Clarithromycin (clarithromycin 500 mg) Dailymed

Microbiology

Microbiology

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis. Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms as well as most Mycobacterium avium complex (MAC) microorganisms. Additionally, the 14-OH clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH clarithromycin is twice as active against Haemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than clarithromycin. The clinical significance of this activity against Mycobacterium avium complex is unknown. Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section: Aerobic Gram-positive Microorganisms Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes Aerobic Gram-negative Microorganisms Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis Other Microorganisms Mycoplasma pneumoniae Chlamydia pneumoniae (TWAR) Mycobacteria Mycobacterium avium complex (MAC) consisting of: Mycobacterium avium Mycobacterium intracellulare Beta-lactamase production should have no effect on clarithromycin activity. NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin. Omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; and lansoprazole/clarithromycin/amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Helicobacter Helicobacter pylori

Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (M93-067, M93-l00) and 9.3% (41/439) in the omeprazole/clarithromycin/amoxicillin triple-therapy studies (126, 127, M96-446). Clarithromycin pretreatment resistance was 12.6% (44/348) in the ranitidine bismuth citrate/clarithromycin b.i.d. versus t.i.d. clinical study (H2BA3001). Clarithromycin pretreatment resistance rates were 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the lansoprazole/clarithromycin/amoxicillin triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399). Amoxicillin pretreatment susceptible isolates (< 0.25 mcg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin clinical studies (126, 127, M96-446). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 mcg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin/amoxicillin study arm. Amoxicillin pretreatment susceptible isolates (< 0.25 mcg/mL) occurred in 97.8% (936/957) and 98% (98/100) of the patients in the lansoprazole/clarithromycin/amoxicillin triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of the 957 patients (2.2%) by E-test and 2 of 100 patients (2%) by agar dilution had amoxicillin pretreatment MICs of > 0.25 mcg/mL. Two patients had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 mcg/mL by E-test. Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes

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Clarithromycin Pretreatment ResultsClarithromycinPost-Treatment ResultsH. pylori negative -H. pylori positive - not eradicatederadicatedPost -Treatment susceptibility results

S

I

R

No MIC

Omeprazole 40 mg q.d./clarithromycin 500 mg t.i.d. for 14 days followed by omeprazole 20 mg q.d. for another 14 days (M93-067, M93-100)

Susceptible

108721269Intermediate

11Resistant

44

Ranitidine bismuth citrate 400 mg b.i.d./clarithromycin 500 mg t.i.d. for 14 days followed by ranitidine bismuth citrate 400 mg b.i.d. for another 14 days (H2BA3001)

Susceptible

124984148Intermediate

321Resistant

171151

Ranitidine bismuth citrate 400 mg b.i.d./clarithromycin 500 mg b.i.d. for 14 days followed by ranitidine bismuth citrate 400 mg b.i.d. for another 14 days (H2BA3001)

Susceptible

12510611125Intermediate

22Resistant

20119

Omeprazole 20 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days (126, 127, M96-446)

Susceptible

171153738Intermediate

Resistant

144163

Lansoprazole 30 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 14 days (M95-399, M93-131, M95-392)

Susceptible

1121057Intermediate

33Resistant

17674

Lansoprazole 30 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days (M95-399)

Susceptible

424011Intermediate

Resistant

413

*

Includes only patients with pretreatment clarithromycin susceptibility tests

Susceptible (S) MIC < 0.25 mcg/mL, Intermediate (I) MIC 0.5 to 1 mcg/mL, Resistant (R) MIC > 2 mcg/mL Patients not eradicated of H. pylori following omeprazole/clarithromycin, ranitidine bismuth citrate/clarithromycin, omeprazole/clarithromycin/amoxicillin, or lansoprazole/clarithromycin/amoxicillin therapy would likely have clarithromycin resistant 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; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; lansoprazole/clarithromycin/amoxicillin triple therapy; or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the omeprazole/clarithromycin/amoxicillin triple therapy clinical trials, 84.9% (157/185) of the patients who had pretreatment amoxicillin susceptible MICs (< 0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results, and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. In the lansoprazole/clarithromycin/amoxicillin triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (< 0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of > 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 12.8% (22/172) of the patients failed the 10 and 14 day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates. The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well controlled clinical trials. Aerobic Gram-positive Microorganisms: Streptococcus agalactiae Streptococci (Groups C, F, G) Viridans group streptococci Aerobic Gram-negative Microorganisms: Bordetella pertussis Legionella pneumophila Pasteurella multocida Anaerobic Gram-positive Microorganisms: Clostridium perfringens Peptococcus niger Propionibacterium acnes Anaerobic Gram-negative Microorganisms: Prevotella melaninogenica (formerly Bacteriodes melaninogenicus)

Susceptibility Testing Excluding Mycobacteria and Helicobacter

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 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder. The MIC values should be interpreted according to the following criteria: For testing Staphylococcus spp.

