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The following in vitro data are available, but their clinical significance is unknown. Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0 µ g/ mL or less against most ( 90%) strains of the following microorganisms; 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 Gram-Positive Microorganisms Streptococci (Groups C, F, G)
Viridans group streptococci Aerobic Gram-Negative Microorganisms Bordetella pertussis
Campylobacter jejuni Haemophilus ducreyi
Legionella pneumophila
Anaerobic Microorganisms Bacteroides bivius
Clostridium perfringens Peptostreptococcus species "Other" Microorganisms Borrelia burgdorferi
Mycoplasma pneumoniae Treponema pallidum
Ureaplasma urealyticum
Susceptibility Testing of Bacteria Excluding Mycobacteria The in vitro potency of azithromycin is markedly affected by the pH of the microbiological growth medium during incubation. Incubation in a 10% CO2 atmosphere will result in lowering of media pH (7.2 to 6.6) within 18 hours and in an apparent reduction of the in vitro potency of azithromycin. Thus, the initial pH of the growth medium should be 7.2-7.4, and the CO2 content of the incubation atmosphere should be as low as practical. Text Continues Below
Azithromycin can be solubilized for in vitro susceptibility testing by dissolving in a minimum amount of 95% ethanol and diluting to working concentration with water. Dilution Techniques: Quantitative methods are used to determine minimal inhibitory concentrations that provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method 1 (broth, agar or microdilution) or equivalent with azithromycin powder. The MIC values should be interpreted according to the following criteria: MIC ( g/ mL) Interpretation 2 Susceptible (S)
4 Intermediate (I) 8 Resistant (R) A report of "Susceptible" indicates that the pathogen is likely to respond to monotherapy with azithromycin. 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 also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable drug concentrations are unlikely to be inhibitory and that other therapy should be selected. Measurement of MIC or MBC and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.) Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard azithromycin powder should provide the following MIC values:
Microorganism MIC ( g/ mL) Escherichia coli ATCC 25922 2.0-8.0
Enterococcus faecalis ATCC 29212 1.0-4.0 Staphylococcus aureus ATCC 29213 0.25-1.0 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 procedure 2 that has been recommended for use with disks to test the susceptibility of microorganisms to azithromycin uses the 15-µ g azithromycin disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimal inhibitory concentration (MIC) for azithromycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 µ g azithromycin disk should be interpreted according to the following criteria:
Zone Diameter (mm) Interpretation 18 (S) Susceptible
14-17 (I) Intermediate 13 (R) Resistant Interpretation should be as stated above for results using dilution techniques.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms. The 15-µ g azithromycin disk should provide the following zone diameters in these laboratory test quality control strains:
Microorganism Zone Diameter (mm) Staphylococcus aureus ATCC 25923 21-26 In Vitro Activity of Azithromycin Against Mycobacteria. Azithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) organisms. While gene probe techniques may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on M. avium complex (MAC) isolates. Azithromycin has also been shown to be active against phagocytized M. avium complex (MAC) organisms in mouse and human macrophage cell cultures as well as in the beige mouse infection model. Various in vitro methodologies employing broth or solid media at different pHs, with and without oleic acid-albumin dextrose-catalase (OADC), have been used to determine azithromycin MIC values for Mycobacterium avium complex strains. In general, azithromycin MIC values decreased 4 to 8 fold as the pH of Middlebrook 7H11 agar media increased from 6.6 to 7.4. At pH 7.4, azithromycin MIC values determined with Mueller-Hinton agar were 4 fold higher than that observed with Middlebrook 7H12 media at the same pH. Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values. The relationship between azithromycin and clarithromycin MIC values has not been established. In general, azithromycin MIC values were observed to be 2 to 32 fold higher than clarithromycin independent of the susceptibility method employed. The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues. (See CLINICAL PHARMACOLOGY) Drug Resistance: Complete cross-resistance between azithromycin and clarithromycin has been observed with Mycobacterium avium complex (MAC) isolates. In most isolates, a single point mutation at a position that is homologous to the Escherichia coli positions 2058 or 2059 on the 23S rRNA gene is the mechanism producing this cross-resistance pattern. 3,4 Mycobacterium avium complex (MAC) isolates exhibiting cross-resistance show an increase in azithromycin MICs to 128 µ g/ mL with clarithromycin MICs increasing to 32 µ g/ mL. These MIC values were determined employing the radiometric broth dilution susceptibility testing method with Middlebrook 7H12 medium. The clinical significance of azithromycin and clarithromycin cross-resistance is not fully understood at this time but preclinical data suggest that reduced activity to both agents will occur after M. avium complex strains produce the 23S rRNA mutation. Susceptibility testing for Mycobacterium avium complex (MAC): The disk diffusion techniques and dilution methods for susceptibility testing against Gram-positive and Gram-negative bacteria should not be used for determining azithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimal inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Azithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of media and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to azithromycin have not been established. The clinical relevance of azithromycin in vitro susceptibility test results for other mycobacterial species, including Mycobacterium tuberculosis, using any susceptibility testing method has not been determined. INDICATIONS AND USAGE ZITHROMAX ® (azithromycin) is indicated for the treatment of patients with mild to moderate infections (pneumonia: see WARNINGS) caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Lower Respiratory Tract Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae. Community-acquired pneumonia of mild severity due to Streptococcus pneumoniae or Haemophilus influenzae in patients appropriate for outpatient oral therapy. NOTE: Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for outpatient oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with nosocomially acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, elderly or debilitated patients, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia). Upper Respiratory Tract Streptococcal pharyngitis/ tonsillitis– As an alternative to first line therapy of acute pharyngitis/ tonsillitis due to Streptococcus pyogenes occurring in individuals who cannot use first line therapy. NOTE: Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes infection and the prophylaxis of rheumatic fever. ZITHROMAX ® is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available. Skin and Skin Structure Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage.
Sexually Transmitted Diseases Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis. ZITHROMAX ® , at the recommended dose, should not be relied upon to treat gonorrhea or syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating gonorrhea or syphilis. All patients with sexually-transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed. Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with ZITHROMAX ® may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zithromax (azithromycin) and other antibacterial drugs, Zithromax (azithromycin) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Mycobacterial Infections Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease ZITHROMAX ® , taken alone or in combination with rifabutin at its approved dose, is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in persons with advanced HIV infection. (See DOSAGE AND ADMINISTRATION, CLINICAL STUDIES) Treatment of Disseminated Mycobacterium avium complex (MAC) Disease ZITHROMAX ® , taken in combination with ethambutol, is indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection. (See DOSAGE AND ADMINISTRATION, CLINICAL STUDIES) Page: << Prev | 1 | 2 | 3 | 4 | 5
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