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Is azithromycin the first-choice macrolide for treatment of community-acquired pneumonia?

Combination treatment with a beta-lactam plus a macrolide may improve the outcome for elderly patients with community-acquired pneumonia (CAP). The prognoses and mortality rates for elderly patients with CAP who receive ceftriaxone combined with a 3-day course of azithromycin or a 10-day course of clarithromycin were compared in an open-label, prospective study. Of 896 assessable patients, 220 received clarithromycin and 383 received azithromycin. There were no significant differences between groups with regard to the severity score defined by the Pneumonia Patient Outcomes Research Team (PORT) study group; the incidence of bacteremia was also not significantly different. However, for patients treated with azithromycin, the length of hospital stay was shorter (mean+/-SD, 7.4+/-5 vs. 9.4+/-7 days; P<.01) and the mortality rate was lower (3.6% vs. 7.2%; P<.05), compared with those treated with clarithromycin. There might be a difference in the outcome for patients with CAP depending on the macrolide used. A shorter treatment course with azithromycin may result in better compliance with therapy.

Adult↗

Azithromycin modulates murine immune responses to pneumococcal conjugate vaccine and inhibits nasal clearance of bacteria.

Macrolide antibiotics, including azithromycin, have been implicated in the modulation of host immune responses, independently of their antimicrobial properties. The present work was designed to study the effect that azithromycin has on protective humoral immune responses induced by a 7-valent, polysaccharide, pneumococcal conjugate vaccine (PCV7). By use of a murine vaccination/challenge model, it was found that inoculation with azithromycin led to significantly lower primary antibody responses, decreased recall proliferative responses, and, in nasal cavities, impaired clearance of Streptococcus pneumoniae serotype 14 from the nasal cavities. The results demonstrate that azithromycin can be inhibitory with regard to protective immune responsiveness.

Animals↗

Ultrashort regimen of lansoprazole-amoxicillin-azithromycin for eradicating Helicobacter pylori.

The efficacy and safety of two ultrashort azithromycin-containing regimens for Helicobacter pylori infection were studied. Patients positive for H. pylori infection were assigned to receive either a three-day drug regimen (group A) or a five-day regimen (group B). In both groups, patients received lansoprazole 30 mg p.o. twice daily on day 1 and, on days 2 and 3, lansoprazole 30 mg p.o. twice daily, amoxicillin 1 g (of anhydrous amoxicillin) p.o. twice daily, and azithromycin 500 mg (of anhydrous azithromycin) p.o. twice daily. Group B patients received lansoprazole 30 mg p.o. twice daily and amoxicillin 1 g p.o. twice daily for two additional days. Gastric biopsy specimens were subjected to culture and susceptibility testing. A minimum of four weeks after the completion of therapy, the patients underwent a 14C-urea breath test to determine whether H. pylori had been eradicated. A total of 28 patients were enrolled (15 in group A and 13 in group B). Treatment was well tolerated. H. pylori was eradicated in 4 (36%) of 11 patients in group A and 2 (22%) of 9 group B patients (26.6% and 15.4%, respectively, in intention-to-treat analysis). None of the isolates of H. pylori showed resistance to amoxicillin or clarithromycin. Regimens consisting of lansoprazole plus two or four days of azithromycin and amoxicillin therapy eradicated H. pylori in 36% and 22% of patients, respectively.

2-Pyridinylmethylsulfinylbenzimidazoles↗

Bacteriostatic and bactericidal activity of azithromycin against Haemophilus influenzae.

Macrolide antibiotics, commonly used in upper and lower respiratory tract infections, are inconsistently active against Haemophilus influenzae. The new azalide, azithromycin, was compared with erythromycin and roxithromycin against this pathogen. Azithromycin (MIC range 0.06-1 mg/l) was four to eight times more potent than erythromycin (MIC range 0.5-8 mg/l) and roxithromycin (MIC range 0.5-16 mg/l). At 1 mg/l, 100% of the strains of H. influenzae were inhibited by azithromycin compared with 16% with erythromycin and 5% with roxithromycin. Azithromycin exhibited a rapid bactericidal effect, with a 99.9% kill at 4 h. The MBC was equal to or up to four-times greater than the MIC.

Azithromycin↗

In-vitro and in-vivo susceptibility of Borrelia burgdorferi to azithromycin.

