Xl V

Uses

Ceftriaxone is used for the treatment of the following infections when caused by susceptible organisms:

Lower Respiratory Tract Infections caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, E. coli, Enterobacter aerogenes, Proteus mirabilis, Serratia marcescens.

Acute Bacterial Otitis Media caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains), Moraxella catarrhalis (including beta-lactamase producing strains).

Skin and Skin Structure Infections caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci, E. coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii, Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis, Peptostreptococcus species.

Urinary Tract Infections (complicated and uncomplicated) caused by E. coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Klebsiella pneumoniae.

Uncomplicated Gonorrhea (cervical, urethral, pharyngial and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae.

Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae.

Bacterial Septicemia caused by Staphylococcus aureus, Streptococcus pneumoniae, E. coli, Haemophilus influenzae, Klebsiella pneumoniae.

Bone and Joint Infections caused by Staphylococcus aureus, Streptococcus pneumoniae, E. coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species.

Intra-abdominal Infections caused by E. coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species, Peptostreptococcus species.

Meningitis caused by Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae. Ceftriaxone has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis and E. coli.

Surgical Prophylaxis: The preoperative administration of a single 1 gm dose of Ceftriaxone may reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated.

Vancomycin is used for potentially life-threatening infections which cannot be treated with other effective, less toxic antimicrobial drugs including the penicillins and cephalosporins. Vancomycin is useful in the therapy of severe staphylococcal infections in patients who cannot receive or who have failed to respond to the penicillins and cephalosporins or who have infections with staphylococci, resistant to other antibiotics. Vancomycin is used in the treatment of endocarditis and as prophylaxis against endocarditis in patients undergoing dental or surgical procedures.Its effectiveness has been documented in other infections due to staphylococci including osteomyelitis, pneumonia, septicemia and soft tissue infections.

Xl V is also used to associated treatment for these conditions: Arthritis gonococcal, Bacterial Endocarditis, Bacterial Infections, Bacterial Sepsis, Bacterial Sinusitis, Bone and Joint Infections, Brain abscess, Chancroid, Community Acquired Pneumonia (CAP), Conjunctivitis gonococcal neonatal, Epididymitis, Epiglottitis, Gonococcal infection of pharynx, Gonococcal pelvic inflammatory disease, Intra-Abdominal Infections, Lower respiratory tract infection bacterial, Lyme Neuroborreliosis, Meningitis, Bacterial, Ophthalmia neonatorum due to gonococcus, Postoperative Infections, Prosthetic Joint Infection, Salmonella Typhi Infection, Septic Arthritis, Shigellosis, Skin and Subcutaneous Tissue Bacterial Infections, Syphilis, Vulvovaginitis gonococcal, Whipple Disease, Bacterial otitis media, Complicated Bacterial Urinary Tract Infections, Susceptible Bacterial Infections, Uncomplicated Gonorrhea, Uncomplicated Urinary tract infection bacterialClostridium Difficile-Associated Diarrhea (CDAD), Enterocolitis caused by Staphylococcus aureus, Infection caused by staphylococci, Severe Staphylococcal infection

How Xl V works

Ceftriaxone works by inhibiting the mucopeptide synthesis in the bacterial cell wall. The beta-lactam moiety of ceftriaxone binds to carboxypeptidases, endopeptidases, and transpeptidases in the bacterial cytoplasmic membrane. These enzymes are involved in cell-wall synthesis and cell division. Binding of ceftriaxone to these enzymes causes the enzyme to lose activity; therefore, the bacteria produce defective cell walls, causing cell death.

The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix, which forms the major structural component of Gram-positive cell walls. Vancomycin forms hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, preventing the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.

Dosage

Xl V dosage

Generally, Ceftriaxone should be taken once or equally devided twice a day for 4-14 days. Ceftriaxone therapy should be continued for at least 2 days after the sign and symptoms of infection have disappeared.

The usual duration of therapy is 4 to 14 days; in complicated infections longer therapy may be required. No dosage adjustment is required for patients with renal or hepatic impairment.

Concentrations of no more than 5 mg/ml and rates of no more than 10 mg/min are recommended in adults. In selected patients in need of fluid restriction, a concentration up to 10 mg/ml may be used.Patients with Normal Renal Function:

• Adults: Usual daily dose is 2 gm (in 4 or 2 divided doses).
• Children: Total daily dose is 40 mg/Kg (in 4 divided doses).
• Infants and Neonates: An initial dose of 15 mg/Kg is suggested followed by 10 mg/Kg every 12 hours in the first week, then every 8 hours up to 1 month.

