ZITHROMAX(Azithromycin)

Azithromycin is an antibiotic which belongs to a class called macrolide antibiotics. Its main use is in the treatment of mild to moderate infections of several kinds. It works by slowing down protein synthesis and thus disabling bacteria to reproduce and grow. The medication is very effective because it gets carried with white blood cells to the site of the infection, thus resulting in a fast elimination of the infection (within one week). It is used to treat skin infections; upper and lower respiratory tract infections, including pharyngitis, tonsillitis, and pneumonia; sexually transmitted infections of the cervix or urinary tract; and genital ulcer disease in men. In children, azithromycin is also used to treat middle ear infection. A further benefit of the drug is that it shows very limited and light side effects, if at all.
Azithromycin is sold under several brand names, the best known of which Zithromax™ and Sumamed™.

Respir Med. 2005 Jun;99(6):663-9. Epub 2005 Jan 13.
Treatment of acute exacerbation of severe-to-very severe COPD with azithromycin in patients vaccinated against Streptococcus pneumoniae.
Cazzola M, Salzillo A, De Giglio C, Piccolo A, Califano C, Noschese P.
Department of Pneumology, Unit of Pneumology and Allergology, A. Cardarelli Hospital, Naples, Italy.

Sixty-five consecutive eligible adult patients, who were treated as outpatients for stable severe-to-very severe COPD, were enrolled in the study. All of them received 23-valent pneumococcal capsular polysaccharide vaccine intramuscularly. Patients were seen monthly, as well as whenever they had symptoms suggestive of an exacerbation, at our outpatient clinic. Eighteen out of 65 patients suffered from acute exacerbation (AECOPD). Three of these patients presented two episodes of AECOPD. Patients with an acute exacerbation of COPD received azithromycin 500mg/day once daily for 3 days and a short course of oral prednisolone 25mg/die. In 16 cases, a single species was isolated, while in the remaining 5 cases at least two species were recovered. Clinical cure or improvement at the end of therapy (3-5 days post-therapy) was reported in 17 episodes of AECOPD with no relapse at the late post-therapy (10-14 days after the completion of treatment). Bacteriologic eradication or presumptive eradication rates at the end of therapy were 86% (24 out of 28 isolates). Azithromycin eradicated all isolates of Haemophilus influenzae, Moraxella catarrhalis, H. parainfluenzae, Klebsiella pneumoniae, and Klebsiella spp. isolated at baseline. Eradication of Sta aureus occurred in 1 of 3 isolates whereas azithromycin was unable to eradicate Pseudomonas aeruginosa isolates. Our data seem to indicate that pneumococcal vaccination reduces the possibility that an AECOPD is caused by Streptococcus pneumoniae. This finding allows the use of antibiotics such as azithromycin, which, otherwise, should be avoided because of resistances.

J Antimicrob Chemother. 2005 May 12;
Impact of carbon dioxide on the susceptibility of key respiratory tract pathogens to telithromycin and azithromycin.
Bouchillon SK, Johnson JL, Hoban DJ, Stevens TM, Johnson BM.
Laboratories International for Microbiology Studies, Inc., 2122 Palmer Drive, Schaumburg, IL 60173-3817, USA.

OBJECTIVES: To determine the quantitative differences in telithromycin and azithromycin MIC values against Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus pyogenes obtained using two recommended and commonly used methodologies: CLSI reference standard broth microdilution in ambient air and Etest((R)) concentration gradient in CO2. METHODS: Four hundred clinical isolates (S. pneumoniae, n=200; H. influenzae, n=100; S. pyogenes, n=100) were evaluated in seven independent laboratories. Telithromycin and azithromycin MICs were determined using CLSI broth microdilution panels incubated in ambient air and Etest((R)) strips incubated in CO2. Standard quality control reference strains--S. pneumoniae ATCC 49619 (n=10) and H. influenzae ATCC 49247 (n=10)--were also tested. RESULTS: Telithromycin and azithromycin Etest((R)) MICs in CO2 were elevated for all organisms when compared with values obtained using broth microdilution in ambient air. Telithromycin geometric mean MIC values increased in CO2 by 2.05, 1.00 and 1.78 log2 dilutions for S. pneumoniae, H. influenzae and S. pyogenes, respectively. The corresponding values for azithromycin were 2.54, 1.21 and 3.0 log2 dilutions, respectively. CONCLUSIONS: Telithromycin MICs measured using Etest((R)) in CO2 are consistently elevated compared with those generated by CLSI broth microdilution measured in ambient air. These findings indicate that Etest((R)) should not be routinely used for the determination of telithromycin MICs against S. pneumoniae, H. influenzae and S. pyogenes, unless appropriate corrective factors are applied before reporting MICs or applying interpretive susceptibilities. Based on results from this study, Etest((R)) MIC breakpoints and quality control ranges are proposed.

Cochrane Database Syst Rev. 2005 Jan 25;(1):CD004404.
Antibiotics for whooping cough (pertussis).
Altunaiji S, Kukuruzovic R, Curtis N, Massie J.
Zayed Military Hospital, Zayed Street, PO Box 3740, Abu Dhabi, UNITED ARAB EMIRATES.

