Mechanism Of Action
Azithromycin is a macrolide antibacterial drug. [see Microbiology]
Based on animal models of infection, the antibacterial 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 azithromycin.
QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration- dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.
Since the mean Cmax of azithromycin following a 500 mg IV dose given over 1 hr is higher than the mean Cmax of azithromycin following the administration of a 1500 mg oral dose, it is possible that QTc may be prolonged to a greater extent with IV azithromycin at close proximity to a one hour infusion of 500 mg.
In patients hospitalized with community-acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean Cmax ± S.D. achieved was 3.63 ± 1.60 mcg/mL, while the 24-hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC was 9.60 ± 4.80 mcg·hr/mL.
The mean Cmax, 24-hour trough and AUC24 values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03 ±0.86 mcg•hr/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia who received the same 3-hour dosage regimen for 2–5 days.
|Infusion Concentration, Duration||Time after starting the infusion (hr)|
|2 mg/mL, 1 hr||2.98 ± 1.12||3.63 ± 1.73||0.60 ± 0.31||0.40 ± 0.23||0.33 ± 0.16||0.26 ± 0.14||0.27± 0.15||0.20 ± 0.12||0.20 ± 0.15|
|1 mg/mL, 3 hr†||0.91 ± 0.13||1.02 ± 0.11||1.14 ± 0.13||1.13 ± 0.16||0.32 ± 0.05||0.28 ± 0.04||0.27± 0.03||0.22 ± 0.02||0.18 ± 0.02|
| 500 mg (2 mg/mL) for 2–5 days in community-acquired pneumonia patients. |
† 500 mg (1 mg/mL) for 5 days in healthy subjects.
Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin showed only an 8% increase in Cmax but a 61% increase in AUC24 reflecting a threefold rise in C24 trough levels.
Following single-oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, Cmax, trough level, and AUC24 were reported to be 0.41 mcg/mL, 0.05 mcg/mL, and 2.6 mcg·hr/mL, respectively. These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500-mg I.V. 3-hour infusion (Cmax: 1.08 mcg/mL, trough: 0.06 mcg/mL, and AUC24: 5.0 mcg·hr/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval.
The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL.
Tissue concentrations have not been obtained following intravenous infusions of azithromycin, but following oral administration in humans azithromycin has been shown to penetrate into tissues, including skin, lung, tonsil, and cervix.
Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients. Approximately 17 hr after dosing, azithromycin concentrations were 2.7 mcg/g in ovarian tissue, 3.5 mcg/g in uterine tissue, and 3.3 mcg/g in salpinx. Following a regimen of 500 mg on the first day followed by 250 mg daily for 4 days, concentrations in the cerebrospinal fluid were less than 0.01 mcg/mL in the presence of non-inflamed meninges.
In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.
Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination halflife of 68 hr. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.
In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one-hour intravenousdosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hr was about 11% after the 1st dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration.
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 1,000 mg dose of azithromycin, mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). The mean C and AUC increased 61% and 35%, respectively in subjects with severe renal impairment (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min).
The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.
There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.
Pharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration in older volunteers (65–85 years old) were similar to those in younger volunteers (18–40 years old) for the 5-day therapeutic regimen. [see Geriatric Use]
Pharmacokinetic studies with intravenous azithromycin have not been performed in children.
Drug interaction studies were performed with oral azithromycin and other drugs likely to be coadministered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 2.
Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when coadministered with azithromycin.
Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see DRUG INTERACTIONS]
Table 1: Drug Interactions : Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin
|Co- administered Drug||Dose of Coadministered Drug||Dose of Azithromycin||n|| Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); |
No Effect = 1.00
|Mean Cmax||Mean AUC|
|Atorvastatin||10 mg/day for 8 days||500 mg/day orally on days 68||12|| 0.83 |
(0.63 to 1.08)
| 1.01 |
(0.81 to 1.25)
|Carbamazepine||200 mg/day for 2 days, then 200 mg twice a day for 18 days||500 mg/day orally for days 16-18||7|| 0.97 |
(0.88 to 1.06)
| 0.96 |
(0.88 to 1.06)
|Cetirizine||20 mg/day for 11 days||500 mg orally on day 7, then 250 mg/day on days 8-11||14|| 1.03 |
(0.93 to 1.14)
| 1.02 |
(0.92 to 1.13)
|Didanosine||200 mg orally twice a day for 21 days||1,200 mg/day orally on days 8-21||6|| 1.44 |
mycoplasma (0.85 to 2.43)
| 1.14 |
(0.83 to 1.57)
|Efavirenz||400 mg/day for 7 days||600 mg orally on day 7||14||1.04||0.95|
|Fluconazole||200 mg orally single dose||1,200 mg orally single dose||18|| 1.04 |
(0.98 to 1.11)
| 1.01 |
(0.97 to 1.05)
|Indinavir||800 mg three times a day for 5 days||1,200 mg orally on day 5||18|| 0.96 |
(0.86 to 1.08)
| 0.90 |
(0.81 to 1.00)
|Midazolam||15 mg orally on day 3||500 mg/day orally for 3 days||12|| 1.27 |
(0.89 to 1.81)
| 1.26 |
(1.01 to 1.56)
|Nelfinavir||750 mg three times a day for 11 days||1,200 mg orally on day 9||14|| 0.90 |
(0.81 to 1.01)
| 0.85 |
(0.78 to 0.93)
|Sildenafil||100 mg on days 1 and 4||500 mg/day orally for 3 days||12|| 1.16 |
(0.86 to 1.57)
| 0.92 |
(0.75 to 1.12)
|Theophylline||4 mg/kg IV on days 1, 11, 25||500 mg orally on day 7, 250 mg/day on days 8-11||10|| 1.19 |
(1.02 to 1.40)
| 1.02 |
(0.86 to 1.22)
|Theophylline||300 mg orally BID 15 days||500 mg orally on day 6, then 250 mg/day on days 7-10||8|| 1.09 |
(0.92 to 1.29)
| 1.08 |
(0.89 to 1.31)
|Triazolam||0.125 mg on day 2||500 mg orally on day 1, then 250 mg/day on day 2||12||1.06||1.02|
|Trimethoprim/ Sulfamethoxazole||160 mg/800 mg/day orally for 7 days||1,200 mg orally on day 7||12|| 0.85 |
(0.75 to 0.97)/ 0.90
(0.78 to 1.03)
| 0.87 |
(0.80 to 0.95/ 0.96
(0.88 to 1.03)
|Zidovudine||500 mg/day orally for 21 days||600 mg/day orally for 14 days||5|| 1.12 |
(0.42 to 3.02)
| 0.94 |
(0.52 to 1.70)
|Zidovudine||500 mg/day orally for 21 days||1,200 mg/day orally for 14 days||4|| 1.31 |
(0.43 to 3.97)
| 1.30 |
(0.69 to 2.43)
|-90% Confidence interval not reported|
Table 2: Drug Interactions : Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs. [see DRUG INTERACTIONS]
|Co-administered Drug||Dose of Coadministered Drug||Dose of Azithromycin||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 for 7 days||600 mg orally on day 7||14|| 1.22 |
(1.04 to 1.42)
|Fluconazole||200 mg orally single dose||1,200 mg orally single dose||18|| 0.82 |
(0.66 to 1.02)
| 1.07 |
(0.94 to 1.22)
|Nelfinavir||750 mg three times a day for 11 days||1,200 mg orally on day 9||14|| 2.36 |
(1.77 to 3.15)
| 2.12 |
(1.80 to 2.50)
|- 90% Confidence interval not reported|
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 demonstrates cross-resistance with erythromycin-resistant Gram-positive isolates.
Azithromycin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in [see INDICATIONS AND USAGE].
The following in vitro data are available, but their clinical significance is unknown. Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0 mcg/mL or less against most ( ≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of azithromycin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled trials.
Aerobic Gram-positive Bacteria
Streptococci (Groups C, F, G)
Viridans group streptococci
Susceptibility Testing Methods
When available, clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial products used in resident hospitals 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 an antibacterial drug product for treatment.
Quantitative methods are used to determine minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2 (broth, and/or agar). The MIC values should be interpreted according to criteria provided in Table 3.
Quantitative methods that require measurement of zone diameters can provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using standardized methods2,3. This procedure uses paper disk impregnated with 15 mcg azithromycin to test the susceptibility of bacteria to azithromycin. The disk diffusion interpretive criteria are provided in Table 3.
