Antimicrob Agents Chemother. 1992 Dec;36(12):2693-7.
Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin [Zithromax] compared with clindamycin and rifampin.

O'Reilly T, Kunz S, Sande E, Zak O, Sande MA, Tauber MG.

Pharma Research, Ciba-Geigy Ltd., Basel, Switzerland.

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

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1336342&dopt=Abstract Zithromax azithromycin




Scand J Infect Dis Suppl. 1992;83:15-21.
Azithromycin [Zithromax] pharmacokinetics and penetration to lymph.

Bergan T, Jorgensen NP, Olszewski W, Zhang Y.

Department of Microbiology, University of Oslo, Norway.

The study of pharmacokinetics of azithromycin [Zithromax] and penetration to peripheral human lymph was carried out in 14 healthy male volunteers taking 1 g orally after overnight fasting. Samples were analyzed by microbiological assay. The mean peak concentrations were 0.82 +/- 0.23 mg/l after 1.7 +/- 0.5 h in serum and 0.22 +/- 0.07 mg/l after 3.1 h in lymph. Nine of the 14 subjects showed a second and lower serum peak indicating the existence of enterohepatic circulation. The total areas under the serum concentrations curves (AUCs) till infinity were 7.9 +/- 3.1 mg. h/l compared to 4.4 +/- 1.2 mg.h/l in lymph. The mean lymph AUC was 68.1 +/- 20.7% of the serum AUC indicating a penetration ratio of 0.68. However, the actual amounts penetrating the tissues were much higher than this ratio suggests. Thus, after 6 h 81% of the drug was within the tissue compartment and after 120 h, 63% of the azithromycin [Zithromax] was still present in the tissue compartment. The urinary recovery of azithromycin [Zithromax] was 14.7 +/- 7.7% during the first 48 h. The serum curves and lymph curves displayed a distinctly slower phase of elimination after 12 h. The mean serum half-life was 5.4 +/- 3.4 h during the first 12 h (after the peak), whereas the value was 44.2 +/- 10.1 h during the interval 12-120 h. The corresponding half-life values for the peripheral lymph were 5.4 +/- 2.2 h and 50.8 +/- 11.6 h. Azithromycin [Zithromax] possesses key pharmacokinetic properties that are prerequisites for a convenient once-daily dosage schedule which may improve patient compliance.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1336891&dopt=Abstract Zithromax azithromycin




J Antimicrob Chemother. 1992 Oct;30(4):497-507.
Potentiation of azithromycin [Zithromax] activity against Escherichia coli by human serum ultrafiltrate.

Pruul H, McDonald PJ.

Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Bedford Park, Australia.

In this study we investigated the influence of serum ultrafiltrate on the activities of azithromycin, other macrolides and unrelated antibiotics against Escherichia coli. In the presence of serum ultrafiltrate the MIC of azithromycin [Zithromax] was decreased by 10-fold. The activities of erythromycin and roxithromycin were also enhanced, although to a lesser extent. The potentiation of activity was inhibited by divalent cations and by pre-treatment of the ultrafiltrate with trypsin. Potentiation of azithromycin [Zithromax] activity was associated with a pH-independent, early increase in bactericidal activity and inhibition of bacterial metabolism. We postulate that low molecular weight proteinaceous components of normal human serum interact with azithromycin [Zithromax] and other macrolides to alter the susceptibility of Gram-negative bacteria to the antibiotics, possibly through increased macrolide penetration across the bacterial cell membrane permeability barriers.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1337068&dopt=Abstract Zithromax azithromycin




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 [Zithromax] 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 [Zithromax] 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 [Zithromax] 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.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14624138&dopt=Abstract Zithromax azithromycin[PubMed - in process]




J Periodontol. 1999 Sep;70(9):960-6.
Periodontal tissue disposition of azithromycin [Zithromax] in patients affected by chronic inflammatory periodontal diseases.

Blandizzi C, Malizia T, Lupetti A, Pesce D, Gabriele M, Giuca MR, Campa M, Del Tacca M, Senesi S.

Dipartimento di Oncologia, Divisione di Farmacologia e Chemioterapia, Universita di Pisa, Italy.

