Lincomycin

Lincomycin is an antibiotic agent belonging to the pharmacological class of Lincosamide Antibiotics

Lincomycin has been approved to relieve symptoms and also for the treatment and maintenance of severe bacterial infections.

When a 600 mg dose of lincomycin is administered intravenously over two hours, the average maximum plasma concentration (Cmax) reaches approximately 15.9 μg/mL. Similarly, when the same dose is given through intramuscular injection, the average Cmax of lincomycin is approximately 11.6 μg/mL after 60 minutes. Studies have shown that the area under the concentration-time curve (AUC) increases disproportionately to the dose.In healthy adult males receiving intravenous lincomycin, the steady-state volume of distribution ranges from 63.8 to 105.1 L, depending on the dose administered.The metabolic pathways of lincomycin are not well-defined, and the majority of the administered dose is excreted unchanged in humans.After a 600 mg dose of lincomycin via intramuscular or intravenous administration, urinary excretion accounts for 1.8% to 30.3% of the dose. Bile is also considered an important route of elimination. Patients with renal or the hepatic impairment may require dosage adjustments.

The common side effects involved in using Lincomycin are Nausea, Vomiting, Diarrhea, Abdominal pain, Gastrointestinal discomfort, Skin rash, Itching, Hives (urticaria), Injection site pain, Injection site redness, Injection site swelling, Allergic reactions.

Lincomycin is available in the form of Injectables.

Lincomycin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S, and China.

Lincomycin belongs to the pharmacological class of Lincosamide Antibiotics

Lincomycin contains a unique amino acid component called propyl hygric acid, which is linked to the sugar component α-methylthiolincosamine (α-MTL). Similar to other lincosamides, it acts as a structural mimic of the 3' end of L-Pro-Met-tRNA and deacylated-tRNA. This enables lincomycin to interact with the 23S rRNA of the 50S bacterial ribosomal subunit. Studies on the related lincosamide clindamycin have suggested a two-phase binding process. Initially, there is an instantaneous binding to the A-site, followed by a gradual shift towards the P-site over several seconds. This shift is believed to occur due to the rotation of the propyl hygric acid component, while the α-MTL component remains relatively stable. Recent crystal structures of lincomycin bound to the 50S ribosomal subunit of Staphylococcus aureus have shown that the α-MTL moiety forms hydrogen bonds with specific residues (C2611, A2058, G2505, A2059, and G2503) of the 23S rRNA. On the other hand, the propyl hygric acid component interacts primarily through van der Waals contacts, suggesting it has the potential to rotate similarly to clindamycin. This mechanism is supported by the fact that the most common resistance mechanism, which affects macrolides and streptogramin B (MSLB resistance), involves the methylation of A2058.

Lincomycin has been approved to relieve symptoms and also for the treatment and maintenance of severe bacterial infections.

When lincomycin is administered intravenously over a period of two hours at a dosage of 600 mg, the average maximum plasma concentration (Cmax) achieved is approximately 15.9 μg/mL. On the other hand, when the same dose is administered via intramuscular injection, the average Cmax of lincomycin reaches around 11.6 μg/mL after 60 minutes.

The onset of action of lincomycin can vary depending on the condition being treated. Generally, it starts to take effect within 1 to 2 hours after administration.The duration of action of lincomycin also varies depending on the specific condition and individual patient factors. Typically, the effects of a single dose of lincomycin can last for 6 to 12 hours.

Lincomycin is found to be available in the form of Injectables.

Lincomycin can be used in the following treatment:

• Severe bacterial infections

Lincomycin can help to relieve symptoms and also for the treatment and maintenance of Severe bacterial infections.

Lincomycin is approved for use in the following clinical indications:

• Severe bacterial infections

Severe bacterial infection:

• Intramuscular (IM): The recommended dose is 600 mg, to be administered every 12 to 24 hours.
• Intravenous (IV): The recommended dose is 600 mg to 1 g, to be administered every 8 to 12 hours. The maximum daily dose should not exceed 8 g.
• Ophthalmic: For subconjunctival injection, a single dose of 75 mg is administered. The medication reaches levels in the ocular fluid that maintain sufficient minimum inhibitory concentrations (MICs) for at least 5 hours.

• Injectable solution: Lincomycin injection is supplied as a sterile powder that needs to be reconstituted with a compatible diluent. It is available in strengths of 300 mg and 600 mg per vial.

Injections

• Dosage Adjustments in Kidney Patients:

Mild to moderate impairment: The manufacturer's labeling does not recommend any dosage adjustments.