MIC (mcg/mL)Interpretation

2Susceptible (S)4Intermediate (I)8Resistant (R)For testing Streptococcus spp. including Streptococcus pneumoniaea

MIC (mcg/mL)Interpretation

0.25Susceptible (S)0.5Intermediate (I)1Resistant (R)aThese interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.For testing Haemophilus spp.b

MIC (mcg/mL)Interpretation

8Susceptible (S)16Intermediate (I)32Resistant (R)b. These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. usingHaemophilus Testing Medium (HTM). 1 Note: When testing Streptococcus spp., including Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin. A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood 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 in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin powder should provide the following MIC values:

MicroorganismMIC (mcg/mL)

S. aureusATCC 292130.12 to 0.5S. pneumoniae

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ATCC 496190.03 to 0.12Haemophilus influenzae

ATCC 492474 to 16

*

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% to 5% lysed horse blood.

This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using HTM1.

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 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 mcg clarithromycin to test the susceptibility of microorganisms to clarithromycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 mcg clarithromycin disk should be interpreted according to the following criteria: For testing Staphylococcus spp.

Zone diameter (mm)Interpretation

18Susceptible (S)14 to 17Intermediate (I)13Resistant (R)For testing Streptococcus spp. including Streptococcus pneumoniaee

Zone diameter (mm)Interpretation

21Susceptible (S)17 to 20Intermediate (I)16Resistant (R)eThese zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.For testing Haemophilus spp.f

Zone diameter (mm)Interpretation

13Susceptible (S)11 to 12Intermediate (I)10Resistant (R)fThese zone diameter standards are applicable only to tests with Haemophilus spp. using HTM2 Note: When testing Streptococcus spp., including Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin. Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for clarithromycin. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15 mcg clarithromycin disk should provide the following zone diameters in this laboratory test quality control strain:

MicroorganismZone diameter (mm)

S. aureusATCC 2592326 to 32S. pneumoniae

*

ATCC 4961925 to 31Haemophilus influenzae

ATCC 4924711 to 17

*

This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.

This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2.

In vitro Activity of Clarithromycin against Mycobacteria

Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) microorganisms isolated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium species from M. intracellulare, many studies only reported results on M. avium complex (MAC) isolates. Various in vitro methodologies employing broth or solid media at different pH's, with and without oleic acid-albumin-dextrose-catalase (OADC), have been used to determine clarithromycin MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth media increases from 5 to 7.4. At pH 7.4, MIC values determined with Mueller-Hinton agar were 4- to 8-fold higher than those observed with Middlebrook 7H12 media. Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values. Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS patients was evaluated using a microdilution method with Middlebrook 7H9 broth. Results showed an MIC value of4 mcg/mL in 81% and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of the non-AIDS isolates had an MIC value0.5 mcg/mL. Clarithromycin was also shown to be active against phagocytized M. avium complex (MAC) in mouse and human macrophage cell cultures as well as in the beige mouse infection model. Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms. In one study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 mcg/mL. Clarithromycin inhibited all isolates at > 10 mcg/mL.

Susceptibility Testing for Mycobacterium avium Complex (MAC)

The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining clarithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Clarithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to clarithromycin have not been established.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs3. One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107 to 1 x 108 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 35in 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 and amoxicillin MIC values should be interpreted according to the following criteria:

Clarithromycin MIC (mcg/mL)*Interpretation

< 0.25Susceptible (S)0.5 to 1Intermediate (I)> 2Resistant (R)

Amoxicillin MIC (mcg/mL)*Interpretation

< 0.25Susceptible (S)

*

These are tentative breakpoints for the agar dilution methodology, and they should not be used to interpret results obtained using alternative methods.

There were not enough organisms with MICs > 0.25 mcg/mL to determine a resistance breakpoint. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

MicroorganismsAntimicrobial AgentMIC (mcg/mL)*

H. pyloriATCC 43504Clarithromycin0.015 to 0.12 mcg/mLH. pyloriATCC 43504Amoxicillin0.015 to 0.12 mcg/mL

*

These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.