Cefneda Tm

Uses

Sidobac Injection is used for the treatment of patients with infections caused by susceptible strains of the designated organisms in the following diseases:

Lower Respiratory Tract Infections, including pneumonia, caused by Pseudomonas aeruginosa and other Pseudomonas spp., Haemophilus influenzae, including ampicillin-resistant strains; Klebsiella spp.; Enterobacter spp.; Proteus mirabilis; Escherichia coli; Serratia spp.; Citrobacter spp.; Streptococcus pneumoniae; and Staphylococcus aureus (methicillin susceptible strains).

Skin and Skin Structure Infections caused by Pseudomonas aeruginosa; Klebsiella spp.; Escherichia coli; Proteus spp., including Proteus mirabilis and indole-positive Proteus, Enterobacter spp.; Serratia spp.; Staphylococcus aureus (methicillin susceptible strains); and Streptococcus pyogenes (group A beta-hemolytic streptococci).

Urinary Tract Infections, both complicated and uncomplicated, caused by Pseudomonas aeruginosa; Enterobacter spp.; Proteus spp., including Proteus mirabilis and indole-positive Proteus, Klebsiella spp.; and Escherichia coli.

Bacterial Septicemia caused by Pseudomonas aeruginosa, Klebsiella spp., Haemophilus influenzae, Escherichia coli, Serratia spp., Streptococcus pneumoniae, and Staphylococcus aureus (methicillin susceptible strains).

Bone and Joint Infections caused by Pseudomonas aeruginosa, Klebsiella spp., Enterobacter spp., and Staphylococcus aureus (methicillin susceptible strains).

Gynecologic Infections, including endometritis, pelvic cellulitis, and other infections of the female genital tract caused by Escherichia coli.

Intra abdominal Infections, including peritonitis caused by Escherichia coli, Klebsiella spp., and Staphylococcus aureus (methicillin susceptible strains) and polymicrobial infections caused by aerobic and anaerobic organisms and Bacteroides spp.

Central Nervous System Infections, including meningitis, caused by Haemophilus influenzae and Neisseria meningitidis, Pseudomonas aeruginosa and Streptococcus pneumoniae.

Tobramycin Respirator Solution is used for the management of cystic fibrosis patients with Pseudomonas aeruginosa. Also used for severe COPD patients colonized with Pseudomonas aeruginosa. Safety and efficacy have not been demonstrated in patients below the age of 6 years, patients with a forced expiratory volume <25% or >75% predicted, or patients colonized with Burkholderia cepacia.

For the treatment of external infections of the eye and its adnexa caused by susceptible bacteria. Appropriate monitoring of bacterial response to topical antibiotic therapy should accompany its use.

Cefneda Tm is also used to associated treatment for these conditions: Bacteremia, Bacterial Infections, Bloodstream Infections, Bone and Joint Infections, Bronchopulmonary Infection, Central Nervous System Infections, Complicated Intra-Abdominal Infections, Complicated Skin and Soft Tissue Infection, Complicated Urinary Tract Infection, Complicated Urinary Tract Infections caused by susceptible Gram-negative microorganisms, Fever caused by susceptible bacteria, Gynaecological infection, Intra-Abdominal Infections, Lower Respiratory Tract Infection (LRTI), Meningitis, Bacterial, Nosocomial Pneumonia, Peritoneal Dialysis-associated Peritonitis, Urinary Tract Infection, Ventilator-associated Bacterial Pneumonia caused by susceptible Gram-negative microorganisms, Chronic suppurative Otitis media, Hospital-acquired bacterial pneumonia caused by susceptible Gram-negative microorganisms, Malignant Otitis Externa, Skin and skin-structure infections, Susceptible Intra-Abdominal Infection caused by susceptible Gram-negative microorganismBacterial Peritonitis, Bone Infection, Cystic fibrosis, Pseudomonas aeruginosa infection, Eye Infections, Inflammation of the External Auditory Canal, Intra-Abdominal Infections, Lower respiratory tract infection bacterial, Meningitis, Bacterial, Ocular Inflammation, Septicemia gram-negative, Skin and Subcutaneous Tissue Bacterial Infections, Corticosteroid-responsive Disorder of the Ophthalmic, Ear infection-not otherwise specified caused by susceptible bacteria, Ocular bacterial infections, Recurrent Complicated Urinary Tract Infection, Steroid-responsive inflammation

