AZITHROMYCIN (Page 2 of 7)

Drug-Drug Interactions

Drug interaction studies were performed with azithromycin 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 1 and the effect 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 co-administered with azithromycin.

Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. (See PRECAUTIONS — Drug Interactions.)

Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin
Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin n Ratio (with/without azithromycin)
of Co-administered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1
Mean Cmax Mean AUC
Atorvastatin 10 mg/day x 8 days 500 mg/day PO on days 6-8 12 0.83
(0.63 to 1.08) 1.01
(0.81 to 1.25)
Carbamazepine 200 mg/day x 2 days, then 200 mg
BID x 18 days 500 mg/day PO for days 16-18 7 0.97
(0.88 to 1.06) 0.96
(0.88 to 1.06)
Cetirizine 20 mg/day x 11 days 500 mg PO 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 PO BID x 21 days 1,200 mg/day PO on days 8-21 6 1.44
(0.85 to 2.43) 1.14
(0.83 to 1.57)
Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1.04* 0.95*
Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 1.04
(0.98 to 1.11) 1.01
(0.97 to 1.05)
Indinavir 800 mg TID x 5 days 1,200 mg PO on day 5 18 0.96
(0.86 to 1.08) 0.90
(0.81 to 1.00)
Midazolam 15 mg PO on day 3 500 mg/day PO x 3 days 12 1.27
(0.89 to 1.81) 1.26
(1.01 to 1.56)
Nelfinavir 750 mg TID x 11 days 1,200 mg PO on day 9 14 0.90
(0.81 to 1.01) 0.85
(0.78 to 0.93)
Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2-10 6 See footnote
below NA
Sildenafil 100 mg on days 1 and 4 500 mg/day PO x 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 PO 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 PO BID x 15 days 500 mg PO 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 PO on day 1, then 250 mg/day on day 2 12 1.06* 1.02*
Trimethoprim/ Sulfamethoxazole 160 mg/800mg/day PO x 7 days 1,200 mg PO on day 7 12 0.85
(0.75 to 0.97)/ 0.87
(0.80 to 0.95/
0.96
(0.88 to 1.03)
Zidovudine 500 mg/day PO x 21 days 600 mg/day PO x 14 days 5 1.12
(0.42 to 3.02) 0.94
(0.52 to 1.70)
Zidovudine 500 mg/day PO x 21 days 1,200 mg/day PO x 14 days 4 1.31
(0.43 to 3.97) 1.30
(0.69 to 2.43)
NA — Not Available
* — 90% Confidence interval not reported

Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo.

Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs (See PRECAUTIONS — Drug Interactions.)
Co-administered
Drug Dose of
Co-administered
Drug Dose of
Azithromycin n Ratio (with/without
co-administered drug) of
Azithromycin Pharmacokinetic
Parameters (90% CI);
No Effect = 1
Mean Cmax Mean AUC
Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1.22
(1.04 to 1.42) 0.92*
Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 0.82
(0.66 to 1.02) 1.07
(0.94 to1.22)
Nelfinavir 750 mg TID x 11 days 1,200 mg PO on day 9 14 2.36
(1.77 to 3.15) 2.12
(1.80 to 2.50)
Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2-10 6 See footnote
below NA
NA – Not available
* — 90% Confidence interval not reported
Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.

Microbiology:

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.

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
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 and facultative gram-negative microorganisms
Haemophilus ducreyi
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae

“Other” microorganisms
Chlamydia pneumoniae
Chlamydia trachomatis
Mycoplasma pneumoniae

Beta-lactamase production should have no effect on azithromycin activity.
The following in vitro data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for azithromycin. 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
Bordetella pertussis
Legionella pneumophila

Anaerobic microorganisms
Peptostreptococcus species
Prevotella bivia

“Other” microorganisms
Ureaplasma urealyticum

Susceptibility Testing Methods:
When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient use, but could aid the physician in selecting the most effective antimicrobial.

Dilution techniques:
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 1.

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 procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-mcg azithromycin to test the susceptibility of microorganisms to azithromycin. The disk diffusion interpretive criteria are provided in Table 1.

Table 1. Susceptibility Interpretive Criteria for Azithromycin
Susceptibility Test Result Interpretive Criteria

Minimum Inhibitory Disk Diffusion
Pathogen Concentrations (mcg/mL) (zone diameters in mm)
S I Ra S I Ra
Haemophilus spp ≤4 — — ≥ 12 — —
Staphylococcus aureus ≤2 4 ≥ 8 ≥ 18 14-17 ≤ 13
Streptococci including
S. pneumoniaeb ≤0.5 1 ≥ 2 ≥ 18 14-17 ≤ 13

a The current absence of data on resistant strains precludes defining any category other than “susceptible.” If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
b Susceptibility of streptococci including S. pneumoniae to azithromycin and other macrolides can be predicted by testing erythromycin.

No interpretive criteria have been established for testing Neisseria gonorrhoeae. 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.

QUALITY CONTROL:
Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard azithromycin powder should provide the following range of values noted in Table 2. Quality control 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 2. Acceptable Quality Control Ranges for Azithromycin

QC Strain Minimum Inhibitory Disk Diffusion
Concentrations (mcg/mL) (zone diameters in mm)
Haemophilus influenzae 1-4 13-21
ATCC 49247
Staphylococcus aureus 0.5-2
ATCC 29213
Staphylococcus aureus 21-26
ATCC 25923
Streptococcus pneumoniae 0.06-0.25 19-25
ATCC 49619

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