BACKGROUND: Whooping cough is a highly contagious disease. Infants are the population at highest risk of severe disease and death. Erythromycin for 14 days is recommended for treatment and contact prophylaxis but this regime is considered inconvenient and prolonged. The value of contact prophylaxis is uncertain. OBJECTIVES: To study the benefits and risks of antibiotic treatment of and contact prophylaxis against whooping cough. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2004); MEDLINE (January 1966 to February 2004); EMBASE (January 1974 to August 2003); conference abstracts and reference lists of articles were searched. Study investigators and pharmaceutical companies were approached for additional information (published or unpublished studies). There were no constraints based on language or publication status. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials of antibiotics for treatment of and contact prophylaxis against whooping cough were included in the systematic review. DATA COLLECTION AND ANALYSIS: At least three reviewers independently extracted data and assessed the quality of each trial. MAIN RESULTS: Twelve trials with 1,720 participants met the inclusion criteria. Ten trials investigated treatment regimens and two investigated prophylaxis regimens. The quality of the trials was variable. Results showed that short-term antibiotics (azithromycin for three days, clarithromycin for seven days, or erythromycin estolate for seven days) were equally effective with long-term antibiotic treatment (erythromycin estolate or erythromycin for 14 days) in the microbiological eradication of Bordetella pertussis (B. pertussis) from the nasopharynx. The relative risk (RR) was 1.02 (95% confidence interval (CI) 0.98 to 1.05). Side effects were fewer with short-term treatment (RR 0.66; 95% CI 0.52 to 0.83). There were no differences in clinical improvement or microbiological relapse between short and long-term treatment regimens. Contact prophylaxis (of contacts older than six months of age) with antibiotics did not significantly improve clinical symptoms or the number of cases that developed culture positive B. pertussis. AUTHORS' CONCLUSIONS: Antibiotics are effective in eliminating B. pertussis from patients with the disease, rendering them non-infectious, but do not alter the subsequent clinical course of the illness. Effective regimens include: three days of azithromycin, seven days of clarithromycin, seven or 14 days of erythromycin estolate, and 14 days of erythromycin ethylsuccinate. Considering microbiological clearance and side effects, three days of azithromycin or seven days of clarithromycin are the best regimens. Seven days of trimethoprim/sulfamethoxazole also appeared to be effective for the eradication of B. pertussis from the nasopharynx and may serve as an alternative antibiotic treatment for patients who cannot tolerate a macrolide. There is insufficient evidence to determine the benefit of prophylactic treatment of pertussis contacts.

Eur Respir J. 2005 Mar;25(3):490-3.
Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study.
Khalid M, Al Saghir A, Saleemi S, Al Dammas S, Zeitouni M, Al Mobeireek A, Chaudhry N, Sahovic E.
Section of Pulmonary Medicine, Dept of Medicine, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia. mkhalid@kfshrc.edu.sa.

Bronchiolitis obliterans (BO) is a serious noninfectious pulmonary complication following allogeneic bone marrow transplantation (BMT). Azithromycin, a macrolide antibiotic, may have a beneficial effect in BO through its anti-inflammatory effect. The aim of the current study was to investigate the potential effect of azithromycin on pulmonary function tests (PFTs) in BO complicating BMT. PFTs of 153 post-BMT patients were followed; eight patients out of 153 (12%) developed obstructive airway disease on their PFTs, along with characteristic findings of BO on high-resolution computed tomography of the chest. These patients were given azithromycin 500 mg q.d. for 3 days, followed by 250 mg three times a week for 12 weeks. Clinically significant improvements were achieved both in forced vital capacity, where the mean (95% confidence interval) increase reported was 410 mL (0.16-0.65), which was an average improvement of 21.57%, and in the forced expiratory volume in one second, where the mean increase noticed was 280 mL (0.10-0.44), which was an average improvement of 20.58%. In conclusion, the potential role of azithromycin in the treatment of bronchiolitis obliterans is intriguing and it warrants further testing.

Ann Rheum Dis. 2004 Sep;63(9):1113-9.
Three month treatment of reactive arthritis with azithromycin: a EULAR double blind, placebo controlled study.
Kvien TK, Gaston JS, Bardin T, Butrimiene I, Dijkmans BA, Leirisalo-Repo M, Solakov P, Altwegg M, Mowinckel P, Plan PA, Vischer T; EULAR.
Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway. t.k.kvien@medisin.uio.no
OBJECTIVE: To determine the efficacy of weekly treatment with oral azithromycin for 13 weeks on the severity and resolution of reactive arthritis (ReA). METHODS: 186 patients from 12 countries were enrolled in a randomised, double blind, placebo controlled trial. Inclusion criteria were inflammatory arthritis of < or =6 swollen joints, and disease duration of < or =2 months. All patients received a single azithromycin dose (1 g) as conventional treatment for possible Chlamydia infection, and were then randomly allocated to receive weekly azithromycin or placebo. Clinical assessments were made at 4 week intervals for 24 weeks. RESULTS: 152 patients were analysable (34 failed entry criteria), with a mean (SD) age of 33.8 (9.4) and duration of symptoms 30.7 (17.5) days. Mean C reactive protein (CRP) was 48 mg/l, and approximately 50% of those typed were HLA-B27+, suggesting that the inclusion criteria successfully recruited patients with acute ReA. Treatment and placebo groups were well matched for baseline characteristics. There were no statistical differences for changes in any end point (swollen and tender joint count, joint pain, back pain, heel pain, physician and patient global assessments, and CRP) between the active treatment and placebo groups, analysed on an intention to treat basis or according to protocol completion. The time to resolution of arthritis and other symptoms or signs by life table analyses was also not significantly different. Adverse events were generally mild, but were more commonly reported in the azithromycin group. CONCLUSIONS: This large trial has demonstrated that prolonged treatment with azithromycin is ineffective in ReA.