Severe impairment: Caution should be exercised, and the dose should be reduced by 70% to 75%.

End stage renal disease (ESRD) on hemodialysis: The manufacturer's labeling does not provide specific dosage adjustments. However, caution should be exercised when using the medication, as it is not effectively removed by hemodialysis.

Peritoneal dialysis: The manufacturer's labeling does not specify dosage adjustments. Use the medication with caution, as it is not effectively removed by peritoneal dialysis.

• Dosage Adjustments in Pediatric Patients:

Severe bacterial infection:

Infants, Children, and Adolescents:

• Intramuscular (IM): The recommended dose is 10 mg/kg per dose, given every 12 to 24 hours. The usual adult dose is 600 mg per dose. Please note that the frequency of administration may be increased if necessary, depending on the severity of the infection.
• Intravenous (IV): The recommended dose is 10 to 20 mg/kg per day, divided into doses given every 8 to 12 hours. The usual adult dose is 600 to 1,000 mg per dose (maximum daily dose: 8 g per day). It's important to note that higher doses up to 100 mg/kg per day, divided into doses (maximum reported dose: 2,400 mg per dose) given every 6 hours, have been used in a group of 265 pediatric patients (aged 3 weeks to 15 years) with various infections. The duration of therapy ranged from 5 to 63 days, and it was well tolerated.
• Ophthalmic: For subconjunctival injection, a single dose of 75 mg is administered. The concentrations of the medication in the ocular fluid are sufficient to combat most pathogens for at least 5 hours.

There are no specific dietary restrictions associated with the use of Lincomycin.

Lincomycin may be contraindicated under the following conditions:

• Lincomycin should not be used in individuals with a known hypersensitivity or allergic reaction to the drug Lincomycin.

1. Clostridium difficile-associated diarrhea (CDAD) has been observed with the use of almost all types of antibacterial drugs, including Lincomycin. The severity of CDAD can vary from mild diarrhea to life-threatening colitis. When antibacterial agents are used, they disrupt the normal balance of bacteria in the colon, which allows C. difficile to grow excessively.
2. CDAD is caused by C. difficile, which produces toxins A and B that contribute to the development of the condition. Strains of C. difficile that produce high levels of toxins can lead to more severe illness and increased chances of mortality. In some cases, these infections may not respond well to antimicrobial treatment and may require surgical removal of the colon. Therefore, CDAD should be considered in all patients who experience diarrhea after taking antibacterial drugs. It's important to take a detailed medical history as CDAD has been reported to occur even two months after taking antibacterial agents.
3. If CDAD is suspected or confirmed, the continued use of antibacterial drugs that do not target C. difficile may need to be stopped. The appropriate management includes maintaining fluid and electrolyte balance, providing protein supplements, administering antibacterial treatment specifically for C. difficile, and considering surgical evaluation based on clinical indications.
4. Hypersensitivity reactions can occur, including severe allergic reactions such as anaphylaxis and severe skin reactions like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and erythema multiforme (EM), in patients receiving Lincomycin treatment. If an anaphylactic reaction or severe skin reaction occurs, Lincomycin should be discontinued, and appropriate treatment should be initiated.
5. Benzyl alcohol toxicity in the pediatric patients (Gasping Syndrome): This product contains benzyl alcohol as a preservative. The use of benzyl alcohol as a preservative has been associated with serious adverse events, including the development of Gasping Syndrome and even death in pediatric patients. Although the typical doses of this product usually deliver benzyl alcohol amounts that are significantly lower than those reported in association with Gasping Syndrome, the minimum amount at which toxicity may occur is unknown. The risk of benzyl alcohol toxicity depends on the dose administered and the ability of the liver and kidneys to detoxify the chemical. Premature as well as low-birth weight infants may be more susceptible to developing toxicity.
6. Use in Meningitis: While lincomycin is believed to penetrate into the cerebrospinal fluid, the concentrations achieved may not be sufficient for treating meningitis.

While there is no specific food interaction between lincomycin and alcohol, it's generally recommended to avoid alcohol when taking any antibiotic medication. Alcohol can interfere with the effectiveness of the medication and might also exacerbate certain side effects.

Reported concentrations of lincomycin in human milk range from 0.5 to 2.4 mcg/mL. Considering the potential for serious adverse reactions in nursing infants from Lincomycin, it is necessary to make a decision regarding either discontinuing nursing or discontinuing the drug.

