Mechanism of Action
Azithromycin is an antimicrobial agent [See Clinical Pharmacology]
Based on animal models of infection, the antimicrobial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with Zmax.
Zmax is an extended release microsphere formulation. Based on data obtained from studies evaluating the pharmacokinetics of azithromycin in healthy adult subjects a higher peak serum concentration (Cmax) and greater systemic exposure (AUC 0–24) of azithromycin are achieved on the day of dosing following a single 2 g dose of Zmax versus 1.5 g of azithromycin tablets administered over 3 days (500 mg/day) or 5 days (500 mg on day 1, 250 mg/day on days 2–5) [Table 2]. Consequently, due to these different pharmacokinetic profiles, Zmax is not interchangeable with azithromycin tablet 3-day and 5-day dosing regimens.
Table 2. Mean (SD) Pharmacokinetic Parameters for Azithromycin on Day 1 Following the Administration of a Single Dose of 2 g Zmax or 1.5 g of Azithromycin Tablets Given over 3 Days (500 mg/day) or 5 Days (500 mg on Day 1 and 250 mg on Days 2–5) to Healthy Adult Subjects
|Pharmacokinetic ParameterZmax, 3-day and 5-day regimen parameters obtained from separate pharmacokinetic studies||Azithromycin Regimen|
[N=41]N = 21 for AUC0–∞ and t1/2
|SD = standard deviation|
Cmax = maximum serum concentration
Tmax = time to Cmax
AUC = area under concentration vs. time curve
t1/2 = terminal serum half-life
| Cmax (µg/mL) ||0.821|
| TmaxMedian (range) (hr) ||5.0|
| AUC0–24 (µg∙hr/mL) ||8.62|
| AUC0–∞Total AUC for the 1-day, 3-day and 5-day regimens (µg∙hr/mL) ||20.0|
| t1/2 (hr) ||58.8|
The bioavailability of Zmax relative to azithromycin immediate release (IR) (powder for oral suspension) was 83%. On average, peak serum concentrations were achieved approximately 2.5 hours later following Zmax administration and were lower by 57%, compared to 2 g azithromycin IR. Thus, single 2 g doses of Zmax and azithromycin IR are not bioequivalent and are not interchangeable.
Effect of food on absorption: A high-fat meal increased the rate and extent of absorption of a 2 g dose of Zmax (115% increase in Cmax, and 23% increase in AUC0–72) compared to the fasted state. A standard meal also increased the rate of absorption (119% increase in Cmax) and with less effect on the extent of absorption (12% increase in AUC0–72) compared to administration of a 2 g Zmax dose in the fasted state.
Effect of antacids: Following the administration of Zmax with an aluminum and magnesium hydroxide antacid, the rate and extent of azithromycin absorption were not altered.
The serum protein binding of azithromycin is concentration dependent, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg.
Azithromycin concentrates in fibroblasts, epithelial cells, macrophages, and circulating neutrophils and monocytes. Higher azithromycin concentrations in tissues than in plasma or serum have been observed. White blood cell and lung exposure data in humans following a single 2 g dose of Zmax in adults are shown in Table 3. Following a 2 g single dose of Zmax, azithromycin achieved higher exposure (AUC0–120) in mononuclear leukocytes (MNL) and polymorphonuclear leukocytes (PMNL) than in serum. The azithromycin exposure (AUC0–72) in lung tissue and alveolar cells (AC) was approximately 100 times that in serum; and the exposure in epithelial lining fluid (ELF) was also higher (approximately 2–3 times) than in serum. The clinical significance of this distribution data is unknown.