Patients with Impaired Renal Function and Elderly Patients: Dosage adjustment must be made in patients with impaired renal function. In premature infants and the elderly, dosage reduction may be necessary to a greater extent than expected because of decreasing renal function. If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be calculated using the following chart-

• CrCl 100 ml/min: Vancomycin Dose 1545 mg/24 h
• CrCl 90 ml/min:Vancomycin Dose 1390 mg/24 h
• CrCl 80 ml/min:Vancomycin Dose1235 mg/24 h
• CrCl 70 ml/min:Vancomycin Dose1080 mg/24 h
• CrCl 60 ml/min:Vancomycin Dose925 mg/24 h
• CrCl 50 ml/min:Vancomycin Dose770 mg/24 h
• CrCl 40 ml/min:Vancomycin Dose620 mg/24 h
• CrCl 30 ml/min:Vancomycin Dose465 mg/24 h
• CrCl 20 ml/min:Vancomycin Dose310 mg/24 h
• CrCl 10 ml/min:Vancomycin Dose 155 mg/24 h

The initial dose should be not less than 15 mg/kg even in patients with mild to moderate renal insufficiency. Above chart is not valid for functionally anephric patients. For such patients, an initial dose of 15 mg/kg of body weight should be given in order to achieve prompt therapeutic serum concentrations. The dose required to maintain stable concentrations is 1.9 mg/kg/24 h. Since individual maintenance doses of 250-1,000 mg are convenient, 1 dose may be given every several days rather than on a daily basis in patients with marked renal impairment. In anuria, a dose of 1000 mg every 7-10 days has been recommended. Intermittent infusion is the recommended method of administration. Intraperitoneal administration is not recommended.

Use the solution immediately after reconstitution of powder.

Side Effects

Generally Ceftriaxone is well tolerated. However, few side effects including nausea, vomiting, diarrhea, dizziness and fever may occur.

Vancomycin is well tolerated. However during or soon after rapid infusion of Vancomycin, patients may develop anaphylactic reactions including hypotension, wheezing, dyspnoea, urticaria or pruritus. Rapid infusion may also cause flushing of the upper body ("red neck") or pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours. Such events are infrequent if Vancomycin is given by a slow infusion over 60 minutes.

Toxicity

Ceftriaxone overdose may increase the risk of urolithiasis and subsequent post-renal acute renal failure (PARF). Other symptoms of overdose unavailable in the literature. However, they are likely similar to the adverse effects of the medication. If overdose of ceftriaxone occurs, treat with symptomatic and supportive treatment, as ceftriaxone levels will not be reduced by dialysis.

The oral LD₅₀ in mice is 5000 mg/kg. The median lethal intravenous dose is 319 mg/kg in rats and 400 mg/kg in mice.

Conversely, the most common adverse effects associated with vancomycin appear to be nausea, abdominal pain, and hypokalemia . In particular, incidences of hypokalemia, urinary tracy infection, peripheral edema, insomnia, constipation, anemia, depression, vomiting, and hypotension are higher among subjects >65 years of than in those that are 65 years old or younger .

Additionally, nephrotoxicity involving reports of renal failure, renal impairment, elevated blood creatinine, and others has also occurred with vancomycin therapy during studies, and can occur during or after completion of a course of therapy . Risk of such nephrotoxicity is increased in patients greater than 65 years of age .

Ototoxicity has also occurred in patients receiving vancomycin treatment, and it can be transient or permanent. This effect has been reported primarily in patients who have been given excessive intravenous doses, who have kidney dysfunction, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent like an aminoglycoside . Potentially related adverse effects like vertigo, dizziness, and tinnitus have also been reported .

Neutropenia, often beginning one week or more after onset of intravenous vancomycin therapy or after a total dose of more than 25 mg has been observed for several dozen patients as well. This neutropenia however, appears to be promptly reversible when the vancomycin treatment is discontinued. Alternatively, thrombocytopenia has also been reported .

Additionally, a condition has been reported that is described as being similar to IV-induced symptoms involving symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (in what is known as the so-called 'Red Man Syndrome'), pain and muscle spasm of the chest and back. Although on average such reactions usually resolve within 20 minutes, they are just as likely to persist for hours .

In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were assessed when the drug was given intravenously to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. The results obtained demonstrated that vancomycin was found in cord blood but that no sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. Ultimately however, because the number of subjects treated in this study was limited and vancomycin was administered only in the second and third trimesters, it is not formally known whether vancomycin causes fetal harm. Subsequently, vancomycin should be given to a pregnant woman only if clearly needed .

Although it is known that vancomycin is excreted in human milk based on information obtained from the intravenous administration of the medication, it is not known if vancomycin is excreted into human milk after oral administration. However, because of the overall potential for adverse events, caution must be exercised when vancomycin is given to a nursing woman and a decision must be made whether to discontinue nursing or discontinue the drug, taking into consideration the importance of the drug to the mother .

The safety and effectiveness in pediatric patients have not been formally established .

Patients older than 65 years of age may take longer to respond to therapy compared to patients aged 65 year or younger. Vancomycin treatment in patients aged older than 65 years subsequently should not be discontinued or switched to an alternative treatment prematurely .

