these three susceptibility patterns, representative strains were studied for the presence of macrolide efflux pumps and for ribosomal alterations. Macrolide efflux was studied by measuring the accumulation of radioactive azithromycin and clarithromycin in the presence or absence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a protonophore. Treatment with CCCP increased the accumulation of macrolides in baseline as well as high-level resistant strains, demonstrating the presence of an efflux mechanism, but not in the 20 hypersusceptible strains tested. Among the 31 strains studied that showed high-level resistance to both azithromycin and clarithromycin, 28 had ribosomal alterations, 7 had mutations in ribosomal protein L4, 11 had mutations in L22, 2 had mutations in 23S rRNA, 8 had multiple mutations, and 3 had no mutations. From these results, we conclude that the vast majority (>98%) of H. influenzae strains have a macrolide efflux mechanism, with a few of these being hyperresistant (1.3%) due to one or several ribosomal mutations. Occasional hypersusceptible strains (1.8%) were found and had no macrolide resistance mechanisms and appeared to be the only truly macrolide-susceptible variants of H. influenzae.

Topics: Anti-Bacterial Agents; Azithromycin; Clarithromycin; Drug Resistance, Bacterial; Genes, Bacterial; Haemophilus Infections; Haemophilus influenzae; Humans; Microbial Sensitivity Tests; Mutation; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes

Among respiratory tract isolates of Streptococcus pneumoniae from children, resistance to penicillins, cephalosporins, macrolides, and trimethoprim-sulfamethoxazole (SXT) increases on an annual basis. Pediatric patients who do not respond to conventional therapy for respiratory tract infections someday may be treated with fluoroquinolones. In this study, MICs of beta-lactams, azithromycin, SXT, and levofloxacin were determined and interpreted by using NCCLS guidelines for isolates of S. pneumoniae (2,834 from children and 10,966 from adults), Haemophilus influenzae (629 from children and 2,281 from adults), and Moraxella catarrhalis (389 from children and 1,357 from adults) collected during the 2000-2001 and 2001-2002 respiratory illness seasons in the United States as part of the ongoing TRUST surveillance studies. Rates of resistance to penicillin, azithromycin, and SXT were > or = 7.5% higher among patients < or = 4 years old than among patients 5 to 10, 11 to 17, and > or = 18 years old in both the 2000-2001 and the 2001-2002 respiratory illness seasons. Levofloxacin resistance was detected in 2 of 2,834 isolates (0.07%) from patients <18 years old. Levofloxacin MICs of 0.25 to 1 micro g/ml accounted for 99.6, 99.5, 99.3, 99.7, 98.4, and 98.0% of isolates from patients < 2, 2 to 4, 5 to 10, 11 to 17, 18 to 64, and > 64 years old. Multidrug resistance was twice as common among patients < or = 4 years old (25.3%) as among patients 5 to 10 years old (13.7%), 11 to 17 years old (11.9%), 18 to 64 years old (12.1%), and > 64 years old (12.4%). The most common multidrug resistance phenotype in S. pneumoniae isolates for all age groups was resistance to penicillin, azithromycin, and SXT (70.3 to 76.6%). For H. influenzae and M. catarrhalis isolates from patients < 2, 2 to 4, 5 to 10, 11 to 17, 18 to 64, and > 64 years old, levofloxacin MICs at which 90% of the isolates were inhibited were 0.015 and 0.03 to 0.06 microg/ml, respectively, in the 2000-2001 and 2001-2002 respiratory illness seasons. In the 2000-2001 and 2001-2002 respiratory illness season surveillance studies in the United States, 99.9% of pediatric isolates of S. pneumoniae were susceptible to levofloxacin. If fluoroquinolones become a treatment option for pediatric patients, careful monitoring of fluoroquinolone susceptibilities will be increasingly important in future surveillance studies.

