zithromax and Pneumonia--Pneumococcal

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

Azithromycin, a recently introduced antibiotic, offers the potential advantages of short-course administration and lower toxicity compared to other macrolides. Approved for the treatment of mild pneumonia, this drug was investigated in a study of patients hospitalized for community-acquired pneumonia. In an open-labelled randomized study, oral azithromycin was compared with intravenous benzylpenicillin in patients suspected to have pneumococcal pneumonia. Azithromycin was also compared with erythromycin, both administered orally, in all other patients. Three hundred thirty-four patients with community-acquired pneumonia were hospitalized, 108 of whom were randomized; 104 could be evaluated. A need for intravenous therapy was the most common reason for exclusion. In the pneumococcal group, 35 patients received azithromycin and 29 benzylpenicillin. The clinical and radiological success rate achieved with azithromycin (83%) was considerably higher than that achieved with benzylpenicillin (66%), though the difference was not significant. In the non-pneumococcal group, 19 patients received azithromycin and 21 erythromycin; no differences in the success rate were found (79% and 76%, respectively). Eight patients on azithromycin had a blood culture positive for Streptococcus pneumoniae; in three of these patients therapy was changed. None of the five patients with pneumococcal bacteraemia who received benzylpenicillin required a change in therapy. It is concluded that oral azithromycin, administered as short-course therapy, is an appropriate antibiotic for treating patients with community-acquired pneumonia. However, it is not yet certain that azithromycin is a good choice for patients with pneumococcal bacteraemia.

Topics: Administration, Oral; Adult; Aged; Azithromycin; Community-Acquired Infections; Erythromycin; Female; Humans; Injections, Intravenous; Male; Middle Aged; Multivariate Analysis; Penicillin G; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Radiography; Treatment Outcome

Azithromycin is an azalide antibiotic with activity against many of the respiratory pathogens and with marked tissue affinity. In a prospective study, the efficacy of a short-course of azithromycin was evaluated in 25 patients with community-acquired pneumococcal pneumonia. Gram-positive diplococci were abundant in the sputum smears of all patients, and Streptococcus pneumoniae was isolated in the sputum cultures of 15; one patient had pneumococcal bacteremia, as well. Azithromycin was administered at a single dose of 1,000 mg on day 1, and 500 mg on subsequent days for a total of three days in 19 patients, five days in four patients, two and four days in one patient each. Defervescence occurred within 24 hours after the first dose. The overall clinical cure and bacteriologic eradication rates were 96% and 93%, respectively. One patient with pneumococcal bacteremia failed to respond and died in respiratory failure. Side-effects were encountered in three (12%) patients. In conclusion, three-day therapy with a total azithromycin dose of 1,500 mg seems effective and safe in patients with community-acquired pneumococcal pneumonia and no underlying pulmonary condition.

Topics: Adult; Azithromycin; Community-Acquired Infections; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pneumonia, Pneumococcal; Prospective Studies; Sputum; Streptococcus pneumoniae; Transaminases

Previous cohort studies of pneumonia patients reported lower mortality with advanced macrolides. Our aim was to characterize antibiotic treatment patterns and assess the role of quinolones or macrolides in empirical therapy.. An historical cohort, 1 July 2009 to 30 June 2017, included, through active surveillance, all culture-confirmed bacteremic pneumococcal pneumonia (BPP) among adults in Israel. Cases without information on antibiotic treatment were excluded. Logistic regression analysis was used to assess independent predictors of in-hospital mortality.. A total of 2016 patients with BPP were identified. The median age was 67.2 years (interquartile range [IQR] 53.2-80.6); 55.1% were men. Lobar pneumonia was present in 1440 (71.4%), multi-lobar in 576 (28.6%). Median length of stay was 6 days (IQR 4-11). A total of 1921 cases (95.3%) received empiric antibiotics with anti-pneumococcal coverage: ceftriaxone, in 1267 (62.8%). Coverage for atypical bacteria was given to 1159 (57.5%), 64% of these, with macrolides. A total of 372 (18.5%) required mechanical ventilation, and 397 (19.7%) died. Independent predictors of mortality were age (odds ratio [OR] 1.051, 95% confidence interval [CI] 1.039, 1.063), being at high-risk for pneumococcal disease (OR 2.040, 95% CI 1.351, 3.083), multi-lobar pneumonia (OR 2.356, 95% CI 1.741, 3.189). Female sex and macrolide therapy were predictors of survival: (OR 0.702, 95% CI .516, .955; and OR 0.554, 95% CI .394, .779, respectively). Either azithromycin or roxithromycin treatment for as short as two days was predictor of survival. Quinolone therapy had no effect.. Empirical therapy with macrolides reduced odds for mortality by 45%. This effect was evident with azithromycin and with roxithromycin. The effect did not require a full course of therapy.