Table 3. Azithromycin Exposure Data in White Blood Cells and Lung Following a 2 g Single Dose of Zmax in Adults
| A single 2 g dose of Zmax |
|Abbreviation: WBC: white blood cells; MNL: mononuclear leukocytes; PMNL: polymorphonuclear leukocytes; ELF: Epithelial lining fluid|
|WBC||Cmax (µg/mL)||AUC0–24 (µg∙hr/mL)||AUC0–120 (µg∙hr/mL)||Ct=120Azithromycin concentration at 120 hours after the start of dosing (µg/mL)|
||116 ||1790 (540)||4710 (1100)||16.2 (5.51)|
|PMNL||146 (66.0)||2080 (650)||10000 (2690)||81.7 (23.3)|
|LUNG||Cmax (µg/mL)||AUC0–24 (µg∙hr/mL)||AUC0–72 (µg∙hr/mL)|
|Cmax (µg/g)||AUC0–24 (µg∙hr/g)||AUC0–72 (µg∙hr/g)|
| LUNG TISSUE||37.9||505||1693||-|
Following a regimen of 500 mg of azithromycin tablets 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.
In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.
Serum azithromycin concentrations following a single 2 g dose of Zmax declined in a polyphasic pattern with a terminal elimination half-life of 59 hours. The prolonged terminal half-life is thought to be due to a large apparent volume of distribution.
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.
Azithromycin pharmacokinetics were 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 were 5.1% and 4.2% higher, 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 were 61% and 35% higher, respectively in subjects with GFR <10 mL/min compared to subjects with normal renal function. (See Renal Impairment.)
The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.
The pharmacokinetics of azithromycin were characterized following a single 60 mg/kg dose of Zmax in pediatric patients aged 3 months to 16 years. Although there was high inter-patient variability in systemic exposure (AUC and Cmax) across the age groups studied, individual azithromycin AUC and Cmax values in pediatric patients were comparable to or higher than those following administration of 2 g Zmax in adults (Table 4). (See Pediatric Use.)
Table 4. Mean (SD) Pharmacokinetic Parameters for Azithromycin Following Administration of a Single Dose of Zmax (60 mg/kg, maximum dose of 2 g) to Pediatric Subjects Aged 3 Months to 16 Years
|Treatment Group||Pharmacokinetic Parameters|
|TmaxMedian (range) presented only for Tmax|
|Empty stomach = dosed with Zmax at least 1 hour before or 2 hours after a meal (Groups I–VI)|
Fed = dosed with Zmax within 5 minutes of consuming an age-appropriate high-fat breakfast (Group VII)
|Group 1 (N = 6)|
[3 to 18 months]
|0.74 (0.20)||3 (3–3)||6.29 (1.17)||14.1 (2.16)|
(n = 3)
(N = 6)|
[>18 to 36 months]
|1.88 (0.50)||3 (3–3)||19.7 (5.35)||37.3 (12.9)|
(n = 5)
|Group 3 (N = 6)|
[>36 to 48 months]
|1.23 (0.42)||3 (3–6)||12.9 (3.79)||22.4 (5.96)|
|Group 4 (N = 6)|
[>48 months to 8 years]
|1.13 (0.34)||3 (3–6)||13.0 (4.21)||22.2 (6.89)|
|Group 5 (N = 6)|
[>8 to 12 years]
|1.65 (0.38)||3 (3–6)||16.0 (4.99)||30.1 (10.7)|
|Group 6 (N = 6)|
[>12 to 16 years]
|0.98 (0.35)||3 (3–6)||11.0 (4.78)||21.3 (9.37)|
|Pooled 1–6 (N = 36)|
[On an empty stomach]
|1.27 (0.53)||3 (3–6)||13.1 (5.78)||25.2 (10.7)|
(n = 32)
|Group 7One subject vomited immediately after dosing and discontinued from the study (N = 7)|
[Fed; 18 months to 8 years]
|1.41 (0.62)||3 (1.5–3.1)||7.43 (3.00)||18.9 (3.57)|
(n = 3)
The impact of gender on the pharmacokinetics of azithromycin has not been evaluated for Zmax. However, previous studies have demonstrated no significant differences in the disposition of azithromycin between male and female subjects.
Pharmacokinetic Interaction Studies
A drug interaction study was performed with Zmax and antacids. All other drug interaction studies were performed with azithromycin immediate release (IR) formulations (capsules and tablets, doses ranging from 500 to 1200 mg) and other drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 5 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 6.