Topics: Adolescent; Adult; Aged; Anti-Infective Agents; Azithromycin; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Haemophilus Infections; Haemophilus influenzae; Humans; Infant; Lactams; Levofloxacin; Microbial Sensitivity Tests; Middle Aged; Moraxella catarrhalis; Ofloxacin; Pneumococcal Infections; Prospective Studies; Respiratory Tract Infections; Streptococcus pneumoniae; Trimethoprim, Sulfamethoxazole Drug Combination; United States

Treatment of acute otitis media (AOM) with azithromycin results in apparent clinical success, but tympanocentesis performed 4 to 6 days after initiation of therapy in children with nontypeable Haemophilus influenzae (NTHI) recovered from initial middle ear cultures demonstrates persistence of infection in more than 50% of episodes. We sought to determine the effect of azithromycin at different doses on the density of middle ear infection due to NTHI to provide additional understanding of this dichotomy between clinical and microbiologic outcome measures in AOM. In a chinchilla model of experimental otitis media (EOM), animals treated with placebo were compared to animals receiving a single daily dose 30 or 120 mg of azithromycin per kg of body weight per day for 5 days. Microbiologic outcome was assessed by obtaining quantitative cultures from the middle ear during a 5-day course and for 1 week following therapy. Azithromycin concentrations were measured to ascertain whether a concentration-dependent effect was present. Azithromycin at 30 and 120 mg/kg/day demonstrated a dose-dependent effect on the quantitative assessment of middle ear infection due to NTHI. A 30-mg/kg dose of azithromycin daily resulted in levels in serum and areas under the serum concentration-time curve at 24 h comparable to published data obtained with children given azithromycin at 5 to 10 mg/kg in multiday regimens. Increased doses of azithromycin (120 mg/kg) achieved 2.5- to 4-fold-higher levels in serum and 3- to 6-fold-higher total levels and levels in extracellular middle ear fluid as well as more rapid reduction in bacterial density and a greater proportion of middle ears with complete sterilization than either placebo or the 30-mg/kg/day regimen.

Topics: Acute Disease; Animals; Azithromycin; Chinchilla; Dose-Response Relationship, Drug; Haemophilus Infections; Haemophilus influenzae; Otitis Media

Topics: Anti-Bacterial Agents; Azithromycin; Community-Acquired Infections; Drug Resistance, Bacterial; Haemophilus Infections; Haemophilus influenzae; Humans; Infant; Male; Penicillin Resistance; Pneumococcal Infections; Pneumonia, Bacterial; Respiratory Tract Infections; Streptococcus pneumoniae

The National Committee for Clinical Laboratory Standards standard broth microdilution method for testing the susceptibility of Haemophilus influenzae to ampicillin, azithromycin, clarithromycin, and telithromycin was evaluated by altering one variable at a time. Variables that were tested included age of colony for inoculum preparation, inoculum density, test medium, incubation atmosphere, and incubation time. For the macrolide, azalide, and ketolide agents, incubation in 5 to 7% CO(2) most significantly affected the MICs, producing nearly twofold increases for clarithromycin and telithromycin and a greater than threefold increase for azithromycin. For ampicillin, a 10-fold increase in inoculum density increased the geometric mean MICs for beta-lactamase-negative strains from 1. 50 to 2.45 microg/ml. In addition, 206 H. influenzae strains were tested for their susceptibilities to the same drugs by the broth microdilution tests in two media, as well as by agar dilution tests, disk diffusion tests, and Etests, on six different agar media. The three standard methods with Haemophilus test medium (HTM) compared favorably with each other except for a high minor discrepancy rate (27%) by the disk diffusion test with ampicillin and clarithromycin. Agar dilution test MICs on the five comparative media were generally higher than those on HTM agar but were only rarely more than one twofold concentration higher. Etest MICs of azithromycin and telithromycin were more than twofold higher than agar dilution and broth microdilution MICs on HTM; ampicillin Etest MICs were nearly twofold lower. The use of media other than HTM agar appears to have a minimal effect on susceptibility test results for the ketolide, azalide, or macrolide drugs that we tested against H. influenzae.