Antimicrob Agents Chemother. 2004 Sep;48(9):3586-90.
Genetic and culture-based approaches for detecting macrolide resistance in Chlamydia pneumoniae.
Riska PF, Kutlin A, Ajiboye P, Cua A, Roblin PM, Hammerschlag MR.
Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA. riska@att.net
Three clinical Chlamydia pneumoniae isolates for which the MIC of azithromycin increased after treatment were investigated for genetic evidence of macrolide resistance. Attempts to induce antibiotic resistance in vitro were made. No genetic mechanism was identified for the phenotypic change in these C. pneumoniae isolates. No macrolide resistance was obtained in vitro.

Antimicrob Agents Chemother. 2004 Sep;48(9):3457-61.
Azithromycin inhibits MUC5AC production induced by the Pseudomonas aeruginosa autoinducer N-(3-Oxododecanoyl) homoserine lactone in NCI-H292 Cells.
Imamura Y, Yanagihara K, Mizuta Y, Seki M, Ohno H, Higashiyama Y, Miyazaki Y, Tsukamoto K, Hirakata Y, Tomono K, Kadota J, Kohno S.
Second Department of Internal Medicine, School of Medicine, Nagasaki University, Nagasaki 852-8501, Japan.
The features of chronic airway diseases, including chronic bronchitis, cystic fibrosis, bronchiectasis, and diffuse panbronchiolitis, include chronic bacterial infection and airway obstruction by mucus. Pseudomonas aeruginosa is one of the most common pathogens in chronic lung infection, and quorum-sensing systems contribute to the pathogenesis of this disease. The quorum-sensing signal molecule [N-(3-oxododecanoyl) homoserine lactone (3O-C(12)-HSL)] not only regulates bacterial virulence but also is associated with the immune response. In this study, we investigated whether 3O-C(12)-HSL could stimulate the production of a major mucin core protein, MUC5AC. The effect of a macrolide on MUC5AC production was also studied. 3O-C(12)-HSL induced NCI-H292 cells to express MUC5AC at both the mRNA and the protein levels in time- and dose-dependent manners. A 15-membered macrolide, azithromycin, inhibited MUC5AC production that was activated by 3O-C(12)-HSL. 3O-C(12)-HSL induced extracellular signal-regulated kinase (ERK) 1/2 and I-kappa B phosphorylation in cells, and this induction was suppressed by azithromycin. 3O-C(12)-HSL-induced MUC5AC production was blocked by the ERK pathway inhibitor PD98059. Our findings suggest that the P. aeruginosa autoinducer 3O-C(12)-HSL contributes to excessive mucin production in chronic bacterial infection. Azithromycin seems to reduce this mucin production by interfering with intracellular signal transduction.

Biochim Biophys Acta. 2004 Aug 30;1664(2):198-205.
Real-time imaging of drug-membrane interactions by atomic force microscopy.
Berquand A, Mingeot-Leclercq MP, Dufrene YF.
Unite de chimie des interfaces, Universite catholique de Louvain, Croix du Sud 2/18, B-1348 Louvain-la-Neuve, Belgium.
Understanding drug-biomembrane interactions at high resolution is a key issue in current biophysical and pharmaceutical research. Here we used real-time atomic force microscopy (AFM) imaging to visualize the interaction of the antibiotic azithromycin with lipid domains in model biomembranes. Various supported lipid bilayers were prepared by fusion of unilamellar vesicles on mica and imaged in buffer solution. Phase-separation was observed in the form of domains made of dipalmitoylphosphatidylcholine (DPPC), sphingomyelin (SM), or SM/cholesterol (SM/Chl) surrounded by a fluid matrix of dioleoylphosphatidylcholine (DOPC). Time-lapse images collected following addition of 1 mM azithromycin revealed progressive erosion and disappearance of DPPC gel domains within 60 min. We attribute this effect to the disruption of the tight molecular packing of the DPPC molecules by the drug, in agreement with earlier biophysical experiments. By contrast, SM and SM-Chl domains were not modified by azithromycin. We suggest that the higher membrane stability of SM-containing domains results from stronger intermolecular interactions between SM molecules. This work provides direct evidence that the perturbation of lipid domains by azithromycin strongly depends on the lipid nature and opens the door for developing new applications in membrane biophysics and pharmacology.