When used at therapeutic doses, azithromycin IR had a minimal effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, nelfinavir, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine (Table 5). Although the drug interaction studies were not conducted with Zmax, similar modest effect as observed with IR formulation are expected since the total exposure to azithromycin is comparable for Zmax and other azithromycin IR regimens. Therefore, no dosage adjustment of drugs listed in Table 5 is recommended when co-administered with Zmax.
Nelfinavir significantly increased the Cmax and AUC of azithromycin following co-administration with azithromycin IR 1200 mg (Table 6). However, no dose adjustment of azithromycin is recommended when Zmax is co-administered with nelfinavir.
Pharmacokinetic and/or pharmacodynamic interactions with the drugs listed below have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, pharmacokinetic and/or pharmacodynamic interactions with these drugs have been observed with other macrolide products. Until further data are developed, careful monitoring of patients is advised when azithromycin and these drugs are used concomitantly: digoxin, ergotamine or dihydroergotamine, cyclosporine, hexobarbital and phenytoin.
Table 5. Drug Interactions: Pharmacokinetic Parameters of Co-administered Drugs in the Presence of Azithromycin
|Co-administered Drug||Dose of Co-administered Drug||Dose of AzithromycinRefers to azithromycin capsules and tablets unless specified||n||Ratio (with/without Azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00|
|Mean Cmax||Mean AUC|
| Atorvastatin ||10 mg/day × 8 days||500 mg/day PO on days 6–8||12||0.83|
(0.63 to 1.08)
(0.81 to 1.25)
| Carbamazepine ||200 mg/day × 2 days, then 200 mg BID × 18 days||500 mg/day PO for days 16–18||7||0.97|
(0.88 to 1.06)
(0.88 to 1.06)
| Cetirizine ||20 mg/day × 11 days||500 mg PO on day 7, then 250 mg/day on days 8–11||14||1.03|
(0.93 to 1.14)
(0.92 to 1.13)
| Didanosine ||200 mg PO BID × 21 days||1,200 mg/day PO on days 8–21||6||1.44|
(0.85 to 2.43)
(0.83 to 1.57)
| Efavirenz ||400 mg/day × 7 days ||600 mg PO on day 7||14||1.04
| Fluconazole ||200 mg PO single dose ||1,200 mg PO single dose||18||1.04|
(0.98 to 1.11)
(0.97 to 1.05)
| Indinavir ||800 mg TID × 5 days||1,200 mg PO on day 5||18||0.96|
(0.86 to 1.08)
(0.81 to 1.00)
| Midazolam ||15 mg PO on day 3||500 mg/day PO × 3 days||12||1.27|
(0.89 to 1.81)
(1.01 to 1.56)
| Nelfinavir ||750 mg TID × 11 days||1,200 mg PO on day 9||14||0.90|
(0.81 to 1.01)
(0.78 to 0.93)
| Sildenafil ||100 mg on days 1 and 4||500 mg/day PO × 3 days||12||1.16|
(0.86 to 1.57)
(0.75 to 1.12)
| Theophylline ||4 mg/kg IV on days 1, 11, 25||500 mg PO on day 7, then 250 mg/day on days 8–11||10||1.19|
(1.02 to 1.40)
(0.86 to 1.22)
| Theophylline ||300 mg PO BID × 15 days||500 mg PO on day 6, then 250 mg/day on days 7–10||8||1.09|
(0.92 to 1.29)
(0.89 to 1.31)
| Triazolam ||0.125 mg on day 2||500 mg PO on day 1, then 250 mg/day on day 2||12||1.06||1.02|
| Trimethoprim/ |
|160 mg/800 mg/day PO × 7 days||1,200 mg PO on day 7||12||0.85|
(0.75 to 0.97)/
(0.78 to 1.03)
(0.80 to 0.95)/
(0.88 to 1.03)
| Zidovudine ||500 mg/day PO × 21 days||600 mg/day PO × 14 days||5||1.12|
(0.42 to 3.02)
(0.52 to 1.70)
| Zidovudine ||500 mg/day PO × 21 days||1,200 mg/day PO × 14 days||4||1.31|
(0.43 to 3.97)
(0.69 to 2.43)
Table 6. Drug Interactions: Pharmacokinetic Parameters of Azithromycin in the Presence of Co-administered Drugs
|Co-administered Drug||Dose of Co-administered Drug||Dose of AzithromycinRefers to azithromycin capsules and tablets unless specified||n||Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00|
|Mean Cmax||Mean AUC|
| Efavirenz ||400 mg/day × 7 days ||600 mg PO on day 7||14||1.22|
(1.04 to 1.42)
|0.9290% confidence interval not reported|
| Fluconazole ||200 mg PO single dose||1,200 mg PO single dose||18||0.82|
(0.66 to 1.02)
(0.94 to 1.22)
