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Azithromycin was shown to specifically inhibit the protein synthesis of Toxoplasma gondii in experimental systems by using free tachyzoites and T. gondii-infected mouse macrophages. RNA synthesis of the parasite was not affected by azithromycin. Inhibition of protein synthesis was also proportional to the relative anti-Toxoplasma activity of three macrolides.
The in vitro activities of the macrolide antibiotics clarithromycin, 14-hydroxy-clarithromycin, azithromycin, and erythromycin against 19 isolates of Borrelia burgdorferi were investigated. MICs ranged from 0.003 to 0.03 microgram of clarithromycin per ml, 0.007 to 0.03 microgram of 14-hydroxyclarithromycin per ml, 0.003 to 0.03 microgram of azithromycin per ml, and 0.007 to 0.06 microgram of erythromycin per ml. Time-kill studies using the B31 strain of B. burgdorferi demonstrated a > or = 3-log10-unit killing after 72 h with each of the macrolide antibiotics tested in concentrations representing twice the respective MICs.
By using an in vitro microassay to assess drug interaction, azithromycin combined to pyrimethamine was found more active than pyrimethamine alone against Toxoplasma gondii, and additivity between those drugs was demonstrated. Our results show that the combination of azithromycin and pyrimethamine may lead to a more rapid control of T. gondii.
The penetration of azithromycin into the blister fluids of six volunteers was analyzed after a 5-day regimen (total of 1.5 g). Differences in drug concentrations in a paper disk and serum and in the mass of azithromycin from inflammatory blister chamber leukocytes and noninflammatory blister chamber leukocytes were significant (P < 0.05).
The Oxyrase agar dilution method (Oxyrase, Inc., Mansfield, Ohio), which provides an anaerobic environment without added CO2, was compared with the reference agar dilution method recommended by the National Committee for Clinical Laboratory Standards (anaerobic chamber with 10% CO2) to test the susceptibilities of 302 gram-negative and gram-positive anaerobes to erythromycin, azithromycin, clarithromycin, and roxithromycin. For erythromycin, the overall MIC for 50% of isolates tested (MIC50) was 0.5 micrograms/ml and the MIC90 was 8.0 micrograms/ml by the Oxyrase method, whereas they were 4.0 and 64.0 micrograms/ml, respectively, under standard anaerobic conditions with CO2. At a breakpoint of 4.0 micrograms/ml, 88% of strains were susceptible to erythromycin by the Oxyrase method, whereas 63% were susceptible in the chamber. The corresponding MIC50s and MIC90s of azithromycin, clarithromycin, and roxithromycin by the Oxyrase method were 0.5 and 8.0, 0.25 and 4.0, and 0.5 and 16.0 micrograms/ml, respectively, whereas in the chamber they were 4.0 and > 64.0, 2.0 and 64.0, and 2.0 and 64.0 micrograms/ml, respectively. At a breakpoint of 8.0 micrograms/ml for these three drugs, 89, 92, and 85% of the isolates, respectively, were susceptible by the Oxyrase method, whereas 67%, 72, and 68% of the isolates, respectively, were susceptible in the chamber. Most strains resistant to all four compounds by both methods were Bacteroides distasonis, Fusobacterium mortiferum, Fusobacterium varium and non-Clostridium perfringens Clostridium species. Results of the study may lead to a reappraisal of the role played by macrolides and azalides in the treatment of anaerobic infections.
Organisms of the Mycobacterium avium complex (MAC) cause disseminated disease in patients with AIDS, and evidence points to the gastrointestinal tract as the major route of infection. Since MAC can bind to and invade intestinal mucosal cells, we examined whether subinhibitory concentrations of antibiotics which have anti-MAC activity in vitro affect the interaction between MAC and HT-29 intestinal mucosal cells. MAC isolates were exposed to subinhibitory concentrations of rifabutin (MIC, 2.6 micrograms/ml), sparfloxacin (MIC, 8.4 micrograms/ml), or azithromycin (MIC, 32 micrograms/ml) for 30 to 120 min, washed, and incubated with HT-29 cell monolayers for 2 h at 4 degrees C. HT-29 cell monolayers were then washed to remove unbound bacteria and were subsequently lysed. The number of MAC isolates that bound to the HT-29 cells was determined by plating the cell lysate onto 7H10 agar. Preincubation of the MAC isolates with rifabutin at concentrations of 1 and 2 micrograms/ml reduced MAC binding to HT-29 cells by 80 to 90%, while MAC exposed to sparfloxacin at 1 and 7 micrograms/ml inhibited binding by 77 to 93%. Azithromycin at concentrations of 2, 10, and 30 micrograms/ml had no effect on MAC binding to HT-29 cells. Inhibition of MAC binding to the gastrointestinal mucosa may be one underlying mechanism for the prophylactic effects of rifabutin and quinolones.
