Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine

Brown, Sheldon T.; Edwards, F F; Bernard, Edward M.; Tong, William P.; Armstrong, Donald

doi:10.1128/aac.37.3.398

Cited by 29 publications

(13 citation statements)

References 24 publications

(21 reference statements)

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“…Azithromycin is poorly soluble in water and thus requires the use of a cosolvent for subcutaneous administration (4). One cosolvent investigated is polyoxyethylated castor oil (Cremophor EL).…”

Section: Discussionmentioning

confidence: 99%

Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular Mycobacterium avium infection

Nix

Straubinger

1995

Antimicrob Agents Chemother

116

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Mycobacterium avium is an intracellular pathogen that can invade and multiply within macrophages of the reticuloendothelial system. Current therapy is not highly effective. Particulate drug carriers that are targeted to the reticuloendothelial system may provide a means to deliver antibiotics more efficiently to M. aviuminfected cells. We investigated the formulation of the antibiotics ciprofloxacin and azithromycin in liposomes and tested their antibacterial activities in vitro against M. avium residing within J774, a murine macrophagelike cell line. A conventional passive-entrapment method yielded an encapsulation efficiency of 9% for ciprofloxacin and because of aggregation mediated by the cationic drug, was useful only with liposomes containing <50 mol% negatively charged phospholipid. In contrast, ciprofloxacin was encapsulated with >90% efficiency, regardless of the content of negatively charged lipids, by a remote-loading technique that utilized both pH and potential gradients to drive drug into preformed liposomes. Both the cellular accumulation and the antimycobacterial activity of ciprofloxacin increased in proportion to the liposome negative charge; the maximal enhancement of potency was 43-fold in liposomes of distearoylphosphatidylglycerol-cholesterol (DSPG-Chol) (10:5). Azithromycin liposomes were prepared as a freeze-dried preparation to avoid chemical instability during storage, and drug could be incorporated at 33 mol% (with respect to phospholipid). Azithromycin also showed enhanced antimycobacterial effect in liposomes, and the potency increased in parallel to the moles percent of negatively charged lipids; azithromycin in DSPG-Chol (10:5) liposomes inhibited intracellular M. avium growth 41-fold more effectively than did free azithromycin. Thus, ciprofloxacin or azithromycin encapsulated in stable liposomes having substantial negative surface charge is superior to nonencapsulated drug in inhibition of M. avium growth within cultured macrophages and may provide more effective therapy of M. avium infections.Mycobacterium avium infection is a common complication in AIDS (10, 38). For specimens taken from AIDS patients, M. avium could be cultured from 23 to 50% of blood cultures (37). M. avium can invade macrophages of the reticuloendothelial system (39), and intracellular organisms are able to withstand or evade macrophage antibacterial mechanisms. Furthermore, intracellular bacteria are shielded by the host cell from both immune surveillance and extracellular antibiotics.For effective therapy of M. avium infection, drugs must penetrate the host cells in cytostatic or cytotoxic concentrations. However, many antibiotics lack the ability to traverse the cell membrane, are excluded from acidic compartments such as the phagocytic apparatus, or are severely toxic when administered in the high doses necessary to overcome their low cellular permeability (19,36). To maximize the antimycobacterial effects of antibiotics while minimizing their toxicity, drug carriers to target drugs to M. avium-infected c...

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Section: Discussionmentioning

confidence: 99%

Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular Mycobacterium avium infection

Nix

Straubinger

1995

Antimicrob Agents Chemother

116

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“…Azithromycin was selected because of the following properties: prolonged inhibition of the replication of intracellular tachyzoites (Chamberland, Kirst & Current, 1991); in-vitro activity against cyst forms (Huskinson-Mark, ; high tissue specificity, with concentrations in the brain which are almost ten-fold higher than those in serum after oral dosing (Araujo, Shepard & Remington, 1991); significant intracellular accumulation (Gladue el ai, 1989); and potent activity in experimental murine toxoplasmosis (Araujo, Guptill & Remington, 1988;Araujo et al, 1991;Derouin et al, 1992). A number of additional observations also suggested that azithromycin might be suitable in this context: a prolonged half-life (Girard et al, 1987), thereby allowing a simplified dosing schedule; good tolerability; lack of effect on zidovudine disposition in patients with AIDS (Chave et al, 1992); and potential activities against cryptosporidium and the Mycobacterium avium complex (Brown et al, 1993;Vargas et al, 1993). The 100-mg/kg/day dosage was used because it corresponds to that which is appropriate for man after size correction.…”

