CLINICAL PHARMACOLOGY
Pharmacokinetics
Following oral administration, azithromycin is rapidly absorbed and widely distributed throughout the body. Rapid distribution of azithromycin into tissues and high concentration within cells result in significantly higher azithromycin concentrations in tissues than in plasma or serum. The 1 g single dose packet is bioequivalent to four 250 mg azithromycin capsules.
The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-seropositive adults (age 18–40 years old) are portrayed in the following chart:
MEAN (CV%) PK PARAMETER
DOSE/DOSAGE FORM
(serum, except as indicated) |
Subjects |
Day No. |
Cmax
(µg/mL) |
Tmax
(hr) |
C24
(µg/mL) |
AUC
(µg∙hr/mL) |
T½
(hr) | Urinary
Excretion
(% of dose) |
|---|
| 500 mg/250 mg capsule | 12 | Day 1 | 0.41 | 2.5 | 0.05 | 2.6 | – | 4.5 |
| and 250 mg on Days 2–5 | 12 | Day 5 | 0.24 | 3.2 | 0.05 | 2.1 | – | 6.5 |
| 1200 mg/600 mg tablets | 12 | Day 1 | 0.66 | 2.5 | 0.074 | 6.80–last. | 40 | – |
| %CV | | | (62%) | (79%) | (49%) | (64%) | (33%) | |
| 600 mg tablet/day | 7 | 1 | 0.33 | 2.0 | 0.039 | 2.4 | | |
| %CV | | | 25% | (50%) | (36%) | (19%) | | |
| 7 | 22 | 0.55 | 2.1 | 0.14 | 5.8 | 84.5 | - |
| %CV | | | (18%) | (52%) | (26%) | (25%) | | - |
| 600 mg tablet/day (leukocytes) | 7 | 22 | 252 | 10.9 | 146 | 4763 | 82.8 | - |
| %CV | | | (49%) | (28%) | (33%) | (42%) | - | - |
In these studies (500 mg Day 1, 250 mg Days 2–5), there was no significant difference in the disposition of azithromycin between male and female subjects. Plasma concentrations of azithromycin following single 500 mg oral and I.V. doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2–5, Cmin and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin Cmin levels required 5 to 7 days to reach steady-state.
In asymptomatic HIV-seropositive adult subjects receiving 600-mg ZITHROMAX tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing.
When azithromycin capsules were administered with food, the rate of absorption (Cmax) of azithromycin was reduced by 52% and the extent of absorption (AUC) by 43%.
When the oral suspension of azithromycin was administered with food, the Cmax increased by 46% and the AUC by 14%.
The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased Cmax by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%).
The AUC of azithromycin in 250 mg capsules was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with ZITHROMAX (azithromycin); however, the Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.
When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin (500 mg Day 1, 250 mg Days 2–5) in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.
The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in the following table:
AZITHROMYCIN CONCENTRATIONS FOLLOWING TWO 250 mg (500 mg) CAPSULES IN ADULTS TISSUE OR
FLUID | TIME AFTER DOSE (h) | TISSUE OR FLUID
CONCENTRATION
(µg/g or µg/mL) | CORRESPONDING
PLASMA OR SERUM
LEVEL (µg/mL) | TISSUE (FLUID)
PLASMA (SERUM)
RATIO |
|---|
| SKIN | 72–96 | 0.4 | 0.012 | 35 |
| LUNG | 72–96 | 4.0 | 0.012 | >100 |
| SPUTUMSample was obtained 2–4 hours after the first dose | 2–4 | 1.0 | 0.64 | 2 |
| SPUTUMSample was obtained 10–12 hours after the first dose. | 10–12 | 2.9 | 0.1 | 30 |
| TONSIL | 9–18 | 4.5 | 0.03 | >100 |
| TONSIL | 180 | 0.9 | 0.006 | >100 |
| CERVIXSample was obtained 19 hours after a single 500 mg dose. | 19 | 2.8 | 0.04 | 70 |
The extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical significance of these tissue concentration data is unknown.
Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 µg/mL) in the presence of non-inflamed meninges.
Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 µg/mL. Concentrations remained above 32 µg/mL for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte to plasma Cmax ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%), respectively. The clinical relevance of these findings is unknown.
Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-seropositive adults, mean maximum concentration in peripheral leukocytes was 252 µg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 µg/mL (±33%). The mean leukocyte to serum Cmax ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown.
The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.
Renal Insufficiency
Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 × 250 mg capsules), the mean Cmax and AUC0–120 increased by 5.1% and 4.2%, respectively in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0–120 increased 61% and 35%, respectively in subjects with end-stage renal disease (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). Based upon the pharmacokinetic data for azithromycin in subjects with renal impairment, no dose adjustment for Zmax is recommended in patients with GFR >10 mL/min. (See DOSAGE AND ADMINISTRATION.)
Hepatic Insufficiency
The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.
The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses adequate to reach therapeutic steady-state plasma levels is not known. (See PRECAUTIONS.)
Mechanism of Action
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.
Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was >30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.
Microbiology
Azithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic Gram-Positive Microorganisms
- Staphylococcus aureus
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.
Aerobic Gram-Negative Microorganisms
- Haemophilus influenzae
- Moraxella catarrhalis
"Other" Microorganisms
Beta-lactamase production should have no effect on azithromycin activity.
Azithromycin has been shown to be active in vitro and in the prevention and treatment of disease caused by the following microorganisms:
Mycobacteria
- Mycobacterium avium complex (MAC) consisting of:
- Mycobacterium avium
- Mycobacterium intracellulare.