Topics: Adult; Aged; Anti-Bacterial Agents; Azithromycin; Cohort Studies; Female; Humans; Israel; Macrolides; Male; Pneumonia, Pneumococcal; Quinolones; Retrospective Studies; Roxithromycin

Community-acquired pneumonia is a common disease with considerable morbidity and mortality, for which Streptococcus pneumoniae is accepted as a leading cause. Although β-lactam-plus-macrolide combination therapy for this disease is recommended in several guidelines, the clinical efficacy of this strategy against pneumococcal pneumonia remains controversial. In this study, we examined the effects of β-lactam-plus-macrolide combination therapy on lethal mouse pneumococcal pneumonia and explored the mechanisms of action in vitro and in vivo We investigated survival, lung bacterial burden, and cellular host responses in bronchoalveolar lavage fluids obtained from mice infected with pneumonia and treated with ceftriaxone, azithromycin, or both in combination. Although in vitro synergy was not observed, significant survival benefits were demonstrated with combination treatment. Lung neutrophil influx was significantly lower in the ceftriaxone-plus-azithromycin-treated group than in the ceftriaxone-treated group, whereas no differences in the lung bacterial burden were observed on day 3 between the ceftriaxone-plus-azithromycin-treated group and the ceftriaxone-treated group. Notably, the analysis of cell surface markers in the ceftriaxone-plus-azithromycin combination group exhibited upregulation of presumed immune checkpoint ligand CD86 and major histocompatibility complex class II in neutrophils and CD11b-positive CD11c-positive (CD11b(+) CD11c(+)) macrophages and dendritic cells, as well as downregulation of immune checkpoint receptors cytotoxic-T lymphocyte-associated antigen 4 and programmed death 1 in T helper and T regulatory cells. Our data demonstrate that the survival benefits of ceftriaxone-plus-azithromycin therapy occur through modulation of immune checkpoints in mouse pneumococcal pneumonia. In addition, immune checkpoint molecules may be a novel target class for future macrolide research.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; B7-2 Antigen; Bacterial Load; CD11b Antigen; CD11c Antigen; Ceftriaxone; Community-Acquired Infections; Dendritic Cells; Disease Models, Animal; Drug Therapy, Combination; Female; Gene Expression; Histocompatibility Antigens Class II; Humans; Macrophages, Alveolar; Mice; Mice, Inbred CBA; Neutrophils; Pneumonia, Pneumococcal; Programmed Cell Death 1 Receptor; Streptococcus pneumoniae; Survival Analysis; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer

We report an outbreak of four confirmed cases of invasive pneumococcal disease (IPD) in individuals occupationally exposed to welding fumes, at a Belfast shipyard (Northern Ireland). All cases were hospitalised. A high-risk sub-group of 679 workers has been targeted for antibiotic prophylaxis and pneumococcal vaccination. Physicians and public health institutions outside Northern Ireland should be alert to individuals presenting with pneumonia or IPD and recent links to the shipyard, to facilitate early assessment and treatment.

Topics: Adult; Amoxicillin; Antibiotic Prophylaxis; Azithromycin; Disease Outbreaks; Humans; Industry; Inhalation Exposure; Male; Middle Aged; Northern Ireland; Occupational Exposure; Pneumococcal Vaccines; Pneumonia, Pneumococcal; Retrospective Studies; Vaccination; Welding

"Round pneumonia" or "spherical pneumonia" is a well-characterized clinical entity that seems to be less addressed by pediatricians in Taiwan. We herein report the case of a 7-year-old boy who presented with prolonged fever, cough, and chest X-rays showing a well-demarcated round mass measuring 5.9 × 5.6 × 4.3 cm in the left lower lung field, findings which were typical for round pneumonia. The urinary pneumococcal antigen test was positive, and serum anti-Mycoplasma pneumoniae antibody titer measurement using a microparticle agglutination method was 1:160 (+). After oral administration of antibiotics including azithromycin and amoxicillin/clavulanate, which was subsequently replaced by ceftibuten due to moderate diarrhea, the fever subsided 2 days later and the round patch had completely resolved on the 18th day after the diagnosis. Recent evidence suggests treating classical round pneumonia with antibiotics first and waiving unwarranted advanced imaging studies, while alternative etiologies such as abscesses, tuberculosis, nonbacterial infections, congenital malformations, or neoplasms should still be considered in patients with atypical features or poor treatment response.