Pregnancy Category C

Pregnancy

The available data on the use of Lincomycin in pregnant women is limited and inadequate to establish its safety. It is important to note that Lincomycin Sterile Solution contains benzyl alcohol, which can pass through the placenta. Please refer to the WARNINGS section for further details. Lincomycin should only be used during pregnancy if the benefits clearly outweigh the potential risks.

Teratogenic Effects:

In a study involving 60 pregnant women, it was observed that lincomycin crosses the placenta, as cord serum concentrations were approximately 25% of maternal serum concentrations. However, there was no significant accumulation of lincomycin in the amniotic fluid. Additionally, no adverse effects related to pregnancy were reported in 345 obstetrical patients who received Lincomycin.

Studies conducted on pregnant Sprague Dawley rats, where lincomycin was administered orally in diet or via oral gavage during the major organogenesis period, showed no evidence of teratogenicity. Doses up to 5000 mg/kg and 100 mg/kg (approximately 6 times and 0.12 times the maximum recommended human dose [MRHD] respectively, based on body surface area comparison) did not result in teratogenic effects.

Nonteratogenic Effects:

Reproduction studies involving rats that were given oral lincomycin in their diet for two weeks before mating, throughout pregnancy, and during lactation showed no adverse effects on the survival of offspring from birth to weaning. Doses up to 1000 mg/kg (1.2 times the MRHD based on body surface area comparison) were used in this study, and it spanned two generations.

Lincomycin can interact with dairy products, particularly calcium-rich foods, reducing its absorption. It is recommended to avoid consuming dairy products, such as milk, cheese, or yogurt, within two hours before or after taking lincomycin. Grapefruit juice may interfere with the breakdown of certain medications, including lincomycin. It is advisable to avoid consuming grapefruit juice while taking lincomycin to prevent any potential interactions.

The adverse reactions related to Lincomycin can be categorized as follows:

Common:

• Nausea and vomiting
• Diarrhea
• Stomach pain or cramps
• Skin rash or itching
• Swelling or redness at the injection site (if administered as an injection)
• Vaginal itching or discharge (in women)

Less Common:

• Headache
• Dizziness
• Joint or muscle pain
• Fungal infections, such as oral thrush or vaginal yeast infections
• Allergic reactions, including hives, itching, or difficulty breathing

Rare:

• Severe allergic reactions (anaphylaxis), which can cause difficulty breathing, chest tightness, swelling of the face, lips, or tongue, and rapid heartbeat
• Clostridium difficile-associated diarrhea (a severe form of diarrhea)
• Liver problems, including hepatitis or jaundice (yellowing of the skin or eyes)
• Blood disorders, such as decreased white blood cell count, decreased platelets, or decreased red blood cell count
• Kidney damage or kidney failure
• Severe skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (rare but serious conditions that can cause blistering and peeling of the skin).

Caution should be exercised when administering lincomycin to patients receiving other neuromuscular blocking agents, as lincomycin has demonstrated neuromuscular blocking properties that can potentially enhance the effects of these agents.

The following are the side effects involving Lincomycin:

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Gastrointestinal discomfort
• Skin rash
• Itching
• Hives (urticaria)
• Injection site pain
• Injection site redness
• Injection site swelling
• Allergic reactions
• Angioedema (swelling of the face, lips, or throat)
• Anaphylaxis (severe allergic reaction)
• Pseudomembranous colitis (a severe form of antibiotic-associated diarrhea caused by Clostridium difficile overgrowth).

Pregnancy Category C

Pregnancy

The available data on the use of Lincomycin in pregnant women is limited and inadequate to establish its safety. It is important to note that Lincomycin Sterile Solution contains benzyl alcohol, which can pass through the placenta. Please refer to the WARNINGS section for further details. Lincomycin should only be used during pregnancy if the benefits clearly outweigh the potential risks.

Teratogenic Effects:

In a study involving 60 pregnant women, it was observed that lincomycin crosses the placenta, as cord serum concentrations were approximately 25% of maternal serum concentrations. However, there was no significant accumulation of lincomycin in the amniotic fluid. Additionally, no adverse effects related to pregnancy were reported in 345 obstetrical patients who received Lincomycin.

Studies conducted on pregnant Sprague Dawley rats, where lincomycin was administered orally in diet or via oral gavage during the major organogenesis period, showed no evidence of teratogenicity. Doses up to 5000 mg/kg and 100 mg/kg (approximately 6 times and 0.12 times the maximum recommended human dose [MRHD] respectively, based on body surface area comparison) did not result in teratogenic effects.

