Lincomycin Hydrochloride
Indications: Infection
WARNING:
Lincomycin therapy has been associated with severe colitis which may end fatally. Therefore, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in INDICATIONS AND USAGE. It should not be used in patients with nonbacterial infections, such as most upper respiratory tract infections. Studies indicate a toxin(s) produced by Clostridia is one primary cause of antibiotic associated colitis.1-5 (See WARNINGS.) The colitis is usually characterized by severe, persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus. Endoscopic examination may reveal pseudomembranous colitis.
When significant diarrhea occurs, the drug should be discontinued or, if necessary, continued only with close observation of the patient. Large bowel endoscopy has been recommended.
Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen the condition. Vancomycin has been found to be effective in the treatment of antibiotic associated pseudomembranous colitis produced by Clostridium difficile . The usual adult dose is 500 milligrams to 2 grams of vancomycin orally per day in three to four divided doses administered for 7 to 10 days. Cholestyramine or colestipol resins bind vancomycin in vitro . If both a resin and vancomycin are to be administered concurrently, it may be advisable to separate the time of administration of each drug.
Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of therapy with lincomycin.
DESCRIPTION:
Lincocin Capsules and Lincocin Sterile Solution contain lincomycin HCl which is the monohydrated salt of lincomycin, a substance produced by the growth of a member of the lincolnensis group of Streptomyces lincolnensis (Fam. Streptomycetaceae ). It is a white or practically white, crystalline powder and is odorless or has a faint odor. Its solutions are acid and are dextrorotatory. Lincomycin HCl is freely soluble in water; soluble in dimethylformamide and very slightly soluble in acetone.
Lincocin capsules contain the following inactive ingredients: FD&C blue no. 1, gelatin, lactose, magnesium stearate, talc and titanium dioxide.
CLINICAL PHARMACOLOGY:
Microbiology: Lincomycin has been shown to be effective against most of the common gram-positive pathogens. Depending on the sensitivity of the organism and concentration of the antibiotic, it may be either bactericidal or bacteriostatic. Cross resistance has not been demonstrated with penicillin, chloramphenicol, ampicillin, cephalosporins or the tetracyclines. Despite chemical differences, lincomycin exhibits antibacterial activity similar but not identical to the macrolide antibiotics (e.g., erythromycin). Some cross resistance (with erythromycin) including a phenomenon known as dissociated cross resistance or macrolide effect has been reported. Microorganisms have not developed resistance to lincomycin rapidly when tested by in vitro or in vivo methods. Staphylococci develop resistance to lincomycin in a slow, stepwise manner based on in vitro , serial subculture experiments. This pattern of resistance development is unlike that shown for streptomycin.
Studies indicate that lincomycin does not share antigenicity with penicillin compounds.
Biological Studies: In vitro studies indicate that the spectrum of activity includes Staphylococcus aureus , Staphylococcus albus , beta-hemolytic Streptococcus , Streptococcus viridans , Diplococcus pneumoniae , Clostridium tetani , Clostridium perfringens , Corynebacterium diphtheriae and Corynebacterium acnes .
NOTE: This drug is not active against most strains of Streptococcus faecalis , nor against Neisseria gonorrhoeae , Neisseria meningitidis , Hemophilus influenzae , or other gram-negative organisms or yeasts.
Human Pharmacology: Lincomycin is absorbed rapidly after a 500 mg oral dose, reaching peak levels in 2 to 4 hours. Levels are maintained above the MIC (minimum inhibitory concentration) for most gram-positive organisms for 6 to 8 hours. Urinary recovery of drug in a 24-hour period ranges from 1.0 to 31 percent (mean: 4.0) after a single oral dose of 500 mg of lincomycin. Tissue level studies indicate that bile is an important route of excretion. Significant levels have been demonstrated in the majority of body tissues. Although the drug is not present in significant amounts in the spinal fluid of normal volunteers, it has been demonstrated in the spinal fluid of one patient with pneumococcal meningitis.
Intramuscular administration of a single dose of 600 mg of lincomycin produces a peak serum level at 30 minutes with detectable levels persisting for 24 hours. Urinary excretion after this dose ranges from 1.8 to 24.8 percent (mean: 17.3).
The intravenous infusion over a 2-hour interval of 600 mg of lincomycin in 500 ml of 5 percent glucose in distilled water yields therapeutic levels for 14 hours. Urinary excretion ranges from 4.9 to 30.3 percent (mean: 13.8).
The biological half-life, after oral, intramuscular or intravenous administration is 5.4 Β± 1.0 hours.
Hemodialysis and peritoneal dialysis do not effectively remove lincomycin from the blood.
CLINICAL STUDIES:
Experience with 345 obstetrical patients receiving this drug revealed no ill effects related to pregnancy.
INDICATIONS AND USAGE:
Lincomycin HCl capsules and lincomycin HCl sterile solution are indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci. Its use should be reserved for penicillin-allergic patients or other patients for whom, in the judgment of the physician, a penicillin is inappropriate. Because of the risk of colitis, as described in the BOXED WARNING, before selecting lincomycin the physician should consider the nature of the infection and suitability of less toxic alternatives (e.g., erythromycin).