The following in vitro data are available, but their clinical significance is unknown.
Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0 µg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
Aerobic Gram-Positive Microorganisms
- Streptococci (Groups C, F, G)
- Viridans group streptococci
Aerobic Gram-Negative Microorganisms
- Bordetella pertussis
- Campylobacter jejuni
- Haemophilus ducreyi
- Legionella pneumophila
Anaerobic Microorganisms
- Bacteroides bivius
- Clostridium perfringens
- Peptostreptococcus species
"Other" Microorganisms
- Borrelia burgdorferi
- Mycoplasma pneumoniae
- Treponema pallidum
- Ureaplasma urealyticum
Susceptibility Testing of Bacteria Excluding Mycobacteria
The in vitro potency of azithromycin is markedly affected by the pH of the microbiological growth medium during incubation. Incubation in a 10% CO2 atmosphere will result in lowering of media pH (7.2 to 6.6) within 18 hours and in an apparent reduction of the in vitro potency of azithromycin. Thus, the initial pH of the growth medium should be 7.2–7.4, and the CO2 content of the incubation atmosphere should be as low as practical.
Azithromycin can be solubilized for in vitro susceptibility testing by dissolving in a minimum amount of 95% ethanol and diluting to working concentration with water.
Dilution Techniques
Quantitative methods are used to determine minimal inhibitory concentrations that provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method1 (broth, agar or microdilution) or equivalent with azithromycin powder. The MIC values should be interpreted according to the following criteria:
| MIC (µg/mL) | Interpretation |
|---|
| ≤ 2 | Susceptible (S) |
| 4 | Intermediate (I) |
| ≥ 8 | Resistant (R) |
A report of "Susceptible" indicates that the pathogen is likely to respond to monotherapy with azithromycin. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable drug concentrations are unlikely to be inhibitory and that other therapy should be selected.
Measurement of MIC or MBC and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.)
Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard azithromycin powder should provide the following MIC values:
| Microorganism | MIC (µg/mL) |
|---|
| Escherichia coli ATCC 25922 | 2.0–8.0 |
| Enterococcus faecalis ATCC 29212 | 1.0–4.0 |
| Staphylococcus aureus ATCC 29213 | 0.25–1.0 |
Diffusion Techniques
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 that has been recommended for use with disks to test the susceptibility of microorganisms to azithromycin uses the 15-µg azithromycin disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimal inhibitory concentration (MIC) for azithromycin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 µg azithromycin disk should be interpreted according to the following criteria:
| Zone Diameter (mm) | Interpretation |
|---|
| ≥ 18 | (S) Susceptible |
| 14–17 | (I) Intermediate |
| ≤ 13 | (R) Resistant |
Interpretation should be as stated above for results using dilution techniques.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms. The 15-µg azithromycin disk should provide the following zone diameters in these laboratory test quality control strains:
| Microorganism | Zone Diameter (mm) |
|---|
| Staphylococcus aureus ATCC 25923 | 21–26 |
In Vitro Activity of Azithromycin Against Mycobacteria
Azithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) organisms. While gene probe techniques may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on M. avium complex (MAC) isolates. Azithromycin has also been shown to be active against phagocytized M. avium complex (MAC) organisms in mouse and human macrophage cell cultures as well as in the beige mouse infection model.
Various in vitro methodologies employing broth or solid media at different pHs, with and without oleic acid-albumin dextrose-catalase (OADC), have been used to determine azithromycin MIC values for Mycobacterium avium complex strains. In general, azithromycin MIC values decreased 4 to 8 fold as the pH of Middlebrook 7H11 agar media increased from 6.6 to 7.4. At pH 7.4, azithromycin MIC values determined with Mueller-Hinton agar were 4 fold higher than that observed with Middlebrook 7H12 media at the same pH. Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values. The relationship between azithromycin and clarithromycin MIC values has not been established. In general, azithromycin MIC values were observed to be 2 to 32 fold higher than clarithromycin independent of the susceptibility method employed.
The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues. (See CLINICAL PHARMACOLOGY)
Drug Resistance
Complete cross-resistance between azithromycin and clarithromycin has been observed with Mycobacterium avium complex (MAC) isolates. In most isolates, a single point mutation at a position that is homologous to the Escherichia coli positions 2058 or 2059 on the 23S rRNA gene is the mechanism producing this cross-resistance pattern.3,4 Mycobacterium avium complex (MAC) isolates exhibiting cross-resistance show an increase in azithromycin MICs to ≥128 µg/mL with clarithromycin MICs increasing to ≥32 µg/mL. These MIC values were determined employing the radiometric broth dilution susceptibility testing method with Middlebrook 7H12 medium. The clinical significance of azithromycin and clarithromycin cross-resistance is not fully understood at this time but preclinical data suggest that reduced activity to both agents will occur after M. avium complex strains produce the 23S rRNA mutation.
Susceptibility testing for Mycobacterium avium complex (MAC)
The disk diffusion techniques and dilution methods for susceptibility testing against Gram-positive and Gram-negative bacteria should not be used for determining azithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimal inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Azithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of media and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to azithromycin have not been established.
The clinical relevance of azithromycin in vitro susceptibility test results for other mycobacterial species, including Mycobacterium tuberculosis, using any susceptibility testing method has not been determined.
ANIMAL TOXICOLOGY
Phospholipidosis (intracellular phospholipid binding) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs administered doses which, based on pharmacokinetics, are as low as 2 times greater than the recommended adult human dose and in rats at doses comparable to the recommended adult human dose. This effect has been reversible after cessation of azithromycin treatment. The significance of these findings for humans is unknown.
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