| Nelfinavir ||750 mg TID × 11 days||1,200 mg PO on day 9||14||2.36|
(1.77 to 3.15)
(1.80 to 2.50)
| Aluminum and Magnesium hydroxide ||20 mL regular strength, single dose ||2 g Zmax, single dose ||39||0.99|
(0.93 to 1.06)
(0.92 to 1.08)
Mechanism of Action
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms, thus interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.
Spectrum of Activity
Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic and facultative Gram-positive microorganisms
NOTE: Erythromycin- and penicillin-resistant Gram-positive isolates may demonstrate cross-resistance to azithromycin.
Aerobic and facultative Gram-negative microorganisms
Beta-lactamase production should not affect azithromycin activity.
The following in vitro data are available, but their clinical si g nificance is unknown.
At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the azithromycin susceptible breakpoints of <4 µg/mL. 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 and facultative Gram-positive microorganisms
Streptococci (Groups C, F, G)
Viridans group streptococci
Aerobic and facultative Gram-negative microorganisms
Susceptibility Testing Methods:
When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of azithromycin powder. The MIC values should be interpreted according to criteria provided in Table 7.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-µg azithromycin to test the susceptibility of microorganisms to azithromycin. The disk diffusion interpretive criteria are provided in Table 7.
Table 7. Susceptibility Test Result Interpretive Criteria for Azithromycin
(zone diameters in mm)
| Haemophilus influenzae ||≤ 4|| -- || -- ||≥ 12|| -- || -- |
| Streptococcus pneumoniae ||≤ 0.5||1||≥ 2||≥ 18||14–17||≤ 13|
No interpretive criteria have been established for testing Moraxella catarrhalis. This species is not usually tested.
A report of "susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. 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 implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. 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 the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of quality control microorganisms to determine if the test was performed correctly. Standard azithromycin powder should provide the range of values noted in Table 8. Quality control (QC) microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains, which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant.
Table 8. Acceptable Quality Control Ranges for Azithromycin
|QC Strain||Minimum Inhibitory Concentrations (µg/mL)||Disk Diffusion|
(zone diameters in mm)
| Haemophilus influenzae |
| Streptococcus pneumoniae |
1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired fertility due to azithromycin was found in rats given daily doses up to 10 mg/kg (approximately 0.05 times the single 2 g oral adult human dose on a mg/m2 basis).
2 Animal Toxicology and/or Pharmacology
Phospholipidosis (intracellular phospholipid accumulation) 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/or pancreas) in dogs treated with azithromycin at doses which, expressed on the basis of mg/m2, are approximately one-sixth the recommended adult dose, and in rats treated at doses approximately one-fourth the recommended adult dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 µg/mL (1.6 times the observed Cmax of 0.821 µg/mL at the adult dose of 2 g.) Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 µg/mL (1.2 times the observed Cmax of 0.821 µg/mL at the adult dose of 2 g).
Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric dose of 60 mg/kg on a mg/m2 basis, but was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 µg/ml, approximately 1.5 times the Cmax of 1.27 µg/ml at the pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 µg/ml, approximately 3 times the pediatric dose Cmax.
The significance of the finding for animals and for humans is unknown.