After an oral dose of 500 mg of azithromycin in patients with community-acquired pneumonia, their serum concentrations ranged between 0.06 and 0.25 mg/liter during the first 12 hours; the calculated percentages of unbound drug varied between 45 and 86%. This study shows that in these patients, the total levels of azithromycin in serum are lower than those expected and that the percentage of bound drug is clinically irrelevant.
The activities of sparfloxacin, levofloxacin, Bay y 3118, azithromycin, cefprozil, loracarbef, and nine other oral antimicrobial agents against 194 aerobic and anaerobic clinical bite wound isolates were determined by the agar dilution method. Sparfloxacin, levofloxacin, and Bay y 3118 were active against all aerobic isolates (MICs at which 90% of the isolates are inhibited [MIC90], < or = 1.0 microgram/ml for sparfloxacin and levofloxacin and 0.1 microgram/ml for Bay y 3118) and many anaerobic isolates, with the exception of the fusobacteria. Azithromycin was more active than erythromycin by 1 to 2 dilutions against many aerobes, including Pasteurella multocida and Eikenella corrodens, and by 2 to 4 dilutions against anaerobic isolates. Cefprozil was more active (MIC90, < or = 1 microgram/ml) than loracarbef (MIC90, < or = 4 micrograms/ml) against aerobic gram-positive isolates, but both had poor activity (MIC90, > or = 16 micrograms/ml) against peptostreptococci. Both cefprozil and loracarbef had MIC90s of < or = 0.5 micrograms/ml against P. multocida.
Investigations of pharmacodynamic parameters (postantibiotic effect [PAE], sub-MIC effects [SMEs], etc.) have been progressively employed for the design of dosing schedules of antimicrobial agents. However, there are fewer in vivo than in vitro data, probably because of the simplicity of the in vitro procedures. In this study, we have investigated the in vitro PAE, SME, and previously treated (postantibiotic [PA]) SME (1/2 MIC, 1/4 MIC and 1/8 MIC) of azithromycin and isepamicin against standard strains of Staphylococcus aureus and Escherichia coli by using centrifugation to remove the antibiotics. In addition, the in vivo PAE and SME have been studied with the thigh infection model in neutropenic mice. Finally, in vivo killing curves with two dosing schedules were determined to examine whether the PAE can cover the time that antimicrobial agents are below the MIC. The two antimicrobial agents induced moderate-to-high in vitro PAEs, SMEs, and PA SMEs against S. aureus (>8 h) and E. coli (3.38 to >7.64 h). The in vivo PAEs were also high (from 3.0 to 3.6 h), despite the fact that isepamicin had lower times above the MIC in serum. Only azithromycin showed a high in vivo SME against the two strains (1.22 and 1.75 h), which indicated that the in vivo PAEs were possibly overestimated. In the killing kinetics, no great differences (<0.5 log10) were observed between the schedule that took the PAE into account and the continuous administration of doses. These results are comparable with those of other authors and suggest that these antimicrobial agents could be administered at longer intervals without losing effectiveness.
When tested by agar dilution on Mueller-Hinton agar supplemented with 5% horse blood, the ketolides HMR 3004 and HMR 3647 were slightly more active (MIC at which 90% of the isolates were inhibited [MIC90], 0.03 microg/ml) against Bordetella pertussis than azithromycin, clarithromycin, erythromycin A, and roxithromycin. Azithromycin (MIC90, 0.06 microg/ml) was the most active compound against B. parapertussis. Rifampin and rifapentine were considerably less active.