How Cefneda Tm works

The bacterial cell wall, which is located at the periphery of Gram-positive bacteria and within the periplasm of Gram-negative bacteria, comprises a glycopeptide polymer synthesized through cross-linking of glycans to peptide stems on alternating saccharides, which is known commonly as peptidoglycan. Cell wall formation, recycling, and remodelling require numerous enzymes, including a family of enzymes with similar active site character despite distinct and sometimes overlapping roles as carboxypeptidases, endopeptidases, transpeptidases, and transglycosylases, known as "penicillin-binding proteins" (PBPs). The number of PBPs differs between bacteria, in which some are considered essential and others redundant. In general, inhibition of one or more essential PBPs results in impaired cell wall homeostasis, loss of cell integrity, and is ultimately bactericidal.

Ceftazidime is a semisynthetic third-generation cephalosporin with broad activity against numerous Gram-negative and some Gram-positive bacteria. Like other β-lactam antibiotics, ceftazidime exhibits its bactericidal effect primarily through direct inhibition of specific PBPs in susceptible bacteria. In vitro experiments in Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae suggest that ceftazidime primarily binds to PBP3, with weaker binding to PBP1a/1b and PBP2 as well; although binding to other PBPs, such as PBP4, is detectable, the concentrations required are much greater than those achieved clinically. Similarly, ceftazidime showed binding to Staphylococcus aureus PBP 1, 2, and 3 with a much lower affinity for PBP4. Recent data for Mycobacterium abcessus suggest that ceftazidime can inhibit PonA1, PonA2, and PbpA at intermediate concentrations.

Tobramycin is a 4,6-disubstituted 2-deoxystreptamine (DOS) ring-containing aminoglycoside antibiotic with activity against various Gram-negative and some Gram-positive bacteria. The mechanism of action of tobramycin has not been unambiguously elucidated, and some insights into its mechanism rely on results using similar aminoglycosides. In general, like other aminoglycosides, tobramycin is bactericidal and exhibits both immediate and delayed killing, which are attributed to different mechanisms, as outlined below.

Aminoglycosides are polycationic at physiological pH, such that they readily bind to bacterial membranes ("ionic binding"); this includes binding to lipopolysaccharide and phospholipids within the outer membrane of Gram-negative bacteria and to teichoic acid and phospholipids within the cell membrane of Gram-positive bacteria. This binding displaces divalent cations and increases membrane permeability, which allows aminoglycoside entry. Additional aminoglycoside entry ("energy-dependent phase I") into the cytoplasm requires the proton-motive force, allowing access of the aminoglycoside to its primary intracellular target of the bacterial 30S ribosome. Mistranslated proteins produced as a result of aminoglycoside binding to the ribosome (see below) integrate into and disrupt the cell membrane, which allows more of the aminoglycoside into the cell ("energy-dependent phase II"). Hence, tobramycin and other aminoglycosides have both immediate bactericidal effects through membrane disruption and delayed bactericidal effects through impaired protein synthesis; observed experimental data and mathematical modelling support this two-mechanism model.

Inhibition of protein synthesis was the first recognized effect of aminoglycoside antibiotics. Structural and cell biological studies suggest that aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal subunit, altering interactions between h44 and h45. This binding also displaces two important residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur with successful codon-anticodon pairing in the A site. Overall, aminoglycoside binding has several negative effects, including inhibiting translation initiation and elongation and ribosome recycling. Recent evidence suggests that the latter effect is due to a cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit. Also, by stabilizing a conformation that mimics correct codon-anticodon pairing, aminoglycosides promote error-prone translation; mistranslated proteins can incorporate into the cell membrane, inducing the damage discussed above.