Topics: Anti-Bacterial Agents; Azithromycin; Child; Humans; Male; Pneumonia, Bacterial; Pneumonia, Mycoplasma; Pneumonia, Pneumococcal; Taiwan

To assess the effectiveness of guidelines and education on empirical therapy for community-acquired pneumonia.. Administrative records for children with a primary diagnosis of pneumonia from January 2007 to September 2009 were reviewed. Antimicrobial use was measured monthly over 3 periods: (1) before creation of an antimicrobial stewardship task force (ASTF), (2) after ASTF formation but before release of guidelines for antimicrobial use, and (3) after guideline release. Antimicrobial use over time was assessed by using quasi-binomial logistic regression models that incorporated interrupted events, seasonality, and autocorrelation. Allowing calculation of immediate changes due to specific interventions and trends in use over each time period. The primary outcome was use of ampicillin as recommended in the guidelines versus ceftriaxone, the historical standard. Secondary outcomes included other antimicrobial use, length of stay, mortality, and readmission.. One thousand two hundred forty-six children met study criteria. Ampicillin use increased from 2% at baseline to 6% after ASTF formation and 44% after guideline release. Ceftriaxone use increased slightly (from 56% to 59%) after ASTF formation but decreased to 28% after guideline release. An immediate change in prescription occurred in the month after guideline publication and remained stable over the following year.. Guidelines and education can have an impact on antimicrobial use in the pediatric setting. Although the optimal strategies for pediatric antimicrobial stewardship programs still are being determined, we believe that our approach offers an inexpensive and low-risk step in the right direction.

Topics: Ampicillin; Anti-Bacterial Agents; Azithromycin; Ceftriaxone; Child; Child, Preschool; Clindamycin; Community-Acquired Infections; Consensus; Drug Substitution; Drug Utilization; Evidence-Based Medicine; Female; Guideline Adherence; Hospitals, Pediatric; Humans; Infant; Inservice Training; Kentucky; Length of Stay; Logistic Models; Male; Patient Readmission; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Practice Patterns, Physicians'; Survival Analysis; Treatment Outcome; Vancomycin

To compare the probability of target attainment (PTA) for macrolides and ketolides against penicillin-susceptible, intermediate, and resistant Streptococcus pneumoniae in both serum and epithelial lining fluid (ELF) of patients with community-acquired pneumonia (CAP).. Monte Carlo simulations were used to assess the attainment of the bacterial eradication-linked pharmacodynamic index of the free drug area under the concentration-time curve over 24 hours to minimum inhibitory concentration (fAUC(0-24)/MIC90) by azithromycin, clarithromycin, and telithromycin, at therapeutic doses, against penicillin-susceptible, intermediate, and resistant S. pneumoniae.. In serum, azithromycin and clarithromycin were found to have a probability of attaining the recommended fAUC(0-24)/MIC90 ratio of 30 in 50.2% and 74.6%, respectively, of CAP patients with penicillin-intermediate strains, and a probability of 36.9% and 60.7%, respectively, in cases of penicillin-resistant strains. Telithromycin maintained a probability of reaching the fAUC(0-24)/MIC90 ratio of 30 in serum and ELF in 89.1% of CAP patients, regardless of the penicillin resistance of the strain.. Clarithromycin results in a higher PTA than azithromycin in the treatment of penicillin-susceptible S. pneumoniae, but both of these agents exhibit a decreasing efficacy as S. pneumoniae penicillin resistance increases. When compared to clarithromycin and azithromycin, telithromycin maintains higher PTA in CAP patients with penicillin-resistant strains of S. pneumoniae.

Topics: Anti-Bacterial Agents; Area Under Curve; Azithromycin; Clarithromycin; Community-Acquired Infections; Drug Resistance, Bacterial; Humans; Ketolides; Microbial Sensitivity Tests; Monte Carlo Method; Pneumonia, Pneumococcal; Probability; Streptococcus pneumoniae