The activities of HMR 3004 and HMR 3647 and comparator agents, especially macrolides, were determined by the agar dilution method against 262 aerobic and 120 anaerobic strains isolated from skin and soft tissue infections associated with human and animal bite wounds. HMR 3004 and HMR 3647 were active against almost all aerobic and fastidious facultative isolates (MIC at which 90% of the isolates are inhibited [MIC90], < or = 0.5 and 1 microg/ml, respectively) and against all anaerobes [Bacteroides tectum, Porphyromonas macacae (salivosa), Prevotella heparinolytica, Porphyromonas sp., Prevotella sp., and peptostreptococci] at < or = 0.25 and < or = 0.5 microg/ml, respectively, except Fusobacterium nucleatum (HMR 3004, MIC90 = 16 microg/ml; HMR 3647, MIC90 = 8 microg/ml) and other Fusobacterium species (MIC90, 1 and 2 microg/ml, respectively). In general, HMR 3004 and HMR 3647 were more active than any of the macrolides tested. Azithromycin was more active than clarithromycin against all Pasteurella species, including Pasteurella multocida subsp. multocida, Eikenella corrodens, and Fusobacterium species, while clarithromycin was more active than azithromycin against Corynebacterium species, Weeksella zoohelcum, B. tectum, and P. heparinolytica.
The pharmacokinetics in serum and leukocyte (WBC) exposures of 1,500 mg of oral azithromycin administered as 3-day (500 mg/day, days 1 to 3) and 5-day (500 mg on day 1 and 250 mg/day on days 2 to 5) regimens were compared in 12 healthy volunteers. Serum, polymorphonuclear leukocytes, and mononuclear leukocytes were collected over a 12-day period from the start of each regimen. Results of the study indicate that the exposures of serum and both types of WBCs were similar with both regimens. Drug concentrations in day 12 WBCs were well above the MICs for all relevant community-acquired respiratory tract pathogens. Terminal half-lives in serum obtained by both regimens were essentially equal at 66 h and consistent with past reports. These results indicate that the standard 1,500-mg dose of oral azithromycin can be administered over either 5 or 3 days.
The antimicrobial activity of concentrations of selected macrolides found in epithelial cell lining fluid was investigated. Clarithromycin demonstrated greater potency and a significantly longer postantibiotic effect (PAE) than azithromycin against Streptococcus pneumoniae. Azithromycin displayed greater potency, faster killing, and a longer PAE than clarithromycin against Haemophilus influenzae. Drug concentrations in epithelial cell lining fluid similar to those found in tissue did not improve the synergistic potential of 14-hydroxy-clarithromycin and indicate that a maximal PAE may exist despite increasing concentrations of drug.
The intracellular dispositions of clarithromycin and azithromycin in AIDS patients requiring Mycobacterium avium complex (MAC) prophylaxis were studied. The dispositions of both drugs in mononuclear and polymorphonuclear leukocytes were markedly different. Our data support the proven efficacy of these agents for MAC prophylaxis since clarithromycin and azithromycin displayed sustained intracellular concentrations which exceeded their MICs for MAC throughout the dosing periods.
Two patients suffering from Brill-Zinsser disease were treated with azithromycin, which did not prove effective. Rickettsia prowazekii, the agent causing Brill-Zinsser disease, cannot be treated with azithromycin. Both patients had epidemiological features consistent with and a clinical course typical of the disease. The diagnosis of Brill-Zinsser disease was serologically confirmed.
The effects of treatment with azithromycin plus rifampin (A+R), amoxicillin (A), or placebo (P) on the chronic course of experimental Chlamydia pneumoniae pneumonitis in mice were assessed by culture, PCR, and immunocytochemistry as well as by degree of inflammation in lung tissue. Eradication of the pathogen was significantly more frequent and inflammation in tissue was significantly reduced after treatment with A+R compared to after treatment with A or P. Combination therapy with azithromycin plus rifampin showed favorable effects in the chronic course of C. pneumoniae pneumonitis.
This multicenter study evaluated the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin in volunteers with or without human immunodeficiency virus infection. Daily dosing with the combination of azithromycin and rifabutin was poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. No significant pharmacokinetic interactions were found between these drugs.
We determined the protective effect of moxifloxacin, azithromycin, and amoxicillin against Streptococcus pneumoniae infection of respiratory cells. Moxifloxacin and azithromycin effectively killed intracellular S. pneumoniae strains and protected respiratory epithelial cells significantly even when given 6 h after S. pneumoniae challenge. Amoxicillin was less effective.