JAMA. 2004 Aug 11;292(6):721-5.
Feasibility of eliminating ocular Chlamydia trachomatis with repeat mass antibiotic treatments.
Melese M, Chidambaram JD, Alemayehu W, Lee DC, Yi EH, Cevallos V, Zhou Z, Donnellan C, Saidel M, Whitcher JP, Gaynor BD, Lietman TM.
ORBIS International, Addis Ababa, Ethiopia.
CONTEXT: Mass antibiotic administrations for ocular chlamydial infection play a key role in the World Health Organization's trachoma control program. Mathematical models suggest that it is possible to eliminate trachoma locally with repeat mass treatment, depending on the coverage level of the population, frequency of mass treatments, and rate that infection returns into a community after each mass treatment. Precise estimates of this latter parameter have never been reported. OBJECTIVE: To determine the rate at which chlamydial infection returns to a population after mass treatment and to estimate the treatment frequency required for elimination of ocular chlamydia from a community. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal cohort study of 24 randomly selected villages from the Gurage Zone in Ethiopia conducted February 2003 to October 2003. A total of 1332 children aged 1 to 5 years were monitored for prevalence of ocular chlamydial infection pretreatment and 2 and 6 months posttreatment. INTERVENTIONS: All individuals older than 1 year were eligible for single-dose oral azithromycin treatment. Pregnant women were offered tetracycline eye ointment. MAIN OUTCOME MEASURES: Prevalence of ocular chlamydial infection, measured by polymerase chain reaction, in children aged 1 to 5 years, in each of 24 villages at each time point was used to estimate the rate of return of infection and the treatment frequency necessary for elimination. RESULTS: The prevalence of infection was 56.3% pretreatment (95% confidence interval [CI], 47.5%-65.1%), 6.7% 2 months posttreatment (95% CI, 4.2%-9.2%), and 11.0% 6 months posttreatment (95% CI, 7.3%-14.7%). Infection returned after treatment at an exponential rate of 12.3% per month (95% CI, 4.6%-19.9% per month). The minimum treatment frequency necessary for elimination was calculated to be once every 11.6 months (95% CI, 7.2-30.9 months), given a coverage level of 80%. Thus, biannual treatment, already being performed in some areas, was estimated to be more than frequent enough to eventually eliminate infection. CONCLUSION: The rate at which ocular chlamydial infection returns to a community after mass treatment suggests that elimination of infection in a hyperendemic area is feasible with biannual mass antibiotic administrations and attainable coverage levels.

J Antimicrob Chemother. 2004 Aug;54(2):542-5. Epub 2004 Jun 23.
Selection of resistance of telithromycin against Haemophilus influenzae, Moraxella catarrhalis and streptococci in comparison with macrolides.
Drago L, De Vecchi E, Nicola L, Colombo A, Gismondo MR.
Laboratory of Clinical Microbiology, Department of Clinical Sciences L. Sacco Teaching Hospital, University of Milan, Via GB Grassi 74, 20157 Milan, Italy. microbio@unimi.it
OBJECTIVE: The in vitro abilities of telithromycin, azithromycin and clarithromycin to select for resistance were compared by testing isolates of Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and beta-haemolytic streptococci. METHODS: Five strains each of beta-lactamase-positive and beta-lactamase-negative H. influenzae, beta-lactamase-positive and beta-lactamase-negative M. catarrhalis, S. pneumoniae, beta-haemolytic group A, group C and group G streptococci and three strains of beta-lactamase-negative ampicillin-resistant H. influenzae were evaluated. Development of resistance was determined by multi-step and single-step methodologies. For multi-step studies, MIC values were determined after five serial passages on antibiotic-gradient plates and after 10 serial passages on antibiotic-free plates. Acquisition of resistance was defined as an increase of >/=4-fold from the starting MIC. In single-step studies, the rate of spontaneous mutations was calculated after a passage on plates containing antibiotics at concentrations equal to the highest NCCLS breakpoints. RESULTS: Azithromycin, clarithromycin and telithromycin gave a >/=4-fold increase in 20, 20 and 10 streptococcus strains, in 4, 5 and 0 H. influenzae strains and in 2, 7 and 4 M. catarrhalis strains, respectively. After 10 passages on antibiotic-free plates, 21/26 strains for azithromycin, 22/32 for clarithromycin and 1/14 for telithromycin maintained high MIC values. In single-step studies, the frequency of mutations was <10(-10) for H. influenzae and M. catarrhalis for telithromycin, azithromycin and clarithromycin. Telithromycin induced mutations at a lower rate than azithromycin and clarithromycin in streptococcal strains. CONCLUSION: Telithromycin showed a very limited ability to select for resistance in respiratory pathogens compared with azithromycin and clarithromycin.