Sub-MIC levels of macrolides down-regulate bacterial virulence factors and suppress inflammatory processes. The ability of macrolides to reduce the production of pneumolysin has been shown to explain the discrepancy between in vitro resistance and outcomes with macrolides against macrolide-resistant Streptococcus pneumoniae. In this study, we determined whether the ability of macrolides to regulate inflammatory processes is beneficial for innate resistance to macrolide-resistant pneumococci in a murine pneumonia model. Among the macrolides tested, only roxithromycin did not affect in vitro pneumococcal virulence factors at sub-MIC levels. Roxithromycin (1.25 to 10 mg/kg of body weight/day) was administered to mice by oral gavage for 3 days before infection with a resistant strain of S. pneumoniae. We evaluated the efficacy of the treatment by determining mouse survival curves and by measuring bacterial burdens and several inflammatory parameters in the airways. Pneumolysin and PspA in infected lungs were examined by Western blot assay. Roxithromycin at doses of > or =5 mg/kg/day increased the median survival time and retarded bacteremia without suppressing the production of pneumolysin and PspA in infected lungs. This treatment reduced matrix metalloproteinase-7 expression and activation and keratinocyte-derived chemokine production in the lungs, while it increased mononuclear cell responses in the lungs, with enhanced bacterial clearance. Concentrations of roxithromycin in plasma and tissues were below the MICs for the inoculated strain during infection. The treatment also reduced inflammatory responses to killed pneumococci in the lungs. These results suggest that the modification by roxithromycin of airway inflammatory responses, including those of matrix metalloproteinase-7 and phagocytes, is beneficial for initial resistance to macrolide-resistant pneumococci.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Bronchoalveolar Lavage Fluid; Chemokine CCL2; Disease Models, Animal; Drug Resistance, Bacterial; Lung; Macrolides; Male; Matrix Metalloproteinase 7; Mice; Mice, Inbred CBA; Pneumonia, Pneumococcal; Roxithromycin; Streptolysins

Emergence of resistance may be prevented by killing both the parental infecting strain and subsequent less susceptible step-mutants. The present study analyses eradication and resistance selection in Streptococcus pneumoniae with moxifloxacin, levofloxacin and azithromycin, using a parental serotype 3 clinical strain (strain A) and its correspondent step-mutant derivatives resistant to these antibiotics (B, C, D), which were selected in vivo in a patient with pneumonia.. Moxifloxacin, levofloxacin and azithromycin MICs were 1, 2 and 0.5 mg/L for the parental strain; 4, 16 and 4 mg/L for isolate B; and 4, 16 and >128 mg/L for isolates C and D, respectively. A pharmacokinetic computerized device was used to simulate serum and epithelial lining fluid (ELF) concentrations. Initial inoculum was approximately 10(8) cfu/mL. Population analysis profiles were performed using plates with increasing antimicrobial concentrations.. In ELF simulations, moxifloxacin showed a bactericidal pattern against all isolates with a minority (approximately 100 cfu/mL) of the surviving population (isolates B, C and D) growing on plates with moxifloxacin concentrations just above those in ELF. Levofloxacin and azithromycin showed a bactericidal pattern only against isolate A, with the whole population of isolates B, C and D growing on plates with levofloxacin concentrations higher (16-64 mg/L) than those in ELF and in plates with azithromycin concentrations as high as 2048 mg/L (for isolates C and D).. Antimicrobial activity in pulmonary tissue against possible emerging resistant mutants during pneumonia treatment may prevent failures more than the solely activity against the S. pneumoniae parental infecting strain.

Topics: Anti-Bacterial Agents; Aza Compounds; Azithromycin; Community-Acquired Infections; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Levofloxacin; Microbial Sensitivity Tests; Models, Biological; Moxifloxacin; Mutation; Ofloxacin; Pneumonia, Pneumococcal; Quinolines; Serum Bactericidal Test; Streptococcus pneumoniae

A rat model was used to study the effects of cirrhosis on antibiotic therapy of pneumococcal pneumonia. Cirrhotic and control male Sprague-Dawley rats were infected transtracheally with type 3 Streptococcus pneumoniae. Treatment began 18 h later with phosphate-buffered saline (PBS), azithromycin (50 mg/kg), trovafloxacin (50 mg/kg), or ceftriaxone (100 mg/kg) injected subcutaneously twice daily for 5 days. Antibiotic concentrations were measured by high-performance liquid chromatography. Azithromycin, trovafloxacin, and ceftriaxone were all equally effective at preventing mortality in both cirrhotic and normal rats. Free fraction area under the curve to minimum inhibitory concentration ratio (AUC/MIC) and maximum calculated serum concentration to MIC ratio (C(max)/MIC) and percent time that the serum concentration exceeded the MIC (%T > MIC) were greater for ceftriaxone compared with azithromycin or trovafloxacin. Azithromycin achieved higher concentrations in bronchoalveolar lavage fluid (BALF), epithelial lining fluid (ELF), and BAL white blood cells than ceftriaxone or trovafloxacin in cirrhotic rats. Macrolide, beta-lactam, or fluoroquinolone antibiotic efficacy in a pneumococcal pneumonia model does not appear to be affected by hepatic cirrhosis.