Furthermore, clinical studies have demonstrated that geriatric patients are at increased risk of developing nephrotoxicity following treatment with oral vancomycin, which can occur during or after completion of therapy. In patients aged older than 65 years, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin to detect any potential vancomycin induced nephrotoxicity .

Precaution

Ceftriaxone should be administered with caution to individuals with a history of gastrointestinal disease, particularly colitis.

Patients with borderline renal function and individuals over the age of 60 should be given serial tests of auditory function and of Vancomycin blood levels. All patients receiving the drug should have periodic haematological studies, urine analysis and renal function tests. Vancomycin is very irritating to tissue and causes injection site necrosis when injected intramuscularly. It must be infused intravenously. Injection site pain and thrombophlebitis occur in many patients receiving Vancomycin and are occasionally severe.Prolonged use of Vancomycin may result in the overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. In rare instances, there have been reports of pseudomembranous colitis due to C. difficile, developing in patients who received intravenous Vancomycin.

Interaction

May increase nephrotoxicity of aminoglycosides. May diminish therapeutic effect of BCG, typhoid vaccine, Na picosulfate. May increase anticoagulant effect of vit K antagonists (e.g. warfarin). May increase serum level with probenecid.

Volume of Distribution

The apparent volume of distribution of an intravenous or intramuscular dose in healthy patients is 5.78 to 13.5 L. The volume of distribution of an intravenous or intramuscular dose in septic patients is 6.48 to 35.2 L. Ceftriaxone has good enough CSF penetration to be used as an effective treatment of bacterial meningitis.

The volume of distribution, as discussed in the literature, varies between 0.4-1 L/kg .

Elimination Route

Ceftriaxone is only given as an injection, either intramuscularly or intravenously. Ceftriaxone is less than 1% bioavailable if given orally.

Poorly absorbed from gastrointestinal tract, however systemic absorption (up to 60%) may occur following intraperitoneal administration .

Half Life

The elimination half-life of ceftriaxone is 5.8-8.7 hours. The half-life of ceftriaxone in the middle ear fluid has been estimated to be 25 hours.

Half-life in normal renal patients is approximately 6 hours (range 4 to 11 hours). In anephric patients, the average half-life of elimination is 7.5 days .

Clearance

The plasma clearance of ceftriaxone in healthy adults receiving a 0.15-3g dose is 0.58 to 1.45 L/hour. The renal clearance of ceftriaxone is 0.32 to 0.73 L/hour. In intensive care unit patients, ceftriaxone's total drug clearance was 0.96L/h (0.55-1.28 L/h), and unbound drug clearance was 1.91 L/h (1.46-6.20 L/h).

The mean plasma clearance of vancomycin is about 0.058 L/kg/h .

Elimination Route

Ceftriaxone is primarily eliminated in the urine (33-67%). The remainder is eliminated through secretion in the bile and removed from the body via the feces.

In the first 24 hours, about 75-80% of an administered dose of vancomycin is excreted in urine by glomerular filtration .

Pregnancy & Breastfeeding use

Pregnancy: The safety of Ceftriaxone in the treatment of infections during pregnancy has not been established. Ceftriaxone should only be used during pregnancy if the likely benefit outweighs the potential risk to the fetus and/or the mother.

Lactation: Ceftriaxone is excreted in breast milk at low concentrations. Therefore, caution should be exercised when Ceftriaxone is administered to a nursing mother.

It is not known whether it causes foetal harm or not. Vancomycin should be given in pregnancy only if clearly needed and blood levels should be monitored carefully to minimise the risk of foetal toxicity.Vancomycin Hydrochloride is excreted in human milk. Caution should be exercised when Vancomycin is administered to a nursing woman. It is unlikely that a nursing infant can absorb a significant amount of Vancomycin from its gastro-intestinal tract

Contraindication

Ceftriaxone should not be given to patients with a history of hypersensitivity to cephalosporin antibiotics. It is contraindicated in premature infants during the first 6 weeks of life. Its safety in human pregnancy has not been established. Ceftriaxone is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium.

Vancomycin is contraindicated in Patients with known hypersensitivity to Vancomycin

Acute Overdose

There is no specific antidote. Treatment of over dosage should be symptomatic.

Supportive care is advised with maintenance of glomerular filtration. Vancomycin is poorly removed from the blood by haemodialysis or peritoneal dialysis. Haemoperfusion with Amberlite resin XAD-4 has been reported to be of limited benefit

Storage Condition

Store below 25°C, protected from light & moisture. Use reconstituted solutions immediately.

Reconstituted solutions are stable for 6 hours at room temperature and for 24 hours at 2°-8°C. It should not be mixed in the same syringe with any drug other than 1% Lidocaine Hydrochloride injection BP (for IM injection only).

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