BACKGROUND: The recognition that periodontal diseases are associated with specific pathogens has led to interest in the use of antibacterial drugs for inhibition of these microorganisms. On these bases, the present study was aimed at evaluating the tissue distribution of the new macrolide antibiotic azithromycin [Zithromax] in patients subjected to oral surgery for chronic inflammatory diseases of both marginal and periapical periodontium. METHODS: Thirty-two patients were treated with azithromycin [Zithromax] 500 mg/day orally for 3 consecutive days, and drug concentrations in plasma, saliva, normal gingiva, and pathological periodontal tissues were evaluated. For this purpose, samples of blood, saliva, normal gingiva, granulation tissue, and radicular granuloma or cyst wall (from dentigerous cyst) were collected during oral surgery or 0.5, 2.5, 4.5, and 6.5 days after the end of pharmacological treatment; then, azithromycin [Zithromax] levels were measured by a microbiological plate assay, using Micrococcus luteus NCTC 8440 as the indicator organism. RESULTS: The concentrations of azithromycin [Zithromax] in plasma, saliva, normal gingiva, and pathological tissues reached the highest values 12 hours after the last dose (0.37+/-0.05 mg/l, 2.12+/-0.30 mg/l, 6.30+/-0.68 mg/kg, and 11.60+/-1.50 mg/kg, respectively) and then declined gradually. Consistent levels of the drug in normal gingiva and pathological tissues could be detected, however, up to 6.5 days, indicating that azithromycin [Zithromax] was retained in target tissues for a long time after the end of treatment. Moreover, azithromycin [Zithromax] levels in both normal gingiva and pathological tissues exceeded the minimum inhibitory concentrations of most pathogens involved in the pathophysiology of chronic inflammatory periodontal diseases. Notably, azithromycin [Zithromax] levels in pathological tissues were significantly higher than those in normal gingiva 0.5, 2.5, and 4.5 days after the last dose. CONCLUSIONS: The present results indicate a marked penetration of azithromycin [Zithromax] into both normal and pathological periodontal tissues, suggesting that azithromycin [Zithromax] represents a promising option in both adjunctive and prophylactic treatments of chronic inflammatory periodontal diseases.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10505797&dopt=Abstract Zithromax azithromycin




J Infect Dis. 1991 Jun;163(6):1293-6.
Activity of azithromycin [Zithromax] against cryptosporidia in immunosuppressed rats.

Rehg JE.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38101.

Dexamethasone-immunosuppressed rats infected with Cryptosporidium parvum were used to assess the macrolides azithromycin [Zithromax] and spiramycin for anticryptosporidial activity. Azithromycin [Zithromax] consistently prevented ileal infection, while spiramycin was ineffective. The anticryptosporidial activity of azithromycin [Zithromax] was dose-related, 200 mg/kg/day being the minimum dose that prevented infection. Therapeutically, azithromycin [Zithromax] eliminated an established overt infection of the small intestine in immunosuppressed rats, but the infection recurred after azithromycin [Zithromax] treatment was stopped. These findings suggest that azithromycin [Zithromax] is a potentially useful anticryptosporidial agent and that long-term continuous administration may be necessary to treat cryptosporidiosis in the immunocompromised host.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1645382&dopt=Abstract Zithromax azithromycin




Antimicrob Agents Chemother. 1999 Oct;43(10):2468-72.
Decreased azithromycin [Zithromax] susceptibility of Neisseria gonorrhoeae due to mtrR mutations.

Zarantonelli L, Borthagaray G, Lee EH, Shafer WM.

National Center for Gonococcal Antimicrobial Susceptibility Surveillance, Department of Microbiology, School of Chemistry, Montevideo, 11800, Uruguay.

Single-dose azithromycin [Zithromax] therapy has recently been used in Uruguay for the treatment of uncomplicated gonococcal infections. As part of an active surveillance study to monitor the emergence of antibiotic resistance in gonococcal isolates, we examined the levels of azithromycin [Zithromax] susceptibility in 51 consecutive isolates obtained from males with uncomplicated gonococcal urethritis. Isolates with decreased susceptibility to azithromycin [Zithromax] (MICs, 0.25 to 0.5 microg/ml) were common, and these isolates often displayed cross-resistance to hydrophobic antimicrobial agents (erythromycin and Triton X-100). Resistance to erythromycin and Triton X-100 is frequently due to overexpression of the mtrCDE-encoded efflux pump mediated by mutations in the mtrR gene, which encodes a transcriptional repressor that modulates expression of the mtrCDE operon. Accordingly, we questioned whether clinical isolates that express decreased azithromycin [Zithromax] susceptibility harbor mtrR mutations. Promoter mutations that would decrease the level of expression of mtrR as well as a missense mutation at codon 45 in the mtrR-coding region that would result in a radical amino acid replacement within the DNA-binding motif of MtrR were found in these strains. When these mutations were transferred into azithromycin-susceptible strain FA19 by transformation, the susceptibility of gonococci to azithromycin [Zithromax] was decreased by nearly 10-fold. The mtrCDE-encoded efflux pump system was responsible for this property since insertional inactivation of the mtrC gene resulted in enhanced susceptibility of gonococci to azithromycin. We conclude that the mtrCDE-encoded efflux pump can recognize azithromycin [Zithromax] and that the emergence of gonococcal strains with decreased susceptibility to azithromycin [Zithromax] can, in part, be explained by mtrR mutations.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10508026&dopt=Abstract Zithromax azithromycin