Azithromycin Monohydrate (Page 5 of 8)

12.4 Microbiology

Mechanism of Action

Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and interferes with bacterial protein synthesis. Nucleic acid synthesis is not affected.

Cross Resistance

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 [see INDICATIONS AND USAGE (1)].

Gram-Positive Bacteria

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-Negative Bacteria

Haemophilus ducreyi

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

Other Bacteria

Chlamydophila pneumoniae

Chlamydia trachomatis

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown. Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 4.0 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.

Gram-Positive Bacteria

Beta-hemolytic streptococci (Groups C, F, G)

Viridans group streptococci

Gram-Negative Bacteria

Bordetella pertussis

Legionella pneumophila

Anaerobic Bacteria

Prevotella bivia

Peptostreptococcus species

Other Bacteria

Ureaplasma urealyticum

Susceptibility Testing Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antibacterial drugs 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.

Dilution Techniques

Quantitative methods are used to determine minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. The MICs should be determined using a standardized test method ^2,3 (broth or agar). The MIC values should be interpreted according to criteria provided in Table 1.

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 provides an estimate of the susceptibility of bacteria to antibacterial compounds. The zone size should be determined using a standardized method^2,3. 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 1.

* Clarithromycin is used for susceptibility testing due to its better solubility † Insufficient information is available to determine Intermediate or Resistant interpretive criteria
Table 1 : Susceptibility Test Interpretive Criteria for Azithromycin *
Pathogen	Minimum Inhibitory Concentrations ( mcg / mL ) S I R			Disk Diffusion ( zone diameter in mm ) S I R
Haemophilus influenzae †	≤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

The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues. [see CLINICAL PHARMACOLOGY (12)]

A report of “Susceptible” indicates that the pathogen is likely to inhibit growth of the pathogen if the antibacterial 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 antibacterial is not likely to inhibit growth of the pathogen if the antibacterial compound 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. Standard azithromycin powder should provide the following range of MIC values provided in Table 2. For the diffusion technique using the 15-mcg azithromycin disk the criteria provided in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Susceptibility Testing

* ATCC = American Type Culture Collection
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 to 4	13 to 21
Streptococcus pneumoniae ATCC 49619	0.06 to 0.25	19 to 25