J Trop Pediatr. 2004 Aug;50(4):234-6.
The probiotic effect of Saccharomyces boulardii in a pediatric age group.
Erdeve O, Tiras U, Dallar Y.
Ankara Education and Research Hospital, Ankara, Turkey. omererdeve@yahoo.com
The aim of this study was to determine the efficacy of S. boulardii in diarrhea associated with commonly used antibiotics such as sulbactam-ampicillin (SAM) and azithromycin (AZT). Four hundred and sixty-six patients were assigned to four different groups as follows: group 1:117 patients receiving SAM alone; group 2:117 patients receiving SAM and S. boulardii, group 3:105 patients receiving AZT alone; group 4:127 patients receiving AZT and S. boulardii. Antibiotic-associated diarrhea was seen in 42 of the 222 patients (18.9 per cent) receiving an antibiotic without the probiotic, and in 14 of the 244 patients (5.7 per cent) who received both the probiotic and the antibiotic (p < 0.05). In the group receiving SAM where S. boulardii use was found to be significant, the use of S. boulardii decreased the diarrhea rate from 32.3 to 11.4 per cent in the 1-5 years age group (p < 0.05). This is a pioneering study investigating combined antibiotic and probiotic use in pediatric diarrhea patients.

N Engl J Med. 2004 Jul 8;351(2):154-8.
Macrolide resistance in Treponema pallidum in the United States and Ireland.
Lukehart SA, Godornes C, Molini BJ, Sonnett P, Hopkins S, Mulcahy F, Engelman J, Mitchell SJ, Rompalo AM, Marra CM, Klausner JD.
Department of Medicine, University of Washington, Seattle, USA. lukehart@u.washington.edu

Am Heart J. 2004 Jul;148(1):72-9.
Effects of a brief course of azithromycin on soluble cell adhesion molecules and markers of inflammation in survivors of an acute coronary syndrome: A double-blind, randomized, placebo-controlled study.
Hillis GS, Pearson CV, Harding SA, Sutherland S, Ludlam CA, Marioni JC, Prescott RJ, Fox KA, Flapan AD.
Department of Cardiology the Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK. g.hillis@abdn.ac.uk
BACKGROUND: The anti-chlamydial antibiotic, azithromycin, may improve outcome in patients who survive an acute coronary syndrome. The mechanisms are, however, poorly understood. The aims of this study were to define any relationship between Chlamydia pneumoniae seropositivity and levels of specific markers of endothelial activation (soluble cell adhesion molecules) and more general markers of inflammation (C-reactive protein [CRP] and interleukin-6 [IL-6]) and to assess whether azithromycin had any effect on such markers. METHODS: Patients who survived an acute coronary syndrome were randomized to receive treatment with azithromycin (n = 72) or placebo (n = 69) for 5 days. Before therapy, C pneumoniae IgA and IgG titers were checked, with serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, soluble E-selectin (sE-selectin), soluble P-selectin, high-sensitivity CRP, and IL-6. They were rechecked 3 months later. RESULTS: There were no significant correlations between C pneumoniae titers and levels of CRP, IL-6, or soluble cell adhesion molecules. However, azithromycin treatment significantly reduced mean sICAM-1 levels (P =.006). This effect was more marked in patients with elevated titers of C pneumoniae IgA and IgG. Soluble E-selectin levels were also reduced in patients who were seropositive, but no effects were seen on other endothelial or inflammatory markers. CONCLUSIONS: After an acute coronary syndrome, a 5-day course of azithromycin reduces levels of sICAM-1, a marker of endothelial cell activation. Although these data suggest a potentially beneficial role for azithromycin, they should be interpreted with caution.

Antimicrob Agents Chemother. 2004 Jul;48(7):2673-82.
Active efflux of ciprofloxacin from J774 macrophages through an MRP-like transporter.
Michot JM, Van Bambeke F, Mingeot-Leclercq MP, Tulkens PM.
Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique de Louvain, UCL 7370, Ave. E. Mounier 73, B-1200 Brussels, Belgium.
The accumulation and efflux kinetics of ciprofloxacin have been examined by using murine J774 macrophages. Accumulation (at equilibrium) was increased (three- to fourfold) (i) when cells were incubated with high extracellular drug concentrations (typically 200 mg/liter) as opposed to clinically meaningful concentrations (10 mg/liter or lower), (ii) during ATP- depletion and at acid pH, and (iii) during coincubation with probenecid, gemfibrozil and the preferential multidrug resistance-related protein (MRP) inhibitor MK571. All these conditions were also associated with a marked decrease in ciprofloxacin efflux (half-lives increased from <2 min in controls to up to 10 min). Monensin (a proton ionophore), verapamil, and the preferential P-glycoprotein (P-gp) inhibitor GF120918 had no or only minimal effect, while cyclosporin A, which is not specific for P-gp but also acts on MRP, had an intermediate effect. Short-term uptake studies showed that the influence of the modulators on the apparent drug influx was almost immediate (delay of < or =1 min). Cells made resistant to probenecid and showing a marked overexpression of MRP1 (by Western blot analysis and confocal microscopy) accumulated ciprofloxacin to almost the same extent as did control cells, but efflux was inhibited less by probenecid, gemfibrozil, and MK571. We conclude that ciprofloxacin is subject to constitutive efflux in J774 macrophages through the activity of an MRP-related transporter which is probably distinct from MRP1. We also suggest that the cellular accumulation of ciprofloxacin in wild-type cells is constitutively impaired at therapeutically meaningful concentrations.

