Mechanism of Action
Azithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.
Azithromycin demonstrates cross resistance with erythromycin. The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can determine cross resistance to other macrolides, lincosamides, and streptogramin B (MLSB phenotype).
Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage ( 1)] .
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for azithromycin against isolates of similar genus or organism group. However, the efficacy of azithromycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
Beta-hemolytic streptococci (Groups C, F, G)
Viridans group streptococci
Susceptibility Testing Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antibacterial 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 an antibacterial drug for treatment.
Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. The MICs should be determined using a standardized test method 1,2,3,4 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 3.
Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antibacterial compounds. The zone size should be determined using a standardized method 2,3,4. This procedure uses paper disk impregnated with 15 mcg azithromycin to test the susceptibility of bacteria to azithromycin. The disk diffusion breakpoints are provided in Table 3.
|Table 3: Susceptibility Test Interpretive Criteria for Azithromycin a|
|Pathogen||Minimum Inhibitory Concentrations (mcg/mL)||Disk Diffusion (zone diameter in mm)|
|Haemophilus influenzae a||≤4||–||–||≥12||–||–|
|Staphylococcus aureus||≤2||4||≥8||≥18||14 to 17||≤13|
|Streptococci including S. pneumoniae||≤0.5||1||≥2||≥18||14 to 17||≤13|
|Moraxella catarrhalis a||≤0.25||–||–||≥26||–||–|
a Insufficient information is available to determine Intermediate or Resistant interpretive criteria
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at site of the infection. A report of Intermediate (I) 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 a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Quality Control 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 test 1,2,3,4. 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 to 26|
|Staphylococcus aureus ATCC 29213||0.5 to 2||Not Applicable|
|Haemophilus Influenzae ATCC 49247||1.0 to 4.0||13 to 21|
|Streptococcus pneumoniae ATCC 49619||0.06 to 0.25||19 to 25|
|Neisseria gonorrhoeae ATCC 49226||0.25-1||Not Applicable|
*ATCC = American Type Culture Collection
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 0.2 times an adult daily dose of 500 mg based on body surface area).
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 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 C max 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 C max 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 the 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 C max 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 C max . The significance of these findings for animals and for humans is unknown.
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