Sumamecin Actions

• Actions of Sumamecin in details
• Sumamecin administration
• Sumamecin pharmacology
• Sumamecin reviews

Actions of Sumamecin in details

Pharmacology: Like other macrolides, Sumamecin inhibits RNA-dependent protein synthesis by binding to the 50S ribosomal sub unit of the 70S ribosome of susceptible bacteria. The site of action appears to be the same as that of the macrolides, clindamycin, lincomycin, and chloramphenicol. Sumamecin is bactericidal for Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae. It is bacteriostatic for staphylococci and most aerobic gram-negative species. The spectrum of activity of Sumamecin is broader than erythromycin, clarithromycin, or clarithromycin. Sumamecin generally is more active in vitro against gram-negative organism than erythromycin or clarithromycin and has activity comparable to erythromycin against most gram-positive organisms. Beta-lactamases produced by Haemophilus influenzae or Moraxella catarrhalis do not inactivate Sumamecin.

Pharmacokinetics: Following oral intake, Sumamecin is widely distributed throughout the body except to cerebrospinal fluid. Bioavailability ranges from 34-52% and was generally maintained when Sumamecin tablets were administered with a meal. Peak plasma levels are reached in 2-3 hours. Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2-4 days.

After oral administration, Sumamecin is rapidly and widely distributed throughout the body. Unique properties of Sumamecin include extensive tissue distribution and high drug concentrations, within cells (including phagocytes) resulting in much tissue concentrations. Sumamecin concentrates intracellularly, resulting in tissue concentrations 10 to 100 times higher than those found in plasma or serum. Sumamecin is high concentrated in fibroblasts and phagocytic cells, contributing to the distribution of the drug into inflamed and infected tissues. Because of extensive tissue sequestration and binding, the usual elimination half-life of 40-68 hours is prolonged. Penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g. Staphylococcus aureus). Only very low concentrations of Sumamecin have been detected in cerebrospinal fluid in patients with non-inflamed meninges.

Following a single oral dose, plasma concentrations of Sumamecin declined with a polyphasic pattern. Sumamecin undergoes some hepatic metabolism to inactive metabolites but more than 50% of Sumamecin is eliminated through biliary secretion as unchanged drug. Sumamecin is excreted in feces primarily as unchanged drug. Approximately 4.5-6% of a dose is eliminated in urine as unchanged drug within 72 hours.

How should I take Sumamecin?

Your doctor will tell you how much of Sumamecin to use and how often. Do not use more medicine or use it more often than your doctor tells you to. Sumamecin is not for long-term use.

To use the eye drops:

• First, wash your hands. Then turn the closed bottle upside down and shake it one time before putting the medicine in your eye. Remove the cap with the bottle still being held upside down.
• Tilt your head back and pressing your finger gently on the skin just beneath the lower eyelid, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close the eye. Do not blink. Keep the eye closed for 1 or 2 minutes to allow the medicine to be absorbed.
• If you think you did not get the drop of medicine into your eye properly, repeat the directions with another drop.
• Immediately after using the eye drops, wash your hands to remove any medicine that may be on them.
• To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Also, keep the container tightly closed.

To help clear up your eye infection completely, keep using Sumamecin for the full treatment time, even if your symptoms disappeared and even if you feel better after the first few doses. Your infection may not clear up if you stop using the medicine too soon. Do not miss any doses.

Dosing

The dose of Sumamecin will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Sumamecin. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For ophthalmic dosage form (eye drops):
  • For bacterial conjunctivitis:
    • Adults, teenagers, and children 1 year of age and older—Put one drop in the affected eye(s) two times a day for 2 days, with each dose being at least 8 to 12 hours apart. Then, put one drop in the affected eye(s) once a day for the next 5 days.
    • Children younger than 1 year of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of Sumamecin, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Store the unopened bottle in the refrigerator. Do not freeze. Once the medicine is opened, you may store it in the refrigerator or in a closed container at room temperature, away from heat, moisture, and direct light for up to 14 days.

