Clarithromycin (Page 8 of 13)

12.4 Microbiology

Mechanism of Action

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria resulting in inhibition of protein synthesis.

Resistance

The major routes of resistance are modification of the 23S rRNA in the 50S ribosomal subunit to insensitivity or drug efflux pumps. Beta-lactamase production should have no effect on clarithromycin activity.

Most isolates of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.

If H. pylori is not eradicated after treatment with clarithromycin-containing combination regimens, patients may develop clarithromycin resistance in H. pylori isolates. Therefore, for patients who fail therapy, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin-resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; lansoprazole/clarithromycin/amoxicillin triple therapy; or other regimens which include clarithromycin as the sole antibacterial agent.

Antimicrobial Activity

Clarithromycin has been shown to be active against most of the isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1)] .

Gram-Positive Bacteria

  • Staphylococcus aureus
  • Streptococcus pneumoniae
  • Streptococcus pyogenes

Gram-Negative Bacteria

  • Haemophilus influenzae
  • Haemophilus parainfluenzae
  • Moraxella catarrhalis

Other Microorganisms

  • Chlamydophila pneumoniae
  • Helicobacter pylori
  • Mycobacterium avium complex (MAC) consisting of M. avium and M. intracellulare
  • Mycoplasma pneumoniae

At least 90 percent of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clarithromycin susceptible MIC breakpoint for organisms of similar type to those shown in Table 11. However, the efficacy of clarithromycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

  • Streptococcus agalactiae
  • Streptococci (Groups C, F, G)
  • Viridans group streptococci

Gram-Negative Bacteria

  • Legionella pneumophila
  • Pasteurella multocida

Anaerobic Bacteria

  • Clostridium perfringens
  • Peptococcus niger
  • Prevotella melaninogenica
  • Propionibacterium acnes

Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial 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 antimicrobial drug for treatment.

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 test method 1,2 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 11.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. 2,3 This procedure uses paper disks impregnated with 15 mcg of clarithromycin to test the susceptibility of bacteria to clarithromycin. The disk diffusion interpretive criteria are provided in Table 11.

Susceptibility Testing for Mycobacterium avium Complex (MAC)

The reference methodology for susceptibility testing of Mycobacterium avium complex (MAC) is broth dilution (either microdilution or macrodilution method). 4 For broth microdilution testing, cation-adjusted Mueller-Hinton broth (CAMHB) supplemented with 5% OADC is recommended. Transparent colonies should be used for the inoculum, if present. Susceptibility testing at either pH 6.8 or pH 7.4 is acceptable, provided that interpretation is done based on the culture conditions employed. Microdilution trays are incubated at 35 ºC to 37 ºC in ambient air and examined after seven days. Trays should be incubated and read again at 10 to 14 days, if growth is poor on initial inspection.

Susceptibility Testing for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. 5 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 10 7 -1 x 10 8 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (> 2-weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin MIC values should be interpreted according to the criteria in Table 11.

Table 11. Susceptibility Test Interpretive Criteria for Clarithromycin
Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm)
Pathogen S I R S I R
Staphylococcus aureus ≤ 2 4 ≥ 8 ≥ 18 14–17 ≤ 13
Streptococcus pyogenes and Streptococcus pneumoniae ≤ 0.25 a 0.5 a ≥ 1 a ≥ 21 b 17–20 b ≤ 16 b
Haemophilus influenzae ≤ 8 c 16 c ≥ 32 c ≥ 13 d 11–12 d ≤ 10 d
Helicobacter pylori e ≤ 0.25 0.5 ≥ 1
a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation adjusted Mueller Hinton broth with 2-5% lysed horse blood 2. b These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO 2 2. c These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Testing Medium (HTM) 2. d These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM 2. e These are tentative breakpoints for clarithromycin for the agar dilution methodology and should not be used to interpret results obtained using alternative methods 5. Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae , susceptibility and resistance to clarithromycin can be predicted using erythromycin.

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 the site of 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 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 (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagents in the assay, and the techniques of the individual performing the test. 1-5 Standard clarithromycin powder should provide the following range of MIC values as noted in Table 12. For the diffusion technique using the 15 mcg disk, the criteria in Table 12 should be achieved.

Table 12. Acceptable Quality Control Ranges for Clarithromycin
QC Strain MIC (mcg/mL) Zone diameter (mm)
Staphylococcus aureus ATCC 29213 a 0.12 – 0.5
Staphylococcus aureus ATCC 25923 26 – 32
Streptococcus pneumoniae ATCC 49619 0.03 – 0.12 b 25 – 31 c
Haemophilus influenzae ATCC 49247 4 – 16 d 11 – 17 e
Helicobacter pylori ATCC 43504 0.015 – 0.12 f
M. avium ATCC 700898 1 – 4 g
a ATCC is a registered trademark of the American Type Culture Collection. b This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation adjusted Mueller Hinton broth with 2-5% lysed horse blood. 1,2 c This quality control range is applicable only to S. pneumoniae ATCC 49619 for tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood. 2,3 d This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using HTM 1,2. e This quality control limit applies to disk diffusion tests conducted with Haemophilus influenzae ATCC 49247 using HTM 2,3. f These are quality control ranges for the agar dilution methodology 5 and should not be used to control test results obtained using alternative methods. g When tested at pH 6.8 (if tested at pH 5.0 to 7.4 at 7.4, the acceptable range is 0.5 mcg/mL to 2 mcg/mL) 4.

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