Lincomycin has been demonstrated to be effective in the treatment of staphylococcal infections resistant to other antibiotics and susceptible to lincomycin. Staphylococcal strains resistant to lincomycin HCl have been recovered; culture and susceptibility studies should be done in conjunction with therapy with lincomycin HCl. In the case of macrolides, partial but not complete cross resistance may occur (see CLINICAL PHARMACOLOGY, Microbiology). The drug may be administered concomitantly with other antimicrobial agents when indicated.
CONTRAINDICATIONS:
This drug is contraindicated in patients previously found to be hypersensitive to lincomycin or clindamycin. It is not indicated in the treatment of minor bacterial infections or viral infections.
WARNINGS:
(See BOXED WARNING.) Studies indicate a toxin(s) produced by Clostridia is one primary cause of antibiotic associated colitis.1-5 Mild cases of colitis may respond to drug discontinuance alone. Moderate to severe cases should be managed promptly with fluid, electrolyte and protein supplementation as indicated. Vancomycin has been found to be effective in the treatment of antibiotic associated pseudomembranous colitis produced by Clostridium difficile . The usual adult dose is 500 milligrams to 2 grams of vancomycin orally per day in three to four divided doses administered for 7 to 10 days. Cholestyramine or colestipol resins bind vancomycin in vitro . If both a resin and vancomycin are to be administered concurrently, it may be advisable to separate the time of administration of each drug. Other causes of colitis should also be considered.
A careful inquiry should be made concerning previous sensitivities to drugs and other allergens.
Usage in Pregnancy: Safety for use in pregnancy has not been established.
Usage in Newborn: Until further clinical experience is obtained, lincomycin preparations are not indicated in the newborn.
Nursing Mothers: Lincomycin has been reported to appear in breast milk in ranges of 0.5 to 2.4 mcg/ml.
Lincomycin HCl sterile solution contains benzyl alcohol which has been associated with a fatal "gasping syndrome" in infants.
PRECAUTIONS:
Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When lincomycin preparations are indicated in these patients, they should be carefully monitored for change in bowel frequency.
Lincomycin HCl should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
Lincomycin HCl like any drug, should be used with caution in patients with a history of asthma or significant allergies.
The use of antibiotics occasionally results in overgrowth of nonsusceptible organisms--particularly yeasts. Should superinfections occur, appropriate measures should be taken. When patients with pre-existing monilial infections require therapy with lincomycin HCl, concomitant antimonilial treatment should be given.
During prolonged therapy with lincomycin HCl, periodic liver and renal function studies and blood counts should be performed.
Since adequate data are not yet available in patients with pre-existing liver disease, its use in such patients is not recommended at this time unless special clinical circumstances so indicate.
Lincomycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents.
Indicated surgical procedures should be performed in conjunction with antibiotic therapy.
ADVERSE REACTIONS:
Gastrointestinal: Glossitis, stomatitis, nausea, vomiting. Persistent diarrhea, enterocolitis and pruritus ani. (See BOXED WARNING.)
Hematopoietic: Neutropenia, leukopenia, agranulocytosis and thrombocytopenic purpura have been reported. There have been rare reports of aplastic anemia and pancytopenia in which lincomycin HCl could not be ruled out as the causative agent.
Hypersensitivity Reactions: Hypersensitivity reactions such as angioneurotic edema, serum sickness and anaphylaxis have been reported, some of these in patients known to be sensitive to penicillin. Rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with lincomycin HCl preparations. If an allergic reaction should occur, the drug should be discontinued and the usual agents (epinephrine, corticosteroids, antihistamines) should be available for emergency treatment.
Skin and Mucous Membranes: Skin rashes, urticaria and vaginitis and rare instances of exfoliative and vesiculobullous dermatitis have been reported.
Liver: Although no direct relationship of lincomycin HCl to liver dysfunction has been established, jaundice and abnormal liver function tests (particularly elevations of serum transaminase) have been observed in a few instances.
Renal: Although no direct relationship of lincomycin to renal damage has been established, renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria has been observed in rare instances.
Cardiovascular: After too rapid intravenous administration, rare instances of cardiopulmonary arrest and hypotension have been reported. (See DOSAGE AND ADMINISTRATION.)
Special Senses: Tinnitus and vertigo have been reported occasionally.
Local Reactions: Patients have demonstrated excellent local tolerance to intramuscularly administered lincomycin HCl. Reports of pain following injection have been infrequent. Intravenous administration of lincomycin HCl in 250 to 500 ml of 5 percent glucose in distilled water or normal saline produced no local irritation or phlebitis.
DOSAGE AND ADMINISTRATION:
If significant diarrhea occurs during therapy, this antibiotic should be discontinued. (See BOXED WARNING.)
Oral
Adults: Serious Infections: 500 mg 3 times per day (500 mg approximately every 8 hours). More Severe Infections: 500 mg or more 4 times per day (500 mg or more approximately every 6 hours).