Ask your doctor how you should dispose of any medicine you do not use. Throw away any unused medicine after 14 days.

Sumamecin administration

IV: Infuse over 1 hour (2 mg/ml infusion) or over 3 hours (1 mg/ml infusion). Not for IM or IV bolus administration.

Oral: Immediate release suspension and tablet may be taken without regard to food; extended release suspension should be taken on an empty stomach (at least 1 hour before or 2 hours following a meal), within 12 hours of reconstitution.

Sumamecin pharmacology

Mechanism of Action

Sumamecin is a macrolide antibacterial drug.

Sumamecin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was > 30 after one hr of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Pharmacodynamics

Based on animal models of infection, the antibacterial activity of Sumamecin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with Sumamecin.

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with oral Sumamecin (500 mg, 1000 mg, and 1500 mg once daily). Coadministration of Sumamecin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the coadministration of 500 mg, 1000 mg and 1500 mg Sumamecin, respectively.

Pharmacokinetics

The pharmacokinetic parameters of Sumamecin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18 to 40 years old) are portrayed in the following chart:

With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, Cmin and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, Sumamecin Cmin levels required 5 to 7 days to reach steady state.

In asymptomatic HIV-positive adult subjects receiving 600 mg Sumamecin Tablets once daily for 22 days, steady state Sumamecin serum levels were achieved by Day 15 of dosing.

The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.

Absorption

The 1 gram single-dose packet is bioequivalent to four 250 mg Sumamecin capsule

When the oral suspension of Sumamecin was administered with food, the Cmax increased by 46% and the AUC by 14%.

The absolute bioavailability of two 600 mg tablets was 34% (CV = 56%). Administration of two 600 mg tablets with food increased Cmax by 31% (CV = 43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs = 1.00; CV = 55%).

Distribution

The serum protein binding of Sumamecin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL.

The antibacterial activity of Sumamecin is pH related and appears to be reduced with decreasing pH. However, the extensive distribution of drug to tissues may be relevant to clinical activity.

Sumamecin has been shown to penetrate into tissues in humans, including skin, lung, tonsil, and cervix. Extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies of Sumamecin treatment of infections in these additional body sites, the clinical importance of these tissue concentration data is unknown.

Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 mcg/mL. Concentration remained above 32 mcg/mL, for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte-to-plasma Cmax ratios for males and females were 258 (± 77%) and 175 (± 60%), respectively, and the AUC ratios were 804 (± 31%) and 541 (± 28%), respectively. The clinical relevance of these findings is unknown. Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 mcg/mL (± 49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 mcg/mL (± 33%). The mean leukocyte-to-serum Cmax ratio was 456 (± 38%) and the mean leukocyte to serum AUC ratio was 816 (± 31%). The clinical relevance of these findings is unknown.

Metabolism

In vitro and in vivo studies to assess the metabolism of Sumamecin have not been performed.

Elimination

Plasma concentrations of Sumamecin following single 500 mg oral and IV doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hr. Biliary excretion of Sumamecin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

Specific Populations

Renal Insufficiency

Sumamecin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of Sumamecin (4 × 250 mg capsules), the mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively, in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR > 80 mL/min). The mean Cmax and AUC0-120 increased 61% and 35%, respectively, in subjects with end-stage renal disease (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min).

Hepatic Insufficiency

The pharmacokinetics of Sumamecin in subjects with hepatic impairment has not been established.

Gender

There are no significant differences in the disposition of Sumamecin between male and female subjects. No dosage adjustment is recommended on the basis of gender.

Geriatric Patients

Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in younger volunteers (18 to 40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen.

Pediatric Patients

For information regarding the pharmacokinetics of Sumamecin for oral suspension in pediatric patients, see the prescribing information for Sumamecin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles.

Drug-drug Interactions

Drug interaction studies were performed with Sumamecin and other drugs likely to be coadministered. The effects of coadministration of Sumamecin on the pharmacokinetics of other drugs are shown in Table 1 and the effects of other drugs on the pharmacokinetics of Sumamecin are shown in Table 2.

