clarithromycin (clarithromycin 500 mg) Dailymed

Clinical Pharmacology

Pharmacokinetics

Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be given without regard to food.

In nonfasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 1 to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3 to 4 mcg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH clarithromycin, attains a peak steady-state concentration of about 0.6 mcg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 mcg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hours, approximately 40% is excreted in urine as clarithromycin. The renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15% of the dose with either a 250 mg or a 500 mg tablet administered every 12 hours.

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500 or 1000 mg doses of clarithromycin every 12 hours, steady-state clarithromycin C_max values ranged from 2 to 4 mcg/mL and 5 to 10 mcg/mL, respectively.

The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION .)

Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular concentrations, tissue concentrations are higher than serum concentrations. Examples of tissue and serum concentrations are presented below.

CONCENTRATION (after 250 mg q12h)

  Tissue Type	  Tissue (mcg/g)	  Serum (mcg/mL)
  Tonsil	  1.6	  0.8
  Lung	  8.8	  1.7

Clarithromycin extended-release tablets provide extended absorption of clarithromycin from the gastrointestinal tract after oral administration. Relative to an equal total daily dose of immediate-release clarithromycin tablets, clarithromycin extended-release tablets provide lower and later steady-state peak plasma concentrations but equivalent 24-hour AUC's for both clarithromycin and its microbiologically-active metabolite, 14-OH clarithromycin. While the extent of formation of 14-OH clarithromycin following administration of clarithromycin extended-release tablets (2 × 500 mg once daily) is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin AUC relative to administration with food. Therefore, clarithromycin extended-release tablets should be taken with food.
Steady-State Clarithromycin Plasma Concentration-Time Profiles
In healthy human subjects, steady-state peak plasma clarithromycin concentrations of approximately 2 to 3 mcg/mL were achieved about 5 to 8 hours after oral administration of 2 × 500 mg clarithromycin extended-release tablets once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.8 mcg/mL were attained about 6 to 9 hours after dosing. Steady-state peak plasma clarithromycin concentrations of approximately 1 to 2 mcg/mL were achieved about 5 to 6 hours after oral administration of a single 500 mg clarithromycin extended-release tablet once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.6 mcg/mL were attained about 6 hours after dosing.

Microbiology

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria 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) bacteria.

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:

Gram-Positive Microorganisms

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-Negative Microorganisms

Haemophilus influenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

Other Microorganisms

Mycoplasma pneumoniae

Chlamydia pneumoniae (TWAR)

The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most isolates of the following bacteria; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these bacteria have 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

Bordetella pertussis

Legionella pneumophila

Pasteurella multocida

Gram-Positive Bacteria

Clostridium perfringens

Peptococcus niger

Propionibacterium acnes

Gram-Negative Anaerobic Bacteria

Prevotella melaninogenica (formerly Bacteriodes melaninogenicus)

Susceptibility Testing

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 criteria²:

Susceptibility Test Interpretive Criteria for Staphylococcus aureus

  MIC (mcg/mL)	  Interpretation
  ≤ 2	  Susceptible	  (S)
  4	  Intermediate	  (I)
  ≥ 8	  Resistant	  (R)

Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcus pneumoniae^a

 a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
  MIC (mcg/mL)	  Interpretation
  ≤ 0.25	  Susceptible	  (S)
  0.5	  Intermediate	  (I)
  ≥ 1	  Resistant	  (R)

For testing Haemophilus spp.^b

 b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Testing Medium (HTM).1
  MIC (mcg/mL)	  Interpretation
  ≤ 8	  Susceptible	  (S)
  16	  Intermediate	  (I)
  ≥ 32	  Resistant	  (R)

  Note: When testing Streptococcus pyogens and 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.

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.^1,2 Standard clarithromycin powder should provide the following MIC values:

  cATCC is a registered trademark of the American Type Culture Collection. d 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. e This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using HTM1.
  QC Strain		  MIC (mcg/mL)
  S. aureus	  ATCC® 29213c	  0.12 to 0.5
  S. pneumoniae d	  ATCC 49619	  0.03 to 0.12
  Haemophilus influenzae e	  ATCC 49247	  4 to 16

Diffusion Techniques

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

Susceptibility Test Interpretive Criteria for Staphylococcus aureus

  Zone diameter (mm)	  Interpretation
  ≥ 18	  Susceptible	  (S)
  14 to 17	  Intermediate	  (I)
  ≤ 13	  Resistant	  (R)

Susceptibility Test Interpretive Criteria for Streptococcus pyogenes and Streptococcuspneumoniae^f

 f These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
  Zone diameter (mm)	  Interpretation
  ≥ 21	  Susceptible	  (S)
  17 to 20	  Intermediate	  (I)
  ≤ 16	  Resistant	  (R)

For testing Haemophilus spp. ^g

 g These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM2.
  Zone diameter (mm)	  Interpretation
  ≥ 13	  Susceptible	  (S)
  11 to 12	  Intermediate	  (I)
  ≤ 10	  Resistant	  (R)

  Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin.

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.^2,3  For the diffusion technique using the 15 mcg disk, the criteria in the following table should be achieved.

Acceptable Quality Control Ranges for Clarithromycin

 h This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.
 i This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2.
  QC Strain		  Zone diameter (mm)
  S. aureus	  ATCC 25923	  26 to 32
  S. pneumoniae h	  ATCC 49619	  25 to 31
  Haemophilus influenzae i	  ATCC 49247	  11 to 17