Nonteratogenic Effects:

Reproduction studies involving rats that were given oral lincomycin in their diet for two weeks before mating, throughout pregnancy, and during lactation showed no adverse effects on the survival of offspring from birth to weaning. Doses up to 1000 mg/kg (1.2 times the MRHD based on body surface area comparison) were used in this study, and it spanned two generations.

Lactation:

Reported concentrations of lincomycin in human milk range from 0.5 to 2.4 mcg/mL. Considering the potential for serious adverse reactions in nursing infants from Lincomycin, it is necessary to make a decision regarding either discontinuing nursing or discontinuing the drug.

Pediatric:

Lincomycin Sterile Solution is formulated with benzyl alcohol as a preservative. It is important to note that benzyl alcohol had been linked to a potentially fatal condition known as "Gasping Syndrome" in premature infants. The safety and effectiveness of Lincomycin in pediatric patients below the age of 1 month has not been established.

Geriatric Use:

Lincomycin is a medication that may be used in geriatric patients, although certain considerations should be taken into account. Geriatric patients, typically defined as individuals aged 65 years and older, may have age-related changes in their physiology, including changes in organ function and drug metabolism.

Geriatric patients might also have an increased risk of experiencing adverse reactions to medications. Therefore, close monitoring for any signs of adverse effects or drug interactions is essential during Lincomycin treatment in this patient population.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of over dosage of Lincomycin.

Hemodialysis and peritoneal dialysis have minimal impact on serum concentrations of lincomycin.

Pharmacodynamics

Antibacterial Spectrum and Effectiveness

• Derivation and Characteristics: Lincomycin is a lincosamide antibiotic obtained from Streptomyces lincolnensis through natural fermentation. It shares similarities with clindamycin.
• Activity Against Bacterial Strains: Lincomycin exhibits activity against a range of Gram-positive cocci and bacilli, Gram-negative cocci, and certain other organisms like Haemophilus spp.
• Effectiveness: Clinically confirmed efficacy is mainly limited to Staphylococcus spp. and Streptococcus spp., with additional activity observed in vitro.

Cautionary Considerations

• Hypersensitivity Reactions: Lincomycin is associated with severe cutaneous hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and acute generalized exanthematous pustulosis.
• Clostridium difficile Associated Diarrhea (CDAD): Lincomycin has the potential to precipitate CDAD, leading to fatal colitis.
• Precautions for Specific Patient Groups: Special care should be exercised when administering lincomycin to elderly patients, individuals with a history of gastrointestinal disease, and those with a history of asthma or significant allergies.

Pharmacokinetics

1. Absorption

● Intravenous Administration of Lincomycin: A 600 mg dose of lincomycin given over two hours intravenously yields an average Cmax of 15.9 μg/mL.

● Intramuscular Administration of Lincomycin: The same 600 mg dose administered via intramuscular injection results in an average Cmax of 11.6 μg/mL after 60 minutes.

● Lincomycin Pharmacokinetics: In healthy adult male volunteers, intramuscular doses of 600-1500 mg lead to an AUC0-∞ range of 92.22-159.91 μgh/mL. Intravenous infusion of 600-2400 mg results in AUC0-∞ values between 72.5 and 212.8 μgh/mL. The AUC increases disproportionally to the dose.

2. Volume of Distribution

● Steady-State Volume of Distribution: Intravenous administration of lincomycin in healthy adult males reveals a steady-state volume of distribution of 63.8 ± 23.8 L, 78.8 ± 17.0 L, and 105.1 ± 43.1 L for doses of 600 mg, 1200 mg, and 2400 mg, respectively.

3. Protein Binding

● Lincomycin Serum Protein Binding: The extent of lincomycin serum protein binding varies widely depending on the dose, ranging from 28% to 86%. Higher serum concentrations tend to show lower protein binding, suggesting saturable binding. It has been suggested that α1-acid glycoprotein is the primary binding site for lincomycin, similar to clindamycin.

4. Metabolism

● Lincomycin Metabolism: The metabolism of lincomycin is not well defined, but in humans, the primary recovered product after administration is unchanged lincomycin.

5. Route of Elimination

● Urinary Excretion and Bile Elimination: Following a 600 mg dose of lincomycin via intramuscular or intravenous administration, urinary excretion ranges from 1.8% to 30.3% of the administered dose. Bile is also considered an important route of elimination. Dose adjustments are necessary for patients with renal or hepatic impairment.

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