The in-vitro and in-vivo susceptibility of Borrelia burgdorferito tetracycline, erythromycin and azithromycin was investigated. A macrodilution broth technique was used to determine MBCs. B. burgdorferi was most susceptible to azithromycin (MBC 0.04 mg/l) followed by erythromycin (MBC 0.16 mg/l) and tetracycline (MBC 1.6 mg/l). Syrian hamsters were used to determine ED50S for the three antimicrobials. Azithromycin was most effective in the elimination of spirochaetes from experimentally infected hamsters with an ED50 of 3.71 (+/- 1.9) mg/kg followed by tetracycline (ED50 15.6 (+/- 4.58) mg/kg). Erythromycin possessed low activity, having an ED50 of 122.2 (+/- 51.9) mg/kg. Tissue concentrations of azithromycin exceeding the MBC were present 24 h after the final treatment.

Animals↗

In-vitro activity of azithromycin against Chlamydia trachomatis.

We evaluated the efficacy of azithromycin, erythromycin and doxycycline in controlling in-vitro propagation of Chlamydia trachomatis in HeLa 229 cells. Eight recent clinical isolates of C. trachomatis and two fast-growing strains were tested with inocula of 10(3)-10(5) inclusion forming units per well of a 96-well microtitre plate. C. trachomatis inclusions were detected by an immunoperoxidase-antiperoxidase procedure (PAP), including a genus-specific monoclonal antibody. MIC ranges were 0.064-0.25 mg/l azithromycin, 0.064-0.128 mg/l erythromycin and 0.016-0.064 mg/l doxycyline; MBC ranges were 2-8 mg/l azithromycin, 4-64 mg/l erythromycin and 0.5-8 mg/l doxycycline. Since azithromycin appears to be effective against C. trachomatis, clinical studies in sexually transmitted diseases are indicated.

Azithromycin↗

The pharmacokinetics of azithromycin in human serum and tissues.

The pharmacokinetics of azithromycin, a new azalide antibiotic, were examined in man. Approximately 37% of a single oral dose of 500 mg was bioavailable and produced a peak serum concentration of 0.4 mg/l. Multiple dose regimens (two doses of 500 mg separated by 12 h and followed by 500 mg qds for five days, or two doses of 250 mg separated by 12 h and followed by 250 mg qds for nine days) produced only slight increases in peak serum concentrations. The serum protein binding of azithromycin declined from about 50% at 0.02 mg/l to 12% at 0.5 mg/l. Tissue concentrations of azithromycin were much higher than serum concentrations. After two 250 mg doses 12 h apart, peak azithromycin concentrations exceeded 3 mg/kg in prostate, tonsil and many other tissues. Concentrations in tissues declined with apparent half-lives of 2.3 days in prostate and 3.2 days in tonsil. The high tissue concentrations suggest that proposed standard dosage regimens of 500 mg qds on day 1 followed by 250 mg qds for four days, or three daily dosages of 500 mg, will produce tissue concentrations above 3 mg/kg in a variety of tissues. Since these tissue concentrations exceed the MICs of relevant pathogens, these dosage regimens should be effective against respiratory tract and soft-tissue infections. A single 1 g dose may be effective in the treatment of many sexually transmitted diseases.

Adolescent↗

Comparative in-vitro activity of azithromycin, macrolides (erythromycin, clarithromycin and spiramycin) and streptogramin RP 59500 against oral organisms.

The in-vitro activities of azithromycin, clarithromycin, spiramycin and RP 59500 were compared with erythromycin against a wide range of oral organisms which have been implicated in oral infections and/or endocarditis (clindamycin was included for oral streptococci). All compounds tested showed good activity against many of these organisms, although some variation was observed with different species. Clarithromycin was the most active of the antibiotics tested against Gram-positive anaerobes, including Actinomyces spp., Propionibacterium spp., Lactobacillus spp. and Bifidobacterium dentium. Azithromycin was slightly less active than erythromycin against these species. In general, RP 59500 had higher MICs than the macrolides, other than spiramycin, against these organisms, but was superior in activity against Peptostreptococcus spp., inhibiting all isolates at 2 mg/L. Azithromycin was, in general, the most active antibiotic tested against the Gram-negative anaerobes: Fusobacterium spp., Bacteroides spp., Wolinella spp., Actinobacillus actinomycetemcomitans, Selenomonas spp. and Mitsuokella multiacida, including those isolates which were insusceptible to erythromycin. Clarithromycin showed similar activity to erythromycin against most Gram-negative species, but was superior against Capnocytophaga ochraceus and Eikenella corrodens. RP 59500 was less active than the macrolides against most Gram-negative anaerobes, but was superior to erythromycin and clarithromycin against Fusobacterium spp. and Leptotrichia buccalis, some strains of which were moderately resistant to erythromycin. The macrolides and clindamycin were about equally active against the oral streptococci, whereas RP 59500 showed lower inhibitory activity. The in-vitro results suggest that azithromycin and clarithromycin may be of value in the treatment of dental sepsis and the prophylaxis of endocarditis. RP 59500 showed useful activity against Gram-positive anaerobes and, because of its bactericidal activity against oral streptococci, may also prove to have a role in these areas.