Exp Parasitol. 2004 Jul-Aug;107(3-4):120-4.
Plasmodium yoelii: activity of azithromycin in combination with pyrimethamine or sulfadoxine against blood and sporozoite induced infections in Swiss mice.
Neerja J, Puri SK.
Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India.
The efficacy of pyrimethamine or sulfadoxine administered in combination with azithromycin was examined in a rodent malaria model. Outbred Swiss mice infected with blood stage parasites were treated from day 0 to day 3 and efficacy of different regimens was monitored in terms of the curative response and the delay time to reach 2% parasitaemia (2% DT). Administration of azithromycin alone at 60 mg/kg/day produced curative response while lower doses showed marginally delayed 2% DT. A marked potentiation in activities of pyrimethamine (100-fold) or sulfadoxine (10-fold) was observed when administered at non-curative doses of 0.1 mg/kg/day in combination with azithromycin (30 mg/kg/day) against blood stage parasites. A combination of 10 mg/kg/day azithromycin with 0.3 mg/kg/day sulfadoxine was also curative. Likewise in the causal prophylactic test, a combination regimen comprising 1/16th and 1/3rd the individual curative doses of pyrimethamine and azithromycin, respectively, prevented the development of patent infection after Plasmodium yoelii sporozoite challenge. Our results suggest that a combination of azithromycin with the second line treatment regimen of fansidar may enhance the therapeutic efficacy of the latter and also provide better prophylaxis against Plasmodium falciparum malaria.

J Antimicrob Chemother. 2004 Jul;54(1):79-85. Epub 2004 May 26.
Pre-exposure of infected human endometrial epithelial cells to penicillin in vitro renders Chlamydia trachomatis refractory to azithromycin.
Wyrick PB, Knight ST.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. pbwyrick@mail.etsu.edu
OBJECTIVE: The clinical significance of the potential for persistent human chlamydial infections in vivo is being actively reassessed because of the increased frequency of recurrent infection with the same serovar despite compliance with an effective antibiotic regimen. The ability to extend the length of time of in vitro cultivation of polarized human endometrial epithelial cells (HEC-1B) provided the opportunity to establish a model system to determine if a persistent form of Chlamydia trachomatis had the same susceptibility as the actively growing form to a cidal concentration of azithromycin. METHODS: Polarized HEC-1B cells cultivated on extracellular matrix were infected with C. trachomatis serovar E and exposed to penicillin at 24 h post-infection (hpi) to induce a persistent infection characterized by slowly metabolizing but non-dividing, ultrastructurally aberrant reticulate bodies within the chlamydial inclusion; at 48 hpi, infected cultures were exposed to a bactericidal concentration of azithromycin for 72 h. RESULTS: Persistent chlamydiae were phenotypically resistant to azithromycin; the number of chlamydial inclusions on subpassage of progeny from persistent chlamydiae following removal of penicillin and recovery was essentially the same as from progeny from persistent chlamydiae following removal of penicillin and azithromycin and recovery. Neutrophils were attracted in vitro to persistently infected HEC-1B cells that had been exposed to penicillin and azithromycin. CONCLUSIONS: Thus, this study provides evidence at the cellular microbiology level in vitro for mechanisms that could exist in vivo to create sustained, but perhaps clinically inapparent inflammation, which might eventually lead to conditions such as silent pelvic inflammatory disease.

Am J Trop Med Hyg. 2003 Nov;69(5 Suppl):24-8.
The global elimination of blinding trachoma: progress and promise.
Kumaresan JA, Mecaskey JW.
International Trachoma Initiative, New York, New York 10017, USA.
Trachoma is the world's leading cause of preventable blindness. It affects approximately 150 million people living in the world's poorest, rural communities and causes an estimated loss of $2.9 billion in productivity annually. In 1985, the Edna McConnell Clark Foundation joined with the World Health Organization to support studies on trachoma epidemiology and control, resulting in the elaboration of the surgery, antibiotics, facial cleanliness and environmental improvement (SAFE) strategy as the basis for the elimination of this blinding disease. Founded in 1998 by the Clark Foundation and Pfizer, Inc., the International Trachoma Initiative (ITI) is the only organization dedicated to eliminating blinding trachoma through support to national control programs. The availability of donated Zithromax (azithromycin) by Pfizer, Inc. has been paramount to the support of the ITI for implementation of SAFE in 10 country programs. The program has made considerable progress in four years. More than seven million individuals have received treatment, resulting in a cumulative reduction of 50% in active disease rates in children. More than 60,000 have also benefited from lid surgery that has halted progression to blindness. Morocco is expecting to attain the elimination of blinding trachoma by 2005. However, the challenges facing the goal of global elimination by 2020 involve a vital program expansion, increased financial and technical support, environmental improvement, and continued advocacy efforts.