Although direct mutation of the 16S rRNA is a rare resistance mechanism, due to the gene being present in numerous copies, posttranscriptional 16S rRNA modification by 16S rRNA methyltransferases (16S-RMTases) at the N7 position of G1405 or the N1 position of A1408 are common resistance mechanisms in aminoglycoside-resistant bacteria. These mutants also further support the proposed mechanism of action of aminoglycosides. Direct modification of the aminoglycoside itself through acetylation, adenylation, and phosphorylation by aminoglycoside-modifying enzymes (AMEs) are also commonly encountered resistance mutations. Finally, due to the requirement for active transport of aminoglycosides across bacterial membranes, they are not active against obligately anaerobic bacteria.

Dosage

Cefneda Tm dosage

Dosage: The usual adult dosage is 1 gram administered intravenously or intramuscularly every 8 to 12 hours. The dosage and route should be determined by the susceptibility of the causative organisms, the severity of infection and the condition, and renal function of the patient.

Recommended Dosage Schedule

Uncomplicated urinary tract infections: 250 mg IV or IM Q 12h

Bone and joint infections: 2 grams IV Q 12h

Complicated urinary tract infections: 500 mg IV or IM Q 8-12h

Uncomplicated pneumonia; mild skin and skin structure infections: 500 mg -1 gram IV or IM Q 8h

Serious gynecologic and intra-abdominal infections: 2 grams IV Q 8h

Meningitis: 2 grams IV Q 8h

Very Severe life threatening infections, especially in immunocompromised patients: 2 grams IV Q 8h

Lung infections caused by Pseudomonas spp. In patients with cystic fibrosis with normal renal function: 30-50 mg/kg IV to a maximum of 6 grams per day Q 8h

Neonates (0 - 2 months): 25-60 mg/kg/day IV Q 12h

Infants & Children (2 months - 12 years): 30-100 mg/kg/day IV to a maximum of 6 grams per day Q 8-12h.

Impaired Hepatic Function: No adjustment in dosage is required for patients with hepatic dysfunction.

Impaired Renal Function: In patients with impaired renal function (glomerular filtration rate [GFR]<50 mL/min) it is recommended that the dosage of Ceftazidime be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1 gram of Ceftazidime may be given.

Recommended Maintenance Dosages of Ceftazidime in renal insufficiency:

Creatinine clearance 50-31 mL/min: 1 gram Q12h

Creatinine clearance 30-16 mL/min: 1 gram Q24h

Creatinine clearance 15-6 mL/min: 500 mg Q24h

Creatinine clearance <5 mL/min: 500 mg Q48h

Administration: Sidobac may be given intravenously or by deep IM injection into a large muscle mass such as the upper outer quadrant of the gluteus maximus or lateral proof of the thigh. Intra-arterial administration should be avoided. For IV/IM administration, Sidobac should be constituted with the supplied Sterile Water for Injection.

Tobramycin (Respirator Solution) The recommended dosage for, both adult and paediatric patients, 6 years of age and older, is one single-use ampoule (300 mg) administered b.i.d for 28 days. Dosage is not adjusted by weight.

The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.

If you are taking several medications, the recommended order is as follows: bronchodilator first, followed by chest physiotherapy, then other inhaled medications and finally Tobramycin.

You should take Tobramycin in repeated cycles of 28 days on drug, followed by 28 days off drug. You should take Tobramycin twice a day during the 28 day period on drug.

Tobramycin Eye Drops: In mild to moderate disease, 1 drop into the affected eye(s) every 4 hours. In severe infections, 1 drop into the affected eye(s) hourly until improvement, following which dosage should be reduced prior to discontinuation.

Tobramycin Eye Ointment: In mild to moderate disease it should be applied thinly and evenly into the conjunctival sac of the affected eyes 2 to 3 times per day. For severe cases it should be applied thinly and evenly into the conjunctival sac of the affected eyes 3 to 4 times per day. Following improvement, treatment should be reduced prior to discontinuation.

Single-dose vial Administration Amount of WFI to be added:

• 250 mg IM in 1.5 ml
• 250 mg IV in 5 ml
• 500 mg IM in 1.5 ml
• 500 mg IV in 5 ml
• 1 gm IM in 3 ml
• 1 gm IV in 10 ml

Step 1: Add recommended volume of solvent slowly. Remove the syringe needle.

Step 2: Gently shake the vial to dissolve the powder. Carbon dioxide is released & a clear solution will be obtained.

Step 3: Now insert the needle in the free space of the reconstituted vial & withdraw the pressurized air from the free space.

Step 4: Finally withdraw the solution from the vial by syringe

Side Effects

The most common side-effects are local reactions following IV injection and allergic and gastrointestinal reactions. Hypersensitivity reactions are pruritus, rash, and fever. Angioedema and anaphylaxis have been reported very rarely. Gastrointestinal symptoms are diarrhea, nausea, vomiting, and abdominal pain. Central nervous system reactions included headache, dizziness, and paresthesia.

Inhaled Tobramycin is generally well-tolerated. Voice alterations and tinnitus are more common in the on-drug periods. However all the episodes are transient and resolved without discontinuation of the regimen. Others like dizziness and increase in serum creatinine were similar to those occurring with placebo.

The most frequent adverse reactions to Tobramycin are localized ocular toxicity and hypersensitivity, including lid itching and swelling and conjunctival erythema. These reactions occur in less than 3% of patients treated.

Toxicity

Ceftazidime overdosage has occurred in patients with renal failure. Reactions included seizure activity, encephalopathy, asterixis, neuromuscular excitability, and coma. Patients who receive an acute overdosage should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis or peritoneal dialysis may aid in the removal of ceftazidime from the body.

Toxicity information regarding tobramycin is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nephrotoxicity, ototoxicity, neuromuscular blockade, and respiratory failure/paralysis. Symptomatic and supportive measures are recommended; hemodialysis may help clear excess tobramycin. Accidental ingestion of tobramycin is unlikely to result in an overdose, as aminoglycosides are poorly absorbed in the gastrointestinal tract.

Poor gastrointestinal absorption is reflected in animal studies. When administered by the intraperitoneal or subcutaneous route, the LD50 for mice and rats ranges from 367-1030 mg/kg while the oral LD50 values are more than 7500 mg/kg.

Precaution

The total daily dosage should be reduced when Ceftazidime is administered to patients with renal insufficiency. Ceftazidine should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

As with other anti-infective, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If super-infection occurs, discontinue use and institute alternative therapy. Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis.

Warning: Do not touch the dropper or tube opening to any surface, including eyes or hands. The dropper or tube opening is sterile. If it becomes contaminated, it could cause an infection in the eye. Use caution when driving, operating machinery, or performing other hazardous activities. Tobramycin ophthalmic may cause blurred vision. If blurred vision is experienced, avoid these activities. Caution should be taken to wear the contact lenses. After applying the medication, wait at least 15 minutes before inserting contact lenses, unless otherwise directed by doctor. Do not use other eye drops or medications during treatment with tobramycin ophthalmic unless otherwise directed by doctor

Interaction

Increased nephrotoxicity has been reported following concomitant administration of Cephalosporins and aminoglycoside antibiotics.

Patients taking Tobramycin concomitantly with beta agonists, inhaled corticosteroids, other anti pseudomonal antibiotics or parenteral aminoglycosides demonstrated adverse experience profiles.

Specific drug interaction studies on Tobramycin ophthalmic preparation have not been established

Volume of Distribution

Ceftazidime has a volume of distribution of 15-20 L.

Inhalation tobramycin had an apparent volume of distribution in the central compartment of 85.1 L for a typical cystic fibrosis patient.

Elimination Route

Ceftazidime administered intravenously in healthy males produced mean C_max values of between 42 and 170 μg/mL for doses between 500 mg and 2 g, and are reached immediately following the end of the infusion period. The C_max for 1 g of ceftazidime administered intramuscularly is attained approximately one hour following injection and is between 37 and 43 mg/L. Following intramuscular administration of 500 mg and 1 g of ceftazidime, the serum concentration remained above 4 μg/mL for six and eight hours, respectively.

Ceftazidime C_max and AUC show linear proportionality to the dose over the therapeutic range. In individuals with normal renal function, ceftazidime given intravenously every eight hours for 10 days as either 1 or 2 g doses showed no accumulation.

Tobramycin administered by inhalation in cystic fibrosis patients showed greater variability in sputum as compared to serum. After a single 112 mg dose, the serum C_max was 1.02 ± 0.53 μg/mL, which was reached in one hour (T_max), while the sputum C_max was 1048 ± 1080 μg/g. Comparatively, for a 300 mg dose, the serum C_max was 1.04 ± 0.58 μg/mL, which was also reached within one hour, while the sputum C_max was 737 ± 1028 μg/g. The systemic exposure (AUC_0-12) was also similar between the two doses, at 4.6 ± 2.0 μg∙h/mL for the 112 mg dose and 4.8 ± 2.5 μg∙h/mL for the 300 mg dose. When tobramycin was administered over a four-week cycle at 112 mg twice daily, the C_max measured one hour after dosing ranged from 1.48 ± 0.69 μg/mL to 1.99 ± 0.59 μg/mL.

Half Life

Ceftazidime has an elimination half-life of 1.5-2.8 hours in healthy subjects. As ceftazidime is primarily renally excreted, its half-life is significantly prolonged in patients with renal impairment. In patients with creatinine clearance < 12 mL/min, the half-life is prolonged to between 14 and 30 hours.

Tobramycin has an apparent serum terminal half-life of ~3 hours following a single 112 mg inhaled dose in cystic fibrosis patients.

Clearance

The mean renal clearance of ceftazidime in healthy subjects ranges from 72 to 141 mL/min while the calculated plasma clearance is approximately 115 mL/min.

Inhaled tobramycin has an apparent serum clearance of 14.5 L/h in cystic fibrosis patients aged 6-58 years.

Elimination Route

Approximately 80% to 90% of an intramuscular or intravenous dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. When administered intravenously, 50% of the dose appears in the urine within two hours, with another 32% of the dose appearing by eight hours post-administration.

Tobramycin is primarily excreted unchanged in the urine.

Pregnancy & Breastfeeding use

Pregnancy: No adequate and well controlled studies in pregnant women have been conducted with Ceftazidime. Because animal reproduction studies are not always predictive of human response this drug should be used during pregnancy only if clearly needed.

Lactation: Ceftazidime is excreted in human milk in low concentrations. Because many drugs are excreted in human milk and because safety of the component of the injections in nursing infants has not been established, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pregnancy: This drug should be used during pregnancy only if clearly needed.

Lactation: Because of the potential for adverse reactions in nursing infants from Tobramycin, a decision should be made whether to discontinue nursing the infant or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Ceftazidime is contraindicated in patients with known hypersensitivity to cephalosporin antibiotics.

In patients with known hypersensitivity to any component of the product. Partial crossallergenicity to other aminoglycosides has been established.

Special Warning

Renal Impairment: Inhalation: Dosage adjustment needed.

Acute Overdose

Ceftazidime overdosage has occurred in patients with renal failure. Reactions have included seizure activity, encephalopathy, asterixis, neuromuscular excitability, and coma. Patients who receive an acute overdosage should be carefully observed and given supportive treatment.

Symptoms: Nephrotoxicity, auditory and vestibular toxicity (e.g. dizziness, tinnitus, vertigo, loss of high-tone hearing acuity), neuromuscular blockade or resp failure.

Management: Initiate resuscitative measures if resp paralysis occurs. Ca salts may be given to reverse neuromuscular blockade. Haemodialysis or peritoneal dialysis will help remove drug serum levels.

Storage Condition

Store below 25° C, protected from light and moisture. Reconstituted solutions are stable for up to 24 h if stored between 2°-8° C

Store under refrigeration at 2-8° C, and protected from light. Slight color change when unrefrigerated do not indicate any change in the quality of the product. The preparation must not be used if it is cloudy, particles appear in the solution or has been stored at room temperature for over 28 dyas. For use only under the prescription of a registered physician. Do not use beyond the expiration date stamped on the ampoule.

Eye Drops Store in a cool and dry place, away from light. Keep out of reach of children.

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