Coadministration of Sumamecin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when coadministered with Sumamecin.

Coadministration of Sumamecin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of Sumamecin. Nelfinavir significantly increased the Cmax and AUC of Sumamecin. No dosage adjustment of Sumamecin is recommended when administered with drugs listed in Table 2.

Microbiology

Sumamecin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in.

Aerobic Gram-Positive Microorganisms

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

NOTE: Sumamecin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to Sumamecin.

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae

Moraxella catarrhalis

Other Microorganisms

Chlamydia trachomatis

Beta-lactamase production should have no effect on Sumamecin activity.

Sumamecin has been shown to be active in vitro and in the prevention and treatment of disease caused by the following microorganisms:

Mycobacteria

Mycobacterium avium complex (MAC) consisting of:

Mycobacterium avium

Mycobacterium intracellulare

The following in vitro data are available, but their clinical significance is unknown.

Sumamecin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0 mcg/mL or less against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of Sumamecin 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 Sumamecin 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 hr and in an apparent reduction of the in vitro potency of Sumamecin. Thus, the initial pH of the growth medium should be 7.2 to 7.4, and the CO2 content of the incubation atmosphere should be as low as practical.

Sumamecin 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 antibacterial compounds. One such standardized procedure uses a standardized dilution method1 (broth, agar or microdilution) or equivalent with Sumamecin powder. The MIC values should be interpreted according to the following criteria:

A report of “Susceptible” indicates that the pathogen is likely to respond to monotherapy with Sumamecin. 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 minimum bacterial concentration (MBC) and achieved antibacterial compound concentrations may be appropriate to guide therapy in some infections. section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antibacterial drug product.

Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard Sumamecin powder should provide the following MIC values:

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antibacterial compounds. One such standardized procedure2 that has been recommended for use with disks to test the susceptibility of microorganisms to Sumamecin uses the 15 mcg Sumamecin disk. Interpretation involves the correlation of the diameter obtained in the disk test with the MIC for Sumamecin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 mcg Sumamecin disk should be interpreted according to the following criteria:

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 mcg Sumamecin disk should provide the following zone diameters in these laboratory test quality control strains:

In Vitro Activity of Sumamecin Against Mycobacteria

Sumamecin has demonstrated in vitro activity against MAC organisms. While gene probe techniques may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on MAC isolates. Sumamecin has also been shown to be active against phagocytized 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 Sumamecin MIC values for MAC strains. In general, Sumamecin 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, Sumamecin 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 OADC in these assays has been shown to further alter MIC values. The relationship between Sumamecin and clarithromycin MIC values has not been established. In general, Sumamecin 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 Sumamecin concentrates in macrophages and tissues.

Drug Resistance

Complete cross-resistance between Sumamecin and clarithromycin has been observed with 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 MAC isolates exhibiting cross-resistance show an increase in Sumamecin MICs to ≥ 128 mcg/mL with clarithromycin MICs increasing to ≥ 32 mcg/mL. These MIC values were determined employing the radiometric broth dilution susceptibility testing method with Middlebrook 7H12 medium. The clinical significance of Sumamecin and clarithromycin cross-resistance is not fully understood at this time but preclinical data suggest that reduced activity to both agents will occur after MAC strains produce the 23S rRNA mutation.

Susceptibility Testing for MAC

The disk diffusion techniques and dilution methods for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining Sumamecin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining MIC values against MAC organisms have not been standardized or validated. Sumamecin 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 Sumamecin have not been established.

The clinical relevance of Sumamecin in vitro susceptibility test results for other mycobacterial species, including Mycobacterium tuberculosis, using any susceptibility testing method has not been determined.

References

1. DailyMed. "AZITHROMYCIN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
2. NCIt. "Azithromycin: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
3. EPA DSStox. "Azithromycin: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

Reviews

User reports

Consumer reviews

Information checked by Dr. Sachin Kumar, MD Pharmacology