Topics: Animals; Azithromycin; Biological Availability; Blood Chemical Analysis; Bronchoalveolar Lavage Fluid; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Fluoroquinolones; Injections, Subcutaneous; Liver Cirrhosis; Male; Naphthyridines; Pneumonia, Pneumococcal; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Risk Assessment; Sensitivity and Specificity; Survival Rate

Telithromycin (TEL) is a ketolide antimicrobial agent with in vitro activity against Streptococcus pneumoniae (SPN), including macrolide resistant strains. The purpose of this study was to assess the efficacy of TEL against clinical SPN isolates with various genotypic mutations including the newly recognized ribosomal mutations. Pneumonia was induced in either immunocompetent and immunosuppressed mice. Six isolates were included in the study and all were resistant to azithromycin (AZI) by MIC testing. Three oral regimens of TEL were chosen to simulate the human pharmacokinetic (PK) exposures observed in young healthy, healthy elderly (> or =65 years), and infected subjects. An additional group was given AZI in human simulated doses. Bacterial density in lung was determined after each treatment. Telithromycin administered simulating infected patients showed greater efficacy (i.e., change in logCFU) than the azithromycin treated group for all isolates except P1660008. The immune system was responsible for increased efficacy (ranging from 45-146%) for all but one of the telithromycin treatment regimens. Unlike other isolates studied in this in vivo model, P1660008 displayed a highly variable response to therapy, such that the reductions in CFU were not consistent with the microbiological and PK profiles of either compound. For all other isolates, the activity of AZI was comparable with untreated controls. Human simulated exposures of TEL displayed 0.5-3.4 log kill in vivo despite the ribosomal mutations studied. These data support the in vivo efficacy of TEL against a variety of genotypic resistance profiles observed in pneumococci, however, additional studies are required to fully characterize the killing profile of the compound against these recently determined ribosomal mutations.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Azithromycin; Colony Count, Microbial; Disease Models, Animal; Drug Resistance, Bacterial; Genes, rRNA; Ketolides; Lung; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Mutation; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Identification of pathogens in childhood community-acquired pneumonia (CAP) is not easy. However, it is believed that nasopharyngeal colonization of pathogenic bacteria leads to childhood CAP, so the etiology is inferred by the isolates obtained from nasopharynx of children with CAP. Among the pathogens of childhood CAP, Streptococcus pneumoniae (SP) is the most important agent and macrolides resistant SP (MRSP) is increasingly reported. We investigated the characterization of the mechanism of macrolide resistance in isolates of MRSP by the presence of the ermB gene or the mefA gene and clindamycin (CLDM) resistance. In addition, we also assessed the efficacy of azithromycin (AZM) in children with CAP who were isolated MRSP from nasopharynx. During a 6 month period between January and June in 2002, children with CAP who were treated with a 3 day regimen of AZM and isolated SP from nasopharynx were enrolled. Clinical outcome was based on assessment of fever on the fourth day of treatment. MIC measurements were obtained by broth microdilution and interpreted according to NCCLS criteria. 53 patients were enrolled and MRSP were isolated in 41 children. Of 41 MRSP isolates, 25 isolates were identified CLDM resistance. The AZM MIC90 of CLDM resistant MRSP isolates was 128 microg/ml. On the other hand, that of CLDM sensitive MRSP isolates was 8 microg/ml. However, AZM was effective in 20 children isolated CLDM resistant MRSP and 15 out of 16 children isolated CLDM sensitive MRSP. On this background, despite high rates of MRSP in Japan, AZM continues to be clinically effective for the treatment of childhood CAP.