Anti-Bacterial Agents↗

Potentiation of azithromycin activity against Escherichia coli by human serum ultrafiltrate.

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 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 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 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.

Azithromycin↗

In-vitro activity of azithromycin on Chlamydia trachomatis infected, polarized human endometrial epithelial cells.

The in-vitro activity of azithromycin on Chlamydia trachomatis infected human endometrial epithelial cells, both primary and transformed cells growing in a polarized and non-polarized orientation, was analyzed. Addition of azithromycin two hours after adsorption inoculation with continued exposure until 72 h gave an MIC90 and MBC90 of 0.063 and 0.5 mg/L, respectively. In addition, the MBC results were more pronounced in infected cells growing in a polarized orientation. Numerous small fluorescent 'spots' (presumed small abnormal inclusions) were visible in the infected cells exposed to MIC concentrations of azithromycin. Immuno-transmission electron microscopy examination revealed intracellular inclusions filled with chlamydial envelope ghosts. Since standard diagnostic antigen detection methods use anti-envelope antibodies, the aberrant envelope-filled inclusions might be interpreted as viable inclusions by fluorescent microscopy and result in high false positive readings. To simulate treatment of an infected patient, azithromycin was added at 18 h to infected cells containing many reticulate bodies and exposure continued for 54 h after which killing of chlamydiae was seen. The use of polarized human cells may offer a more relevant in-vitro model system for examining the efficacy of antimicrobial action.

Azithromycin↗

Inhibition of Pseudomonas aeruginosa virulence factors by subinhibitory concentrations of azithromycin and other macrolide antibiotics.

The ability of three macrolide antibiotics (erythromycin, clarithromycin and azithromycin) to inhibit the expression of several pathogenicity traits of Pseudomonas aeruginosa at concentrations that do not affect the rate of growth of this microorganism was investigated. Sub-MICs of azithromycin manifested the broadest spectrum of action and strongly suppressed the synthesis of elastase, proteases, lecithinase and DNase. Clarithromycin and erythromycin were far less effective. Gelatinase was reduced almost to the same level by the three antibiotics, while haemolysins and lipase were only marginally affected. Loss of motility was a strain and drug-dependent event, but all the macrolides tested shared the ability to induce this effect. However, only azithromycin totally suppressed synthesis of pyocyanin in all isolates. These results indicate that newer macrolides and especially axithromycin are endowed with a remarkable ability to inhibit in vitro the expression of a number of physiological processes that are considered more essential than replication in the pathogenesis of P. aeruginosa. Since erythromycin sub-MICs have already been shown to exert beneficial effects in clinical practice, our data, pointing to a much higher potency of azithromycin, suggest its use in future studies.

Anti-Bacterial Agents↗

In-vitro concentration of azithromycin in human phagocytic cells.

The in-vitro intraphagocytic uptake and retention of azithromycin in both human polymorphonuclear leucocytes (PMN) and alveolar macrophages was measured by an improved high-performance liquid chromatography (HPLC) method that was approximately three-fold more sensitive than previous methods. Azithromycin was accumulated in PMN and alveolar macrophages (about 300-fold), with maximum uptake being obtained after incubation for 60 min. Azithromycin was eliminated only partially from the cells during the washing process, and was released slowly during re-incubation of phagocytic cells in antibiotic-free medium. This intracellular retention distinguishes azithromycin from most of the macrolides and quinolones which, in spite of high I/E ratios, are released rapidly from cells.

Azithromycin↗

Comparison of azithromycin and doxycycline in the treatment of non-gonococcal urethritis in men.

Azithromycin has activity in vitro against Chlamydia trachomatis, and its novel pharmacokinetics suggest that even single doses may be effective in the treatment of non-gonococcal urethritis (NGU). This study compared the efficacy and safety of a single 1 g oral dose of azithromycin versus doxycycline 100 mg bid for seven days in the treatment of NGU. Men with symptoms and/or signs of NGU, and with > or = 5 polymorphonuclear leucocytes/high-power field in a Gram's-stained urethral smear, were recruited. Investigations included endourethral swabs for C. trachomatis cell culture. Patients were randomized to receive azithromycin or doxycycline, and were re-assessed on day 7-10 and on day 14-21. Of the 143 men recruited, C. trachomatis was isolated from 51 (40%) of the 128 evaluable patients. Both treatments were well tolerated and had comparable cure rates. Azithromycin 1 g appears to be an effective and safe alternative to doxycycline for the treatment of chlamydial and non-chlamydial urethritis, and its single-dose administration is an advantage in terms of patient compliance.