Topics: Ampicillin; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Culture Media; Haemophilus Infections; Haemophilus influenzae; Humans; Ketolides; Macrolides; Microbial Sensitivity Tests; Quality Control

Azithromycin is an azalide with potent activity against Haemophilus influenzae including ampicillin-resistant strains. We evaluated the efficacy of azithromycin, clarithromycin and three beta -lactams when used for 1 day only and for 3 days for the treatment of a murine model of bronchopneumonia, using three strains of H. influenzae, two of which were ampicillin resistant. MICs of azithromycin (1-2 mg/L) and clarithromycin (4-8 mg/L) were similar for the three strains. The MICs of cefdinir and cefcapene for beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae were 32 times higher than those for beta-lactamase-positive ampicillin-resistant and ampicillin-susceptible strains. The viable counts in the infected tissues of azithromycin-treated mice with bronchopneumonia caused by the susceptible strain TUM8, beta-lactamase-positive strain TUH36 and BLNAR strain TUH267 were less than the counts obtained with the other antibiotics used, irrespective of MIC. At a dose of 50 mg/kg, the area under the concentration curve and the half-life of azithromycin in the lungs were respectively three times higher and six times longer than those of clarithromycin. Our results indicate that azithromycin may be useful for both ampicillin-susceptible and ampicillin-resistant bronchopneumonial infections caused by H. influenzae.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; beta-Lactams; Bronchopneumonia; Clarithromycin; Disease Models, Animal; Haemophilus Infections; Haemophilus influenzae; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Treatment Outcome

The in vitro activities of erythromycin, azithromycin, and clarithromycin against 178 clinical isolates from the lower respiratory tract of patients with chronic obstructive pulmonary disease were determined by an agar dilution method. The plates were incubated in air alone or in 5% carbon dioxide. The MICs measured in air alone were lower for most isolates than those measured in 5% carbon dioxide, illustrating the "pH effect" of incubation in carbon dioxide. Testing of isolates in 5% carbon dioxide on pH-adjusted medium (pH 8.4) resulted in MICs of one or two doubling dilutions lower than those obtained on agar with a neutral pH. A bioassay of the three agents incubated in air and in 5% carbon dioxide resulted in a significant loss of activity of all three agents in the carbon dioxide-enriched atmosphere. However, this loss-of-activity effect was significantly reduced when the bioassay medium was adjusted to pH 8.4 prior to incubation in 5% carbon dioxide.

Topics: Anti-Bacterial Agents; Azithromycin; Carbon Dioxide; Clarithromycin; Colony Count, Microbial; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Hydrogen-Ion Concentration; Lung Diseases, Obstructive; Microbial Sensitivity Tests; Moraxella catarrhalis; Neisseriaceae Infections; Pneumococcal Infections; Sputum; Streptococcus pneumoniae

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

The dynamics of clarithromycin and azithromycin efficacy against pulmonary Haemophilus influenzae infection in rats were evaluated. Efficacy was measured by reduction in pulmonary H. influenzae burden on days 3 and 7 postinoculation. Clarithromycin therapy was effective on day 3 or 7 of therapy, while azithromycin was effective on day 7 but not on day 3 of therapy. Both macrolides produced marked efficacy against all six strains of H. influenzae tested, including four strains for which MICs were above the susceptible breakpoint (8 microgram/ml) concentration of clarithromycin. The two macrolides demonstrated markedly different pharmacokinetic characteristics, with clarithromycin present in both blood and tissue, while azithromycin was concentrated primarily in tissue. During pulmonary infection in rats, H. influenzae was found in both intracellular locations and an extracellular location in the lung. Blood concentrations of clarithromycin and azithromycin approximated human pharmacokinetics, and the blood concentrations for either macrolide rarely exceeded MICs for H. influenzae. At dosages producing blood concentrations similar to values achieved clinically, clarithromycin produced efficacy on day 3 of therapy, while both clarithromycin and azithromycin were equally effective on day 7. The different dynamics of clarithromycin and azithromycin suggest that length of therapy should be considered as a key parameter in evaluations of drug efficacy.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Haemophilus Infections; Haemophilus influenzae; Lung Diseases; Rats; Rats, Sprague-Dawley