Topics: Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Clindamycin; Community-Acquired Infections; Drug Resistance, Bacterial; Female; Humans; Infant; Macrolides; Male; Nasopharynx; Pneumonia, Pneumococcal; Streptococcus pneumoniae

In the winter of 1998-1999 an outbreak of pneumococcal pneumonia occurred among Ranger students undergoing high-intensity training. Thirty pneumonia cases (attack rate = 12.6%) were identified among a group of 239 students. Eighteen students were hospitalized; Streptococcus pneumoniae-positive cultures were detected in 11 (61.1%) of these 18 hospitalized cases. Pneumococci were also identified in throat swabs of 30 (13.6%) of 221 nonhospitalized students surveyed. Serum antipneumolysin seroconversions were detected in 30 (18.3%) of 164 students tested. An association between development of serum antipneumolysin antibody and pneumococcal pharyngeal carriage/colonization was found. Of 30 seroconverters, eight (26.7%) had S. pneumoniae-positive cultures compared with only 17 (12.7%) of 134 nonseroconverters (relative risks = 2.02, 95% confidence interval = 1.02-4.02, p = 0.05). The outbreak was controlled by administrating lowdose, oral azithromycin prophylaxis (250 mg weekly for 2 weeks) and was associated with a 69% reduction in pneumococcal carriage and a 94% reduction in pneumonia rates.

Topics: Adult; Anti-Bacterial Agents; Antibiotic Prophylaxis; Azithromycin; Disease Outbreaks; Humans; Incidence; Male; Military Personnel; Pneumonia, Pneumococcal; Risk; United States

Topics: Anti-Bacterial Agents; Azithromycin; Chlamydophila pneumoniae; Drug Resistance, Bacterial; Humans; Military Personnel; Neisseria meningitidis; Pneumonia, Bacterial; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Vaccines

Streptococcus pneumoniae is the leading cause of bacterial pneumonia in all age groups. Identifying outbreaks of pneumococcal disease and key risk factors may lead to improvements in vaccination and prevention strategies for high-risk groups. A significant outbreak of S. pneumoniae pneumonia that occurred among Marine recruits is reported here.. An outbreak was investigated using standard microbiologic procedures and epidemiologic evaluation to define the extent of the outbreak, determine the microbiologic causative agent(s), identify risk factors for the development of disease, and institute preventive measures against further cases of pneumonia among recruits.. Fifty-two cases of radiographically confirmed pneumonia occurred among 3367 Marine recruits over a 2-week period in November 2000. Twenty-five of these cases occurred in a single company of 481 men, with an attack rate of 5.2%. Twelve of the 25 cases were caused by S. pneumoniae, serotypes 4 and 9v. The outbreak rapidly ended following isolation of cases, prophylaxis with oral azithromycin, and administration of the 23-valent pneumococcal vaccine.. This outbreak of pneumococcal disease occurred in the setting of intense military training and a crowded environment. The use of the pneumococcal vaccine year-round in military trainees and other high-risk populations to reduce pneumococcal disease should be considered.

Topics: Adolescent; Adult; Antibiotic Prophylaxis; Azithromycin; California; Disease Outbreaks; Erythromycin; Humans; Male; Military Personnel; Penicillin G Benzathine; Pneumococcal Vaccines; Pneumonia, Pneumococcal; Risk Factors; Streptococcus pneumoniae

Cethromycin (ABT-773), a new ketolide, possesses potent in vitro activity against Streptococcus pneumoniae. The objective of this study was to investigate the in vivo bactericidal activity of cethromycin against macrolide-susceptible and -resistant S. pneumoniae in a murine pneumonia model and to describe the pharmacodynamic (PD) profile of cethromycin. Eight (two macrolide susceptible, six macrolide resistant) clinical isolates of S. pneumoniae were investigated. Cyclophosphamide administration rendered ICR mice transiently neutropenic prior to intratracheal inoculation with 0.05 ml of an S. pneumoniae suspension containing 10(7) to 10(8) CFU/ml. Oral cethromycin was initiated 12 to 14 h postinoculation over a dosage range of 0.1 to 800 mg/kg of body weight/day. Lungs from seven to eight mice per treatment and control groups were collected at 0 and 24 h posttherapy to assess bacterial density. The cumulative mortality (n = 12 to 13) was assessed at 120 h (end of therapy) and at 192 h (3 days posttherapy). Recovery of pneumococci from the lungs of infected animals prior to the initiation of therapy ranged from 4.6 to 7.2 log(10) CFU. Growth in untreated control animals over a 24-h study period increased 0.3 to 2.7 log(10) CFU. Cethromycin demonstrated a substantial bactericidal effect, regardless of macrolide susceptibility. Correlation between changes in bacterial density (24 h) and survival over both 120 and 192 h were statistically significant. All three PD parameters demonstrated a significant correlation with changes in log(10) CFU/lung (Spearman's correlation coefficient, P < 0.001); however, the goodness of fit as assessed with the maximum effect (E(max)) model revealed that the maximum concentration of free drug in serum (C(max free))/MIC and the area under the free drug concentration-time curve (AUC(free))/MIC best explained the relationship between drug exposure and reductions in viable bacterial counts. These data reveal that an approximate cethromycin AUC(free)/MIC of 50 or C(max free)/MIC of 1 results in bacteriostatic effects, while higher values (twofold) maximize survival.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Azithromycin; Clindamycin; Disease Models, Animal; Drug Resistance, Bacterial; Erythromycin; Female; Humans; Ketolides; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Topics: Amoxicillin; Azithromycin; Bronchitis; Child, Preschool; Drug Resistance, Microbial; Female; Humans; Pneumonia, Pneumococcal