Administration, Oral↗

Selection of dose regimens of azithromycin .

The unique pharmacokinetics of azithromycin are characterized by high, sustained tissue concentrations. The concentrations of azithromycin were predicted, following various multiple dose regimens, from concentrations in tonsillar, prostatic, and uterine tissues following single oral doses. Following a five-day treatment regimen (500 mg on day 1, followed by 250 mg on days 2-5), or a three-day regimen (500 mg daily for three days), concentrations of azithromycin in tonsillar tissue, representative of respiratory tract tissues, will continuously be greater than the MICs for key target pathogens (Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus) in infections of the respiratory tract for up to 10 days. Since tissue concentrations above the MICs for infecting organisms were correlated with efficacy in animal models of infection, short treatment regimens consisting of once-daily oral administration of azithromycin should be effective in the treatment of a variety of infections. A single 1 g oral dose will provide concentrations in the uterus and prostate, representing urogenital tissues, above the MIC for Chlamydia trachomatis for approximately 10 days. Thus, this regimen should be effective in the treatment of chlamydial infections of the genital tract.

Administration, Oral↗

Pharmacokinetics of azithromycin in patients with impaired hepatic function.

The pharmacokinetics of azithromycin were determined over a 192-h period following oral administration of a single 500-mg dose to six healthy volunteers and to 16 cirrhotic patients (ten class A and six class B; Pugh's classification). Plasma and urinary levels were determined by microbiological assay. The mean Cmax, obtained 2-3 h after administration, was 0.29 mg/L in volunteers, and 0.39 and 0.51 mg/L in class A and class B cirrhosis, respectively. The elimination half-life was 53.5 h in control subjects, and 60.6 and 68.1 h in class A and class B cirrhotic patients, respectively. The mean residence time was significantly higher in class B patients, but AUC, Vd, Cltot and Clr values appeared to be similar in all groups. The mean urinary recovery of azithromycin at 192 h varied from 11-15.7%, and did not differ significantly among groups. These results demonstrate that azithromycin pharmacokinetics do not differ consistently in patients with mild or moderate hepatic impairment in comparison with healthy volunteers. Therefore, no dosage modifications of azithromycin seem to be required for patients with class A or B liver cirrhosis.

Adult↗

Azithromycin uptake and intracellular accumulation by Toxoplasma gondii-infected macrophages.

The uptake of azithromycin and erythromycin was measured in RAW 264.7 mouse macrophages infected with Toxoplasma gondii to determine whether the activity of macrolides could be correlated with their degree of host cell penetration. Uptake was expressed as the ratio of the intracellular (I) to the extracellular (E) concentrations. After infection, the intracellular accumulation of macrolides was equivalent to that measured in uninfected cells and azithromycin reached an I/E ratio of 105.8 +/- 8.0 in infected macrophages incubated with 20 mg/L of drug. The release of azithromycin from macrophages previously exposed to the drug was enhanced by exposure to Micrococcus luteus and phorbol myristate acetate but not after infection with T. gondii. Azithromycin accumulates readily and remains inside T. gondii-infected macrophages thereby interfering with the growth of the parasite which was confirmed by growth-inhibition experiments and by electron microscopy.

Animals↗

Azithromycin in an experimental Staphylococcus aureus abscess model.

We studied the efficacy and pharmacokinetics of azithromycin in a rabbit tissue-cage Staphylococcus aureus abscess model. A dosage of 15 mg/kg/day azithromycin was administered to rabbits with 24 h or 2 week old infected tissue cages and to uninfected controls. Concentrations of azithromycin were higher in the infected compared with the uninfected tissue cages. Azithromycin was effective in reducing the bacterial concentrations in both groups of infected tissue cages by approximately 3 log10 cfu/mL compared with untreated controls after 8 days of therapy. Fifty percent of the 24 h and 29% of the 2 week infected tissue cages became culture-negative.

Abscess↗

The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension.

Present product labelling indicates that azithromycin capsules should not be taken with food. However, three recent studies demonstrated that food does not significantly decrease the bioavilabilities of three new formulations of azithromycin (250 mg tablets, 1000 mg sachet, 500 mg paediatric suspension). With a 500 mg dosage, the mean relative bioavailability of azithromycin following ingestion of a standard high-fat breakfast was 96% when administered as two 250 mg tablets and 113% when administered as a suspension. The mean relative bioavailability of a 1000 mg sachet was 112%. The absolute bioavailability of the sachet formulation, relative to a 1 h iv infusion of 1000 mg, was 44%. Thus, azithromycin tablets, suspension and sachet may be given without regard to meals, further enhancing the convenience of once-daily, short-duration dosing regimens.

Adolescent↗