Azithromycin reaches high concentrations in phagocytic and other host cells, suggesting that they may transport this agent to specific sites of infection. Models of localized infection (Haemophilus influenzae middle ear infection in gerbils, Streptococcus pyogenes implanted contaminated paper disc and Streptococcus pneumoniae pneumonia in mice) that induced severe inflammatory response after challenge were used to explore this hypothesis. Animals were given a single 100 or 50 mg/kg po dose of azithromycin at various times from 2 to 120 h following introduction of a pathogen or sterile medium. When azithromycin was given during a period of little or no inflammation, there was marginal difference between concentrations found in infected or non-infected sites (bulla, disc, lung). However, when the compound was given during a period of inflammation, considerably higher drug concentrations were found in infected sites than in non-infected sites at 5-24 h after dosing (0.38-0.44 mg/c compared with 0.07-0.14 mg/L of bulla wash; 1.01-1.75 micrograms compared with < or = 0.01-0.03 microgram at the disc site; 1.72-5.28 mg/kg compared with 0.7-1.53 mg/kg of lung). When the observation periods were extended to include 48, 56 or 96 h after dosing, the ratio of azithromycin infection site concentration: serum concentration steadily increased with time in all model systems (middle ear, implanted disc and pneumonia), reflecting the maintenance of concentrations at the sites of infection, while serum concentrations declined. Bioassay of cell pellets and supernatants, obtained from pooled bulla washes of gerbils treated with azithromycin during a period of inflammation, revealed that cellular components accounted for about 75% of the azithromycin detected. These data show that increased azithromycin concentrations occur at sites of localized infection. This correlates with the presence of inflammation and is associated with the cellular components of the inflammatory response. Therefore, phagocytes may be important vehicles for delivering azithromycin to and sustaining azithromycin concentrations at sites of infection.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bacterial Infections; Blister; Female; Gerbillinae; Haemophilus Infections; Haemophilus influenzae; Lung; Male; Mice; Otitis Media; Phagocytes; Pneumococcal Infections; Streptococcal Infections; Streptococcus pneumoniae; Streptococcus pyogenes

One hundred eighty consecutive, unduplicate isolates of Haemophilus influenzae from clinical specimens collected from November 1994 through February 1995 in nine general hospitals throughout Belgium were examined for beta-lactamase production using a nitrocefin-based test, and for their in vitro susceptibilities to ampicillin, amoxycillin/clavulanate, cefaclor, cefuroxime, cefotaxime, clarithromycin and azithromycin by means of the NCCLS agar dilution test. The isolates were all from respiratory tract specimens. The prevalence of capsular type b was 1.1%, and the overall rate of beta-lactamase production 16.7%. Rates of beta-lactamase production were higher in isolates from children (22.0%) than in those from adults (15.3%), and in isolates from upper respiratory tract specimens (22.0%) than in those from the lower respiratory tract (15.1%). Beta-lactamase-negative ampicillin resistance amounted to 1.1%. Cefotaxime had the highest activity on a weight basis [MIC (minimal inhibitory concentration) for 50% of the isolates tested (MIC50) < or = 0.06 microgram/ml], followed by ampicillin (MIC50 of 0.25 microgram/ml), amoxycillin/clavulanate and cefuroxime (MIC50 of 0.5 microgram/ml), azithromycin (MIC50 of 2 micrograms/ml), cefaclor (MIC50 of 4 micrograms/ml), and clarithromycin (MIC50 of 8 micrograms/ml). Cefotaxime was also the most active drug in terms of susceptibility rates of the isolates (100.0%), followed by amoxycillin/clavulanate and azithromycin (98.9%), cefuroxime (97.2%), cefaclor (89.4%), clarithromycin (82.8%), and ampicillin (82.2%). In conclusion, amoxycillin/clavulanate and cefuroxime retain an excellent activity against H. influenzae, while cefaclor lost some of its activity. The rate of susceptibility to azithromycin was markedly higher than that to clarithromycin; however, its ability to accumulate intracellularly while concentrations in serum and interstitial fluid remain low, should be considered, as it may represent a major drawback to its use in H. influenzae infections.