Since the first strains of penicillin-resistant Streptococcus pneumoniae were isolated in the 1960s, the rate of resistance has increased world- wide, though with geographic variations. Currently, the prevalence and patterns of antibiotic resistance in this microorganism vary widely from one country to another, as well as within in the same country. In our study we evaluated the in vitro susceptibility of 299 isolates of S. pneumoniae from patients with community-acquired respiratory tract infections from 1998-2000 to different antimicrobial agents. The following resistance results were obtained: 32.11% to penicillin, 4.35% to amoxicillin, 3.68% to amoxicillin-clavulanic acid, 69.9% to cefaclor, 32.44% to cefpodoxime, 34.11% to cefuroxime, and 24.41% to azithromycin. For cefixime and ceftibuten there are no NCCLS breakpoint criteria.

Topics: Amoxicillin; Anti-Bacterial Agents; Azithromycin; Cefaclor; Cefixime; Cefpodoxime; Ceftibuten; Ceftizoxime; Cefuroxime; Cephalosporins; Clavulanic Acid; Community-Acquired Infections; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Penicillin Resistance; Pneumonia, Pneumococcal; Spain; Streptococcus pneumoniae

Three patients with bacteremic pneumonia caused by multidrug-resistant Streptococcus pneumoniae were treated unsuccessfully with azithromycin. One S. pneumoniae isolate carried a mef determinant for an efflux pump; a second isolate had an erm determinant. All 3 patients were successfully treated with levofloxacin, an antipneumococcal fluoroquinolone.

Topics: Adult; Aged; Anti-Bacterial Agents; Anti-Infective Agents; Azithromycin; Bacteremia; Drug Resistance, Microbial; Drug Resistance, Multiple; Female; Humans; Levofloxacin; Male; Microbial Sensitivity Tests; Middle Aged; Ofloxacin; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Azithromycin; Drug Resistance, Microbial; Fatal Outcome; Female; Humans; Middle Aged; Pneumonia, Pneumococcal

A rat model of ethanol feeding was used to study the effects of ethanol on antibiotic therapy of pneumococcal pneumonia. Male Sprague-Dawley rats (150 g) received a liquid diet containing 36% of total calories as ethanol. Controls were pair-fed a liquid diet without ethanol or received rat chow. Diets began 7 days pre- and continued postinfection. Rats were infected transtracheally with type 3 Streptococcus pneumoniae and then treated with azithromycin (50 mg/kg), trovafloxacin (50 mg/kg), or ceftriaxone (100 mg/kg) injected subcutaneously twice daily for 5 days. Antibiotic levels in serum, lung cells, and lavage fluid were measured by HPLC. Ethanol- and pair-fed rats had depressed baseline peripheral neutrophil counts but were able to generate adequate numbers of peripheral and pulmonary polymorphonuclear leukocytes early in the course of their infection. Ethanol feeding did not alter the pharmacokinetics of azithromycin, trovafloxacin, or ceftriaxone. All three antibiotics were equally effective in curing experimental pneumococcal pneumonia, and survival rates were similar in treated ethanol-fed and control rats.

Topics: Animals; Anti-Infective Agents; Azithromycin; Bronchoalveolar Lavage Fluid; Ceftriaxone; Disease Models, Animal; Ethanol; Feeding Behavior; Fluoroquinolones; Leukocyte Count; Male; Naphthyridines; Neutrophils; Pneumonia, Pneumococcal; Rats; Rats, Sprague-Dawley

Topics: Anti-Bacterial Agents; Azithromycin; Chlamydia Infections; Humans; Pneumonia; Pneumonia, Pneumococcal