Curr Opin Lipidol. 2003 Dec;14(6):605-14.
Antibiotic treatment of atherosclerosis.
Muhlestein JB.
SUMMARY: PURPOSE OF REVIEW Several lines of evidence have demonstrated an association between a variety of chronic bacterial infections and atherosclerotic cardiovascular disease. This has led to the proposal that antibiotic therapy might be helpful in the secondary prevention of atherosclerosis. A variety of smaller pilot studies have been reported testing this hypothesis and several large multicenter trials are also underway. The purpose of this review is to summarize the results of these studies and comment on their implications for the treatment of atherosclerosis.RECENT FINDINGS Most of the antibiotic studies to date have been secondary prevention studies that have targeted patients exposed to Chlamydia pneumoniae. Most have used either azithromycin or roxithromycin with treatment courses ranging from a few days to 3 months. Several small studies of coronary artery disease patients have shown significant promise for reducing cardiovascular events such as death, myocardial infarction, or admission for unstable angina. However, other studies have not been so positive. Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, WIZARD, the largest study to date, in which stable post-myocardial infarction patients were randomized to receive a 3-month course of azithromycin or placebo, demonstrated a significant reduction in death and myocardial infarction by 6 months, but this benefit was not sustained throughout the remaining course of follow-up. The Azithromycin and Coronary Events (ACES) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials are ongoing and are testing the effect of more prolonged treatment duration.SUMMARY A variety of antibiotic trials for the secondary prevention of atherosclerosis have been performed. Several pilot studies have shown significant positive clinical effects, but, thus far, no large randomized trial has confirmed those findings. Some concerns over the antibiotics chosen and the duration of treatment have been raised. Other trials are underway to address some of those concerns. In the meantime, no recommendation for the use of antibiotic therapy for the secondary prevention of atherosclerosis can yet be made.

Am J Obstet Gynecol. 2003 Nov;189(5):1398-400.
Kigozi GG, Brahmbhatt H, Wabwire-Mangen F, Wawer MJ, Serwadda D, Curr Opin Lipidol. 2003 Dec;14(6):605-14.
Antibiotic treatment of atherosclerosis.
Muhlestein JB.
SUMMARY: PURPOSE OF REVIEW Several lines of evidence have demonstrated an association between a variety of chronic bacterial infections and atherosclerotic cardiovascular disease. This has led to the proposal that antibiotic therapy might be helpful in the secondary prevention of atherosclerosis. A variety of smaller pilot studies have been reported testing this hypothesis and several large multicenter trials are also underway. The purpose of this review is to summarize the results of these studies and comment on their implications for the treatment of atherosclerosis.RECENT FINDINGS Most of the antibiotic studies to date have been secondary prevention studies that have targeted patients exposed to Chlamydia pneumoniae. Most have used either azithromycin or roxithromycin with treatment courses ranging from a few days to 3 months. Several small studies of coronary artery disease patients have shown significant promise for reducing cardiovascular events such as death, myocardial infarction, or admission for unstable angina. However, other studies have not been so positive. Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, WIZARD, the largest study to date, in which stable post-myocardial infarction patients were randomized to receive a 3-month course of azithromycin or placebo, demonstrated a significant reduction in death and myocardial infarction by 6 months, but this benefit was not sustained throughout the remaining course of follow-up. The Azithromycin and Coronary Events (ACES) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials are ongoing and are testing the effect of more prolonged treatment duration.SUMMARY A variety of antibiotic trials for the secondary prevention of atherosclerosis have been performed. Several pilot studies have shown significant positive clinical effects, but, thus far, no large randomized trial has confirmed those findings. Some concerns over the antibiotics chosen and the duration of treatment have been raised. Other trials are underway to address some of those concerns. In the meantime, no recommendation for the use of antibiotic therapy for the secondary prevention of atherosclerosis can yet be made.

JAMA. 2003 Oct 1;290(13):1749-56.
Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.
Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd; Macrolide Study Group.
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY 10032-3784, USA.
CONTEXT: Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF. OBJECTIVE: To determine if an association between azithromycin use and pulmonary function exists in patients with CF. DESIGN AND SETTING: A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States. PARTICIPANTS: Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV1) of 30% or more. Participants were stratified by FEV1 (> or =60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center. INTERVENTION: The active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets. MAIN OUTCOME MEASURES: Change in FEV1 from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain. RESULTS: The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023-0.165; P =.009). Nausea occurred in 17% more participants in the azithromycin group (P =.01), diarrhea in 15% more (P =.009), and wheezing in 13% more (P =.007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P =.02). CONCLUSION: Zithromax treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.