Topics: Adolescent; Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Azithromycin; Cefaclor; Cefotaxime; Cefuroxime; Child; Child, Preschool; Clarithromycin; Clavulanic Acids; Cross Infection; Haemophilus Infections; Haemophilus influenzae; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Middle Aged

The prevalence of penicillin-resistant Streptococcus pneumoniae and beta-lactamase-producing Haemophilus influenzae in otitis media infections is increasing; emergence of these pathogens has complicated treatment.. To evaluate the incidence of penicillin resistance and the in vitro activity of amoxicillin/clavulanate, cefaclor, loracarbef, cefixime, trimethoprim/sulfamethoxazole, azithromycin and clarithromycin in S. pneumoniae isolates. The in vitro activity of azithromycin, clarithromycin and cefaclor was also evaluated in beta-lactamase-positive and -negative isolates of H. influenzae.. Bacterial isolates of S. pneumoniae and H. influenzae were obtained by tympanocentesis and subsequent culture of middle ear effusion from children with acute otitis media enrolled in a multicenter trial. Susceptibility to test agents was assessed by disk diffusion and broth dilution techniques with criteria established by the National Committee for Clinical Laboratory Standards.. Nineteen (31%) of the 61 S. pneumoniae isolates were resistant to penicillin. A significantly lower percentage of the S. pneumoniae isolates were resistant to azithromycin (16%) and clarithromycin (11%) than to penicillin, amoxicillin/ clavulanate, cefaclor, loracarbef or cefixime (31% in all cases). Azithromycin was also more active than cefaclor and significantly more active than clarithromycin against the 55 H. influenzae isolates.. The susceptibility of resistant and nonresistant strains of S. pneumoniae to azithromycin and clarithromycin and of isolates of H. influenzae to azithromycin, coupled with penetration of azithromycin into the middle ear, may provide a significant advantage in the treatment of otitis media.

Topics: Anti-Bacterial Agents; Azithromycin; beta-Lactamases; Child; Clarithromycin; Haemophilus Infections; Haemophilus influenzae; Humans; Incidence; Microbial Sensitivity Tests; Otitis Media; Penicillin Resistance; Pneumococcal Infections; Streptococcus pneumoniae

We compared the activities of azithromycin and erythromycin against Haemophilus influenzae in a mouse model of nonparenchymatous lower respiratory tract infection. In vitro and in vivo efficacy data for both drugs were analyzed relative to their pharmacokinetics in lungs and in vivo uptake by phagocytes. Aged C57BL/6 mice (mean age, 15.1 +/- 1.9 months) were infected intratracheally with 10(8) CFU of H. influenzae serotype b. Oral drug administration was initiated 4 h after infection by various dosage regimens. In terms of bacterial killing in the lung, azithromycin was much more active than erythromycin (P less than 0.01). Its in vivo activity was also more durable after a single administration relative to the durability of three doses of erythromycin given at 6-h intervals. The MIC of azithromycin was eightfold lower than that of erythromycin, and better penetration and a longer half-life in lung tissue were achieved after a single oral administration. Phagocytes delivered increased amounts of both drugs to the infected lungs, particularly at the site of infection (bronchoalveolar airspaces), and detectable levels of azithromycin were maintained locally for long periods. The fact that the efficacy of azithromycin coincided with the arrival of large numbers of polymorphonuclear leukocytes within the airspaces suggests that active extracellular concentrations were provided by the release of azithromycin from these cells. This further supports the potential value of once-daily azithromycin regimens for the treatment of lower respiratory tract infections in humans, provided that inhibitory concentrations against common pathogens such as H. influenzae are maintained for adequate periods of time.

Topics: Administration, Oral; Animals; Azithromycin; Bronchoalveolar Lavage Fluid; Drug Evaluation, Preclinical; Erythromycin; Female; Haemophilus Infections; Haemophilus influenzae; Lung; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Models, Biological; Phagocytes; Respiratory Tract Infections

The efficacy of an investigational macrolide, azithromycin, in the treatment of acute otitis media consequent to an infection by a strain of beta-lactamase-producing Haemophilus influenzae, was evaluated using the chinchilla animal model. The results indicate that the azithromycin high-dosage (30 mg/kg/d) group has a significantly higher rate for effusion sterilization and resolution as compared with the other treatment groups. Unique pharmacokinetic properties of this investigational antimicrobial were demonstrated. Clinical trials using azithromycin for the treatment of upper respiratory tract infections, including otitis media, are warranted.

Topics: Acute Disease; Ampicillin; Animals; Azithromycin; Chinchilla; Disease Models, Animal; Erythromycin; Haemophilus Infections; Haemophilus influenzae; Otitis Media