Children Over 1 Month of aAge: Serious Infections: 30 mg/kg/day (15 mg/lb/day) divided into 3 or 4 equal doses. More Severe Infections: 60 mg/kg/day (30 mg/lb/day) divided into 3 or 4 equal doses.
With beta-hemolytic streptococcal infections, treatment should continue for at least 10 days to diminish the likelihood of subsequent rheumatic fever or glomerulonephritis.
Note: For optimal absorption it is recommended that nothing be given by mouth except water for a period of one to two hours before and after oral administration of lincomycin preparations.
Intramuscular
Adults: Serious Infections: 600 mg (2 ml) intramuscularly every 24 hours. More Severe Infections: 600 mg (2 ml) intramuscularly every 12 hours or more often.
Children Over 1 Month of Age: Serious Infections: one intramuscular injection of 10 mg/kg (5 mg/lb) every 24 hours. More Severe Infections: one intramuscular injection of 10 mg/kg (5 mg/lb) every 12 hours or more often.
Intravenous
Adults: The intravenous dose will be determined by the severity of the infection. For serious infections doses of 600 mg of lincomycin (2 ml of lincomycin HCl) to 1 gram are given every 8-12 hours. For more severe infections these doses may have to be increased. In life-threatening situations daily intravenous doses of as much as 8 grams have been given. Intravenous doses are given on the basis of 1 gram of lincomycin diluted in not less than 100 ml of appropriate solution (see Physical Compatibilities) and infused over a period of not less than one hour. (See TABLE 1.)
TABLE 1
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Dose Vol. Diluent Time
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600 mg 100 ml 1 hr
1 gram 100 ml 1 hr
2 grams 200 ml 2 hr
3 grams 300 ml 3 hr
4 grams 400 ml 4 hr
These doses may be repeated as often as required to the limit of the maximum recommended daily dose of 8 grams of lincomycin.
Children Over 1 Month of Age: 10-20 mg/kg/day (5-10 mg/lb/day) depending on the severity of the infection may be infused in divided doses as described above for adults.
NOTE: Severe cardiopulmonary reactions have occurred when this drug has been given at greater than the recommended concentration and rate.
Subconjunctival Injection: 0.25 ml (75 mg) injected subconjunctivally will result in ocular fluid levels of antibiotic (lasting for at least 5 hours) with MIC's sufficient for most susceptible pathogens.
Patients With Diminished Renal Function: When therapy with lincomycin HCl is required in individuals with severe impairment of renal function, an appropriate dose is 25 to 30% of that recommended for patients with normally functioning kidneys.
Physical Compatibilities
Physically compatible for 24 hours at room temperature unless otherwise indicated.
Infusion Solutions
Dextrose in Water, 5% and 10%.
Dextrose in Saline, 5% and 10%.
Ringer's Solution.
Sodium Lactate 1/6 Molar.
Travert 10%--Electrolyte No. 1.
Dextran in Saline 6% w/v.
Vitamins in Infusion Solutions
B-Complex.
B-Complex with Ascorbic Acid.
Antibiotics in Infusion Solutions
Penicillin G Sodium (Satisfactory for 4 hours).
Cephalothin.
Tetracycline HCl.
Cephaloridine.
Colistimethate (Satisfactory for 4 hours).
Ampicillin.
Methicillin.
Chloramphenicol.
Polymyxin B Sulfate.
Physically Incompatible with:
Novobiocin.
Kanamycin.
IT SHOULD BE EMPHASIZED THAT THE COMPATIBLE AND INCOMPATIBLE DETERMINATIONS ARE PHYSICAL OBSERVATIONS ONLY, NOT CHEMICAL DETERMINATIONS. ADEQUATE CLINICAL EVALUATION OF THE SAFETY AND EFFICACY OF THESE COMBINATIONS HAS NOT BEEN PERFORMED.
ANIMAL PHARMACOLOGY:
In vivo experimental animal studies demonstrated the effectiveness of lincomycin HCl preparations (lincomycin) in protecting animals infected with Streptococcus viridans , beta-hemolytic Streptococcus , Staphylococcus aureus , Diplococcus pneumoniae and Leptospira pomona . It was ineffective in Klebsiella , Pasteurella , Pseudomonas , Salmonella and Shigella infections.
REFERENCES:
1. Bailey, WR, Scott, EG, Diagnostic Microbiology CV Mosby Company, St. Louis, 1978.
2. Bartlett, JG,et al. , "Clindamycin-associated Colitis due to Toxin-producing Species of Clostridium in Hamsters" J. inf. Dis. 136 (5):701-705, (November) 1977.
3. Larson, HE, Price, AB,"Pseudomembranous Colitis: Presence of Clostridial Toxin," Lancet , 1312-1314 (December) 24 and 31, 1977.
4. Lusk, RH, et al., "Clindamycin-Induced Enterocolitis in Hamsters",J. Inf. Dis. 137 (4):464-474 (April) 1978.
5. "Antibiotic-associated Colitis: A Progress Report", British Med. J. 1 :669-671 (March 18) 1978.