Section: Treated Animalsmentioning

confidence: 99%

Evaluation of the efficacy of prolonged administration of azithromycin in a murine model of chronic toxoplasmosis

Dumas¹,

Chang²,

Mermillod

et al. 1994

J Antimicrob Chemother

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“…Numerous studies have been performed either in vitro (25,28,36,49) or on macrophages (46) and in animal models (6,21,34,38,39) with classic or more recent antituberculous agents (ciprofloxacin, sparfloxacin, azithromycin, and clarithromycin) alone or in combi-…”

mentioning

confidence: 99%

“…For each type of tissue assay, an antibiotic calibration range was determined with the organ involved (6,45). The elimination half-life (t1/2/) was calculated according to a single-compartment model by exponential regression of the concentrations in serum from 0.25 to 2 h. Areas under the curve (AUCs) from 0 to 6 h were calculated by the trapezoidal rule method.…”

mentioning

confidence: 99%

Pharmacokinetics, toxicity, and efficacy of liposomal capreomycin in disseminated Mycobacterium avium beige mouse model

Conte¹,

Gallou²,

Potel³

et al. 1994

Antimicrob Agents Chemother

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Capreomycin was incorporated into multilamellar vesicles of pure dipalmitoylphosphatidylcholine. The pharmacokinetics and nephrotoxicity of capreomycin in the free and liposomal forms were studied in normal mice. The efficacies of the two forms were evaluated by using the Mycobacterium avium complex beige mouse model. Approximately 107 viable M. avium cells were injected intravenously. Seven days later, treatment with either liposomal or free capreomycin at 60 or 120 mg/kg of body weight was administered daily for 5 days. Mice were sacrificed 5 days after the end of treatment, and the viable bacteria in liver, spleen, lungs, and blood were counted. After 5 days of treatment with dosages of 60 or 120 mg/kg/day, the level of blood urea nitrogen increased in the group treated with free capreomycin but not in the group treated with liposomal capreomycin. After intravenous injection of 120 mg/kg, liposomes enhanced the diffusion of capreomycin in the spleen, lungs, and kidneys and increased the half-life in serum. The 120-mg/kg dose of liposomal capreomycin significantly reduced the number of viable mycobacteria in the liver, spleen, and blood compared with those in the controls. Although these results are promising, further studies are needed to assess the efficacy of liposomal capreomycin for the treatment of M. avium complex infections.Since the appearance of the human immunodeficiency virus (HIV), the incidence of Mycobacterium avium complex (MAC) infections has increased considerably and has involved between 18 and 50% of HIV-infected patients (17,24,33). Treatment is difficult because of the weakened immune defense system of the host and the resistance of MAC strains to many classic antituberculous agents. Moreover, the phenotypes of resistance of these strains are very heterogeneous (25,26,49).Experimental infection models involving animal or human macrophage cultures and acute or chronic infections in the mouse have been developed to assess the activities of antiinfectious agents against MAC (32). Numerous studies have been performed either in vitro (25,28,36,49) or on macrophages (46) and in animal models (6,21,34,38,39) with classic or more recent antituberculous agents (ciprofloxacin, sparfloxacin, azithromycin, and clarithromycin) alone or in combi-

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Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine

Cited by 29 publications

References 24 publications

Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular Mycobacterium avium infection

Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular Mycobacterium avium infection

Evaluation of the efficacy of prolonged administration of azithromycin in a murine model of chronic toxoplasmosis

Pharmacokinetics, toxicity, and efficacy of liposomal capreomycin in disseminated Mycobacterium avium beige mouse model

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