Table 3: Susceptibility Interpretive Criteria for Azithromycin
|Pathogen||Minimum Inhibitory Concentrations ( mcg/mL)||Disk Diffusion (zone diameters in mm)|
|Haemophilus influenzae.||≤ 4||--||--||≥ 12||--||--|
|Staphylococcus aureus||≤ 2||4||> 8||≥ 18||14-17||≤ 13|
|Streptococci including S. pneumoniae||≤ 0.5||1||> 2||≥ 18||14-17||≤ 13|
|Insufficient information is available to determine Intermediate or Resistant interpretive criteria|
A report of “Susceptible” indicates that the pathogen is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. 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. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3. Standard azithromycin powder should provide the following range of MIC values provided in Table 4. For the diffusion technique using the 15-mcg azithromycin disk the criteria provided in Table 4 should be achieved.
Table 4: Acceptable Quality Control Ranges for Susceptibility Testing
|Quality Control Organism||Minimum Inhibitory Concentrations (mcg/mL)||Disk Diffusion (zone diameters in mm)|
|Staphylococcus aureus ATCC 25923||Not Applicable||21-26|
|Staphylococcus aureus ATCC 29213||0.5-2||Not Applicable|
|Haemophilus Influenzae ATCC 49247||1-4||13-21|
|Streptococcus pneumoniae ATCC 49619||0.06-0.25||19-25|
|ATCC = American Type Culture Collection|
The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues. [see CLINICAL PHARMACOLOGY]
Animal Toxicology And/Or Pharmacology
Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple oral 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 and rats treated with azithromycin at doses which, expressed on the basis of body surface area, are similar to or less than the highest recommended adult human 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 mcg/mL (1.6 times the observed Cmax of 0.821 mcg /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 mcg /mL (1.2 times the observed Cmax of 0.821 mcg /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 based on body surface area. It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 mcg /ml, approximately 1.5 times the Cmax of 1.27 mcg/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 mcg /ml, approximately 3 times the pediatric dose Cmax. The significance of the findings for animals and for humans is unknown.
In a controlled trial of community-acquired pneumonia performed in the U.S., azithromycin (500 mg as a single daily dose by the intravenous route for 2 to 5 days, followed by 500 mg/day by the oral route to complete 7 to 10 days therapy) was compared to cefuroxime (2250 mg/day in three divided doses by the intravenous route for 2 to 5 days followed by 1000 mg/day in two divided doses by the oral route to complete 7 to 10 days therapy), with or without erythromycin. For the 291 patients who were evaluable for clinical efficacy, the clinical outcome rates, i.e., cure, improved, and success (cure + improved) among the 277 patients seen at 10 to 14 days post-therapy were as follows:
|Success (Cure + Improved)||78%||74%|
In a separate, uncontrolled clinical and microbiological trial performed in the U.S., 94 patients with community-acquired pneumonia who received azithromycin in the same regimen were evaluable for clinical efficacy. The clinical outcome rates, i.e., cure, improved, and success (cure + improved) among the 84 patients seen at 10 to 14 days post-therapy were as follows:
|Success (Cure + Improved)||89%|
Microbiological determinations in both trials were made at the pre-treatment visit and, where applicable, were reassessed at later visits. Serological testing was done on baseline and final visit specimens. The following combined presumptive bacteriological eradication rates were obtained from the evaluable groups:
Combined Bacteriological Eradication Rates for Azithromycin:
|(at last completed visit)||Azithromycin|
|S. pneumonia||64/67 (96%)|
|H. influenzae||41/43 (95%)|
|M. catarrhalis||9/10 (90%)|
|S. aureus||9/10 (90%)|
|Nineteen of twenty-four patients (79%) with positive blood cultures for S. pneumoniae were cured (intent-to-treat analysis) with eradication of the pathogen.|
The presumed bacteriological outcomes at 10 to 14 days post-therapy for patients treated with azithromycin with evidence (serology and/or culture) of atypical pathogens for both trials were as follows:
|Evidence of Infection||Total||Cure||Improved||Cure + Improved|
|Mycoplasma pneumoniae||18||11 (61%)||5 (28%)||16 (89%)|
|Chlumyuiu pneumoniae||34||15 (44%)||13 (38%)||28 (82%)|
|Legionella pneumophila||16||5 (31%)||8 (50%)||13 (81%)|
1. Clinical and Laboratory Standards Institute (CLSI) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically: Approved Standard-Ninth Edition. CLSI Document M07-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
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