JAMA. 2003 Sep 17;290(11):1459-66.
Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial.
O'Connor CM, Dunne MW, Pfeffer MA, Muhlestein JB, Yao L, Gupta S, Benner RJ, Fisher MR, Cook TD; Investigators in the WIZARD Study.
Duke University, Durham NC, USA.
CONTEXT: Several lines of evidence have implied an association between Chlamydia pneumoniae infection and atherogenesis. OBJECTIVE: To determine the effect of 12 weeks of antibiotic therapy on coronary heart disease events in patients with stable coronary artery disease and known C pneumoniae exposure. DESIGN, SETTING, AND PARTICIPANTS: Randomized, placebo-controlled trial of 7747 adults with previous myocardial infarction that had occurred at least 6 weeks previously (median, 2.6 years) and a C pneumoniae IgG titer of 1:16 or more. Patients were recruited from 271 clinical practices in North America, Europe, Argentina, and India, from October 10, 1997, to July 22, 2001. INTERVENTION: The patients received either azithromycin (600 mg/d for 3 days during week 1, then 600 mg/wk during weeks 2-12; n = 3879) or placebo (n = 3868). MAIN OUTCOME MEASURES: The primary event was the first occurrence of death from any cause, nonfatal reinfarction, coronary revascularization, or hospitalization for angina. Patients were followed up until 1038 events accrued. RESULTS: After a median of 14 months of follow-up, there was no significant risk reduction in the likelihood of a primary event with azithromycin vs placebo (7% [95% confidence interval, -5% to 17%], P =.23). Analysis of hazard ratios suggested early benefits of azithromycin on the primary event and on death or reinfarction, but these decreased over time. There were no significant risk reductions for any of the components of the primary end point including death (8%), recurrent myocardial infarction (7%), revascularization procedures (5%), or hospitalizations for angina (-1%). Adverse events related to study drug were reported by 13.2% of those randomized to receive azithromycin, predominantly a result of diarrhea, compared with 4.6% randomized to receive placebo, and resulted in discontinuation of drug in 1.6% of those taking azithromycin and 0.4% taking placebo. CONCLUSION: Among stable patients with previous myocardial infarction and with evidence of C pneumoniae exposure, a 3-month course of zithromax did not significantly reduce the clinical sequelae of coronary heart disease.

Kurume Med J. 2003;50(1-2):9-15.
Macrolide antibiotics directly reduce active oxygen generation by neutrophils in human peripheral blood.
Sugihara E, Koyanagi T, Niizeki T, Hirota N, Nagafuchi M, Yamada K, Kido Y, Ono N, Rikimaru T, Aizawa H.
Departme, Rikimaru T, Aizawa H.
Departmey School of Medicine, Kurume 830-0011, Japan.
Since a "low-dose and long-term" administration of erythromycin (EM) was reported to be effective in patients with chronic respiratory diseases, including diffuse panbronchiolitis (DPB), the modulation of host defense responses by EM has attracted much attention. Despite considerable controversy, it was recently demonstrated that macrolides reduced neutrophil function. In this study, we investigated the effects of EM, a 14-membered ring macrolide, azithromycin (AZM), a 15-membered ring macrolide, and rokitamycin (RKM), a 16-membered ring macrolide, on neutrophil function in terms of active oxygen generation of neutrophils in the absence and presence of mononuclear cells in vitro. EM and AZM significantly suppressed active oxygen generation by neutrophils in the absence of mononuclear cells at low concentration (0.5 microgram/ml. p < 0.05). At the next step, to confirm that EM and AZM directly reduced active oxygen generation by neutrophils, we investigated whether mononuclear cells affected this effect of EM and AZM. In the presence of mononuclear cells pretreated with EM or AZM, both antibiotics suppressed active oxygen generation at concentrations ranging from 0.5 to 20 micrograms/ml. However, the inhibition rates induced by EM and AZM at low concentrations were not so different between the absence and the presence of mononuclear cells. These results indicated that EM and AZM have direct effects on the active oxygen generation by neutrophils and those effects that were not influenced by mononuclear cells. This inhibitory effect may be responsible for the therapeutic efficacy of these 14-membered and 15-membered ring macrolides in patients with DPB.

Jpn J Antibiot. 2003 Jun;56(3):163-70.
Antimicrobial activities of macrolides against recent clinical isolates, and analysis of resistant mechanisms
Okubo T, Iyobe S, Fujiki Y, Sagai H.
Laboratory of Drug Resistance in Bacteria, Gunma University School of Medicine, 3-39-22, Showamachi, Maebashi, Japan.
We examined antibacterial activities of 4 kinds of macrolides, erythromycin (EM), clarithromycin (CAM), azithromycin (AZM) and rokitamycin (RKM), against 6 bacterial species of clinical strains isoleted in 2002. Bacterial isolates used were each 50 strains of methicillin-susceptible Staphylococcus aureus (MSSA), Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Haemophilus influenzae and 43 strains of Streptococcus pneumoniae. S. agalactiae were derived from gynecological samples, and other species were isolated from respiratory specimens. Antimicrobial activities against S. aureus, S. pyogenes, S. agalactiae, M. catarrhalis and H. influenzae of 14-membered macrolides, such as EM and CAM, were higher than those of 16-membered macrolide, RKM. By contrast, against S. pneumoniae, RKM was more effective than 14-membered macrolides. Six, three and four strains of S. aureus, S. pyogenes and S. agalactiae, respectively, were resistant to macrolides. Thirty-five among 43 pneumococcal isolates were resistant, and 15 of the 35 were highly-resistant, MIC of > 128 micrograms/ml, to any one of EM, CAM or AZM. Isolation frequency of resistant strains to RKM was lower than those to 14- and 15-membered macrolides: only one strain was highly-resistant and 12 were intermediately-resistant. No resistant strain was recognized in M. catarrhalis and H. influenzae. Further, we analyzed the resistant mechanisms, methylation or efflux, of macrolide resistant strains by the double-disk method. Methylation was major mechanism in S. aureus, and in S. pyogenes, all of the resistance was caused by methylation. In S. agalactiae and S. pneumoniae, methylation and efflux shared about half and half.