In this study, we determined the efficacy of various dosing regimens for erythromycin and azithromycin against four pneumococci with different susceptibilities to penicillin in an in vitro pharmacokinetic model and in a mouse peritonitis model. The MIC was 0.03 microg/ml, and the 50% effective doses (determined after one dose) of both drugs were comparable for the four pneumococcal strains and were in the range of 1.83 to 6.22 mg/kg. Dosing experiments with mice, using regimens for azithromycin of one to eight doses/6 h, showed the one-dose regimen to give the best result; of the pharmacodynamic parameters tested (the maximum drug concentration in serum [Cmax], the times that the drug concentration in serum remained above the MIC and above the concentration required for maximum killing, and the area under the concentration time curve), Cmax was the best predictor of outcome. The bacterial counts in mouse blood or peritoneal fluid during the first 24 h after challenge were not correlated to survival of the mice. The serum concentration profiles obtained with mice for the different dosing regimens were simulated in the in vitro pharmacokinetic model. Here as well, the one-dose regimen of azithromycin showed the best result. However, the killing curves in vivo in mouse blood and peritoneal fluid and in the vitro pharmacokinetic model were not similar. The in vitro killing curves showed a decrease of 2 log10 within 2 and 3 h for azithromycin and erythromycin, respectively whereas the in vivo killing curves showed a bacteriostatic effect for both drugs. It is concluded that the results in terms of predictive pharmacodynamic parameters are comparable for the in vitro and in vivo models and that high initial concentrations of azithromycin favor a good outcome.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Disease Models, Animal; Erythromycin; Female; Mice; Peritonitis; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Azithromycin; Bacteremia; Disease Models, Animal; Lung; Mice; Pneumonia, Pneumococcal; Respiratory Tract Infections; Tissue Distribution

The relations between the clinical efficacy, phagocytic transport phenomena, tissular and sera kinetics have been assessed in a pneumonia murine model. At first, the correlation between the clinical efficacy and pharmacokinetics characteristics has been studied for the erythromycin, spiramycin, roxithromycin, clarithromycin and azithromycin. An in vivo clinical efficacy hierarchy has been established (azi > ery > roxi = azi > spira). A hierarchy identical to the clinical efficacy, has been recognised for the pulmonary elimination half lives and the pulmonar AUC. These could be considered as predictive of these antibiotics activity in the respiratory infections. In a second time, the tissular pharmacokinetics of the azithromycin in leukopenic mice allowed to confirm the leukocytes role in the transport and release of this antibiotic in the midst of the infections site. Finally, this antibiotic demonstrated its efficacy in a bacterienic infection even when administered at a low dosage thus allowing to have sera concentrations identical to those obtained in human clinical case and close to MIC's for S. pneumoniae. The pharmacokinetic novelty displayed by its strong tissular penetration can explain its remarkable efficacy.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Disease Models, Animal; Erythromycin; Injections, Subcutaneous; Mice; Pneumonia, Pneumococcal; Roxithromycin; Spiramycin

Azithromycin is a new acid-stable 15-membered-ring macrolide that exhibits an extended half-life and excellent tissue distribution, including distribution in the lung. We compared its in vivo activity with that of erythromycin using two models of Streptococcus pneumoniae pneumonia, namely, a model of acute infection in Swiss mice and a model of subacute infection in C57BL/6j mice. Female mice were infected by oral delivery into the trachea of 10(5) CFU of a virulent serotype 3 strain of S. pneumoniae (P 4241). Prophylactic and therapeutic treatments were given orally (p.o.) or subcutaneously (s.c.) by various regimens. In the model of subacute infection, a single dose of azithromycin, 25 mg/kg, given p.o. 7 h before infection protected 92% of the mice, while erythromycin was completely ineffective. In the model of acute infection, a single dose of azithromycin, 50 mg/kg, given s.c. 24 h prior to challenge protected 80% of the mice, whereas only 35% of the mice survived with erythromycin, 50 mg/kg, 1 h before challenge. Therapy, which was studied exclusively in the model of subacute infection, was initiated 48 h postinfection. Two doses of 12.5 mg/kg given p.o. 12 h apart resulted in 80% survival of mice treated with azithromycin versus 7% survival of mice treated with erythromycin. Pulmonary clearance of bacteria was consistent with the survival rates. Two doses (25 mg/kg) of azithromycin given s.c. at 48 and 65 h after infection led to complete clearance of bacteria from the lungs and blood, whereas erythromycin-treated mice remained bacteremic. The pharmacokinetics of azithromycin account for its superior efficacy against S. pneumoniae pneumonia relative to the efficacy of erythromycin.

Topics: Animals; Azithromycin; Blood; Drug Evaluation, Preclinical; Erythromycin; Female; Lung; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal