Ceftazidime

"Ceftazidime" belongs to the pharmacological class of Third-generation cephalosporin antibiotics.

"Ceftazidime" has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cystic fibrosis, Diabetic foot infection, Endophthalmitis, Intra-abdominal infection, Intracranial abscess and spinal epidural abscess, Melioidosis, Meningitis, Neutropenic fever, Osteomyelitis and/or discitis, Peritonitis, Pneumonia, Prosthetic joint infection, Septic arthritis, Skin and soft tissue infection, Urinary tract infection.

Ceftazidime has linear proportionality between Cmax and AUC over its therapeutic range, and its intravenous administration produces Cmax values of 42-170 μg/mL for doses ranging from 500 mg to 2 g. Cmax for 1 g of intramuscular ceftazidime is attained about an hour post-injection, with a concentration range of 37-43 mg/L. Serum concentration remains above 4 μg/mL for six and eight hours after intramuscular administration of 500 mg and 1 g, respectively. Ceftazidime is said to have a volume of distribution of 15-20 L, with protein binding ranging from 5-22.8%. The drug is excreted mostly unchanged through the kidneys, with 80-90% of the dose excreted within 24 hours after administration, and it is not appreciably metabolized. In individuals with normal renal function, there is no accumulation of the drug after ten days of intravenous administration every eight hours.

The common side effects of "Ceftazidime" are nausea, vomiting, gas, weakness, tiredness, itching, diarrhea, headache, upset stomach, etc.

"Ceftazidime" is available in the form of Intravenous injection, Intravenous Solution, Intramuscular Injection, Inhalation Solution.

"Ceftazidime" is approved in Germany, Japan, Malaysia, India, China, Canada, the U.S., U.K.

"Ceftazidime" belongs to the pharmacological class of Third-generation cephalosporin antibiotics.

Ceftazidime is a broad-spectrum, third-generation cephalosporin that exhibits its bactericidal effect primarily through direct inhibition of a specific PBPs in susceptible bacteria. In vitro experiments suggest that ceftazidime primarily binds to PBP3 in Gram-negative bacteria like Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. It also binds to PBP1a/1b and PBP2 with weaker affinity, while binding to other PBPs like PBP4 is detectable but at much higher concentrations. Ceftazidime also showed binding to Staphylococcus aureus PBP 1, 2, and 3, with lower affinity for PBP4. Recent data for Mycobacterium abscessus suggest that ceftazidime can inhibit PonA1, PonA2, and PbpA at some intermediate concentrations.

"Ceftazidime" has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cystic fibrosis, Diabetic foot infection, Endophthalmitis, Intra-abdominal infection, Intracranial abscess and spinal epidural abscess, Melioidosis, Meningitis, Neutropenic fever, Osteomyelitis and/or discitis, Peritonitis, Pneumonia, Prosthetic joint infection, Septic arthritis, Skin and soft tissue infection, Urinary tract infection.

"Ceftazidime" is found to be available in the form of Intravenous injection, Intravenous Solution, Intramuscular Injection, Inhalation Solution.

"Ceftazidime" can be used in the following treatment:

• Bloodstream infection
• Cystic fibrosis
• Diabetic foot infection
• Endophthalmitis
• Intra-abdominal infection
• Intracranial abscess and spinal epidural abscess
• Melioidosis
• Meningitis
• Neutropenic fever
• Osteomyelitis and/or discitis
• Peritonitis
• Pneumonia
• Prosthetic joint infection
• Septic arthritis
• Skin and soft tissue infection
• Urinary tract infection

"Ceftazidime” can help to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cystic fibrosis, Diabetic foot infection, Endophthalmitis, Intra-abdominal infection, Intracranial abscess and spinal epidural abscess, Melioidosis, Meningitis, Neutropenic fever, Osteomyelitis and/or discitis, Peritonitis, Pneumonia, Prosthetic joint infection, Septic arthritis, Skin and soft tissue infection, Urinary tract infection.

"Ceftazidime” is approved for use in the following clinical indications:

● Bloodstream infection

● Cystic fibrosis

● Diabetic foot infection

● Endophthalmitis

● Intra-abdominal infection

● Intracranial abscess and spinal epidural abscess

● Melioidosis

● Meningitis

● Neutropenic fever

● Osteomyelitis and/or discitis

● Peritonitis

● Pneumonia

● Prosthetic joint infection

● Septic arthritis

● Skin and soft tissue infection

● Urinary tract infection

• Bloodstream infection (gram-negative bacteremia):

IV: 2 g every 8 hours.

Duration of therapy: Usual duration is about 7 to 14 days depending on source, pathogen, extent of infection, and clinical response.

• Antibiotic lock technique (catheter-salvage strategy):

Intracatheter: Prepare lock solution to final concentration of ceftazidime 5 to 10 mg/mL; may be combined with heparin. Instill into each lumen of the catheter access port using a volume sufficient to fill the catheter (2 to 5 mL) with a dwell time of up to 72 hours, depending on frequency of catheter use.

Antibiotic lock therapy is given for the same duration as systemic antibiotics.

• Cystic fibrosis, acute pulmonary exacerbation:

Traditional intermittent infusion method: IV: Usual dose: 2 g every 6 to 8 hours or 150 to 200 mg/kg/day divided every 6 to 8 hours; doses up to 200 to 400 mg/kg/day divided every 6 to 8 hours (maximum: 12 g daily) have also been recommended.

Extended infusion method: IV: 2 g every 8 hours over 3 to 4 hours.

Continuous infusion method: IV: Usual dose: 6 g over 24 hours.

Duration of therapy: Duration is usually 10 to 14 days depending on clinical response.

The dosage for ceftazidime inhalation solution for cystic fibrosis patients with chronic Pseudomonas aeruginosa infection typically ranges from 300 mg to 600 mg administered 3 times a day via nebulization. However, the exact dosage may vary depending on the patient's age, weight, and overall health condition

• Diabetic foot infection, moderate to severe:

IV: 1 to 2 g every 8 hours.

Duration (which may include oral step-down therapy) is usually 2 to 4 weeks in the absence of osteomyelitis.

• Endophthalmitis, bacterial (empiric therapy):

Intravitreal: 2 to 2.25 mg/0.1 mL NS or sterile water in combination with vancomycin.

A repeat dose(s) may be considered at 24 to 48 hours based on culture result, severity of infection, and response to treatment.

Intra-abdominal infection, health care-associated or high-risk community-acquired infection:

• Cholecystitis, acute: IV: 2 g every 8 hours; continue for 1 day after gallbladder removal or until clinical resolution in patients managed nonoperatively.

• Other intra-abdominal infections (eg, cholangitis, appendicitis, diverticulitis, intra-abdominal abscess): IV: 2 g every 8 hours in combination with metronidazole and, when appropriate, other agents.

• The total duration of therapy (which may include transition to oral antibiotics) is 4 to 5 days following adequate source control; for diverticulitis or uncomplicated appendicitis managed without intervention, duration is 10 to 14 days.

• Intracranial abscess (brain abscess, intracranial epidural abscess) and spinal epidural abscess: IV 2 g every 8 hours as part of an appropriate combination regimen. The duration generally ranges from 4 to 8 weeks for brain abscess and spinal epidural abscess and 6 to 8 weeks for intracranial epidural abscess.

• Melioidosis (Burkholderia pseudomallei infection) (off-label use): Initial intensive therapy: IV 2 g every 6 to 8 hours or 2 g as a single dose followed by 6 g daily by continuous infusion. The duration is 10 to 14 days, although a longer duration may be necessary depending on disease severity and site of infection.

• Meningitis, bacterial: IV 2 g every 8 hours as part of an appropriate combination regimen.

• Neutropenic fever, high-risk cancer patients (empiric therapy): IV 2 g every 8 hours as part of an appropriate combination regimen. Continue until afebrile for ≥48 hours and resolution of neutropenia or standard duration for the specific infection identified if longer than the duration for neutropenia.

• Osteomyelitis and/or discitis: IV 2 g every 8 hours, generally for ≥6 weeks; for empiric therapy, use as part of an appropriate combination regimen.

• Peritonitis, treatment (peritoneal dialysis patients) (off-label use): Intraperitoneal administration is preferred to IV administration. The dose varies based on the method of administration.

• Pneumonia:

Community-acquired pneumonia: IV 2 g every 8 hours as part of an appropriate combination regimen. Total duration (which may include oral step-down therapy) is for a minimum of 5 days; a longer course may be required for patients with an immunocompromising condition, severe or complicated infection, or for P. aeruginosa infection.

Hospital-acquired or ventilator-associated pneumonia: IV 2 g every 8 hours as part of an appropriate combination regimen. Duration varies based on disease severity and response to therapy; treatment is typically given for 7 days.

• Prosthetic joint infection (alternative agent): IV 2 g every 8 hours. The duration varies but is generally 4 to 6 weeks for patients who undergo resection arthroplasty.

• Septic arthritis: IV 2 g every 8 hours. For empiric therapy, use in combination with other appropriate agents. Total treatment duration is 3 to 4 weeks (in the absence of osteomyelitis), including oral step-down therapy.

• Skin and soft tissue infection, moderate to severe: IV 2 g every 8 hours as part of an appropriate combination regimen. The duration of therapy is generally 7 to 14 days.

Injectable solutions: 1g/50mL, 2g/50mL

Powder for injections :250mg, 500mg, 1g, 2g, 10g, 100g

Intravenous injection: Ceftazidime is available as a sterile powder that is reconstituted with sterile water for injection or other appropriate diluents for intravenous administration.

Intravenous infusion: Ceftazidime can also be given as an intravenous infusion after reconstitution of the sterile powder in a suitable diluent.

Intramuscular injection: Ceftazidime is available in some countries as a sterile powder that can be reconstituted with a diluent for intramuscular injection.

Inhalation solution: Ceftazidime is available as an inhalation solution for the treatment of respiratory tract infections in patients with cystic fibrosis.

• Dosage Adjustments in Kidney Patients:

Dosage adjustments for ceftazidime in patients with kidney impairment should be made based on the patient's renal function. The dosage should be adjusted downward in patients with creatinine clearance (CrCl) less than or equal to 50 mL/min. The recommended dosage adjustments for ceftazidime in pediatric and adult patients with renal impairment are as follows:

For Adults:

CrCl greater than 50 mL/min: No dosage adjustment necessary

CrCl 30 to 50 mL/min: 1 to 2 g every 12 hours

CrCl 10 to 29 mL/min: 0.5 to 1 g every 12 hours

CrCl less than 10 mL/min: 0.5 to 1 g every 24 hours

For Pediatric Patients:

CrCl greater than 70 mL/min/1.73m2: No dosage adjustment necessary

CrCl 30 to 70 mL/min/1.73m2: 30 mg/kg every 12 hours

CrCl 16 to 29 mL/min/1.73m2: 15 mg/kg every 12 hours

CrCl less than 15 mL/min/1.73m2: 15 mg/kg every 24 hours.

• Dosage Adjustments in Pediatric Patients:

The dosage of ceftazidime in pediatric patients is based on the weight of the patient and the severity of the infection. The recommended dosage range for ceftazidime in pediatric patients is 30 mg/kg to 50 mg/kg every 8 hours.

For neonates up to 2 weeks of age or premature infants, the recommended dosage is 20 mg/kg every 12 hours.

For patients with renal impairment, dosage adjustments may be necessary depending on the degree of renal dysfunction. In patients with a creatinine clearance of less than 50 mL/min, the dosage should be reduced to 50% of the usual dose. In patients on hemodialysis, a supplementary dose of 1 g of ceftazidime should be administered at the end of each dialysis session.

There are no specific dietary restrictions associated with the use of ceftazidime. However, it is important to follow any instructions provided by your healthcare provider regarding the use of this medication, including dosing instructions and any food or drink interactions to avoid. In general, it is recommended to take ceftazidime on an empty stomach, at least an 1 hour before or 2 hours after a meal, unless otherwise instructed by your healthcare provider. Additionally, it is important to stay well-hydrated while taking this medication, so be sure to drink plenty of fluids unless instructed otherwise by your healthcare provider.

"Ceftazidime” may be contraindicated under the following conditions:

• Hypersensitivity: Ceftazidime should not be administered to patients who have a history of hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other beta-lactam antibiotics.
• Hemolytic Anemia: Patients who have a history of hemolytic anemia associated with cephalosporin use should not receive ceftazidime.
• Renal Impairment: Ceftazidime is primarily excreted by the kidneys, so patients with severe renal impairment should not receive the drug. Dosage adjustment is necessary for the patients with mild to moderate renal impairment.
• Neonates: Ceftazidime for Injection, USP should not be given to neonates (0-28 days) with hyperbilirubinemia or jaundice, as it may worsen these conditions.
• Premature Infants: Ceftazidime for Injection, USP should not be given to premature infants (less than 32 weeks gestational age) or neonates (less than 7 days old) because of the potential risk of renal dysfunction.
• Colitis: Ceftazidime should not be used in patients with a history of colitis, as it may worsen the condition.
• Severe allergic reaction: Ceftazidime should not be given to patients who have had a severe allergic reaction to the drug in the past.

The physician should closely monitor the patients as well as keep pharmacovigilance as follows:

Hypersensitivity

Before beginning treatment with Ceftazidime for Injection, USP, it is important to thoroughly investigate whether the patient has had any previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. Administration of this medication should be approached with caution in patients with a history of allergies, particularly to drugs. If a patient is allergic to penicillin, care should be taken when administering Ceftazidime for Injection, USP, as cross-hypersensitivity among β-lactam antibiotics has been documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Ceftazidime for Injection occurs, treatment with the drug should be discontinued immediately. Severe acute hypersensitivity reactions may require emergency measures such as epinephrine.

Clostridium difficile-associated disease:

The use of many antibacterial agents, including Ceftazidime for Injection, USP, has been associated with the development of Clostridium difficile-associated disease (CDAD). Patients who present with diarrhea, symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent should be evaluated for CDAD. CDAD may range in severity from mild diarrhea to fatal colitis and can occur up to 2 months after the administration of antibacterial agents. Treatment for CDAD may include discontinuation of antibacterial agents not directed against Clostridium difficile, fluids and electrolytes, protein supplementation, and management with an antibacterial agent clinically effective against Clostridium difficile. In severe cases, surgical intervention may be required.

Hemolytic Anemia:

Patients with a history of cephalosporin-associated hemolytic anemia should not use Ceftazidime for Injection, USP, as the recurrence of hemolysis may be much more severe. An immune-mediated hemolytic anemia has been observed in patients receiving cephalosporin-class antibacterials, including Ceftazidime for Injection, USP. Severe cases of hemolytic anemia, including fatalities, have been reported in both adults and children. If a patient develops anemia anytime during or within 2-3 weeks subsequent to the administration of Ceftazidime for Injection, USP, the diagnosis of a cephalosporin-associated anemia should be considered, and the drug should be discontinued until the etiology is determined. Periodic monitoring for signs and symptoms of hemolytic anemia, including measurement of hematological parameters or drug-induced antibody testing, may be beneficial for patients.

Ceftazidime has been found to be excreted in low concentrations (3.8 - 5.2 mg/mL) in human milk. Therefore, caution should be taken while administering Ceftazidime for Injection, USP to nursing women.

Pregnancy Category B

The safety of using Ceftazidime for Injection, USP in the treatment of infections during pregnancy is not yet known. It is advised that the potential benefits and possible risks to the fetus should be carefully evaluated before administering ceftazidime to pregnant patients.

There are no specific food warnings for Ceftazidime. However, the medication should be taken on an empty stomach or at least 1 hour before or 2 hours after a meal. This is because food can decrease the absorption of ceftazidime, which may reduce its effectiveness.

The adverse reactions related to "Ceftazidime" can be categorized as follows:

Common

• Nausea
• Diarrhea
• Rash
• Injection site pain or irritation
• Headache
• Fever

Less common

• Vomiting
• Abdominal pain
• Swelling or redness at the injection site
• Yeast infections (in women)
• Dizziness
• Altered taste sensation
• Elevated liver enzymes
• Blood abnormalities such as anemia or leukopenia

Rare

• Severe allergic reactions, including anaphylaxis (a life-threatening reaction that can cause difficulty breathing, swelling of the face and throat, and shock)
• Clostridioides difficile-associated diarrhea (a serious and sometimes life-threatening intestinal infection)
• Stevens-Johnson syndrome (a rare but serious skin condition that can cause blisters and peeling skin)
• Hepatitis (inflammation of the liver)
• Kidney dysfunction or failure

The clinically relevant drug interactions of "Ceftazidime" is briefly summarized here:

Aminoglycosides: Ceftazidime may interact with aminoglycosides (such as gentamicin), which can increase the risk of kidney damage.

Diuretics: Ceftazidime may interact with diuretics (such as furosemide), which can increase the risk of kidney damage.

Probenecid: Probenecid may increase the levels of ceftazidime in the blood, which can increase the risk of side effects.

Anticoagulants: Ceftazidime may interact with anticoagulant medications (such as warfarin), which can increase the risk of bleeding.

Other antibiotics: Ceftazidime may interact with other antibiotics (such as tetracyclines or erythromycin), which can reduce the effectiveness of either medication.

Oral contraceptives: Ceftazidime may interact with oral contraceptives, which can reduce the effectiveness of the contraceptive.

The following are the side effects involving "Ceftazidime":

• Diarrhea
• Nausea and vomiting
• Pain, redness, or swelling at the injection site
• Headache
• Rash or itching

Pregnancy

Category B

The safety of using Ceftazidime for Injection, USP in the treatment of infections during pregnancy is not yet known. It is advised that the potential benefits and possible risks to the fetus should be carefully evaluated before administering ceftazidime to pregnant patients.

Lactation:

Ceftazidime has been found to be excreted in low concentrations (3.8 - 5.2 mg/mL) in human milk. Therefore, caution should be taken while administering Ceftazidime for Injection, USP to nursing women.

Pediatrics:

The safety of using Ceftazidime for Injection, USP in infants who are one month old or younger has not been established.

Geriatrics:

In elderly patients, the elimination of ceftazidime from the body may be impaired due to renal function impairment.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of "Ceftazidime."

Overdosing with ceftazidime has been reported in patients with renal failure, resulting in various reactions such as seizures, encephalopathy, asterixis, and neuromuscular excitability. Supportive treatment and careful observation should be given to patients who receive an acute overdosage. Hemodialysis or peritoneal dialysis may be beneficial for the removal of ceftazidime from the body in the presence of renal insufficiency. In some cases, administration of large doses of parenteral cephalosporins may lead to dizziness, paresthesias, and headaches. Seizures may also occur, especially in patients with renal impairment who are likely to accumulate the drug.

Elevations in creatinine, BUN, liver enzymes and bilirubin, positive Coombs' test, thrombocytosis, thrombocytopenia, eosinophilia, leukopenia, and prolongation of the prothrombin time are some laboratory abnormalities that may occur after an overdose. In case of seizures, prompt discontinuation of the drug and administration of anticonvulsant therapy, if clinically indicated, is recommended. The patient's airway, ventilation, perfusion, vital signs, blood gases, and serum electrolytes should be closely monitored and maintained within acceptable limits.

If response to conservative therapy fails, combined hemodialysis and hemoperfusion may be considered for severe over dosage, especially in patients with renal failure. However, there is no clinical data to support such therapy for ceftazidime overdose.

Pharmacodynamics

Ceftazidime is a third-generation cephalosporin antibiotic that inhibits enzymes involved in cell-wall synthesis, specifically PBP3, and has a broad spectrum of activity against Gram-negative bacteria, including Pseudomonas aeruginosa. However, it is less effective against Gram-positive bacteria and anaerobes. It is effective against clinically relevant Gram-negative bacteria, such as Citrobacter spp., Enterobacter spp., Klebsiella spp., Proteus spp., Serratia spp., Escherichia coli, Haemophilus influenzae, Neisseria meningitidis, Pseudomonas aeruginosa, and also some Gram-positive bacteria including Staphylococcus spp. as well as Streptococcus spp. Although in vitro data suggest that ceftazidime is effective against other bacteria, such as Acinetobacter baumannii and Neisseria gonorrhoeae, no clear clinical studies support its use for these infections.

While β-lactam antibiotics like ceftazidime are generally well-tolerated, patients with a known allergy to the drug ceftazidime or any other β-lactam antibiotic are at higher risk of serious acute hypersensitivity reactions. There is also a risk of Clostridium difficile-associated diarrhea (CDAD) and the overgrowth of non-susceptible organisms with the use of ceftazidime, which can have potentially serious effects. Ceftazidime is primarily excreted by the kidneys, and high and prolonged serum concentrations can occur in patients with renal insufficiency, leading to seizures, encephalopathy, coma, and other neurological symptoms. Resistance to ceftazidime can develop with its use, and periodic susceptibility testing is recommended. The use of ceftazidime may decrease prothrombin activity, which can be addressed with vitamin K supplementation. Inadvertent intra-arterial administration of ceftazidime can result in distal necrosis.

Pharmacokinetics

· Absorption:

When administered to healthy men, Ceftazidime produced mean Cmax values ranging from 42 to 170 μg/mL for doses between 500 mg and 2 g when administered intravenously, with peak levels immediately following the infusion. On the other hand, when administered intramuscularly, the Cmax for 1 g of ceftazidime was achieved approximately an hour after injection and ranged from 37 to 43 mg/L. The serum concentration for 500 mg and 1 g intramuscular administration of ceftazidime remained above 4 μg/mL for six and eight hours, respectively. The proportionality of Ceftazidime Cmax and AUC to the dose is linear over the therapeutic range, and no accumulation was observed in individuals with normal renal function when ceftazidime was administered intravenously every eight hours for ten days at either 1 or 2 g doses.

• Volume of distribution:

The volume of distribution for Ceftazidime is between 15-20 L, and its plasma protein binding ranges from 5-22.8% and is typically less than 10%, with no correlation to concentration. Ceftazidime has been demonstrated to bind to human serum albumin.

• Protein binding:

Ceftazidime is highly protein-bound, with a binding rate of 95%.

• Metabolism:

Ceftazidime is not significantly metabolized, and approximately 80% to 90% of an intramuscular or intravenous dose is excreted unchanged by the kidneys over a 24-hour period.

• Route of elimination:

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.

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