ZAVICEFTA

Bacteria possess a cell wall comprising a glycopeptide polymer commonly known as peptidoglycan, which is synthesized and remodelled through the action of a family of enzymes known as "penicillin-binding proteins" (PBPs). 1 β-lactam antibiotics, including cephalosporins, are PBP inhibitors that, through inhibition of essential PBPs, result in impaired cell wall homeostasis, loss of cell integrity, and ultimately bacterial cell death. 1, 2, 3 Ceftazidime is a third-generation cephalosporin with broad-spectrum antibacterial activity, including against some treatment-resistant bacteria such as Pseudomonas aeruginosa.

Ceftazidime was approved by the FDA on July 19, 1985, and is currently available either alone or in combination with the non-β-lactam β-lactamase inhibitor avibactam to treat a variety of bacterial infections. 12, 13.

Ceftazidime is indicated for the treatment of lower respiratory tract infections, skin and skin structure infections, urinary tract infections, bacterial septicemia, bone and joint infections, gynecologic infections, intra-abdominal infections (including peritonitis), and central nervous system infections (including meningitis) caused by susceptible bacteria.

Ceftazidime is indicated in combination with avibactam to treat infections caused by susceptible Gram-negative organisms, including complicated intra-abdominal infections (cIAI), in conjunction with metronidazole, and complicated urinary tract infections (cUTI), including pyelonephritis, in adult and pediatric patients (at least 31 weeks gestational age).

This combination is also indicated to treat hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) in adult and pediatric patients (at least 31 weeks gestational age).

In all cases, to mitigate the risk of bacterial resistance and preserve clinical efficacy, ceftazidime should only be used for infections that are confirmed or strongly suspected to be caused by susceptible bacterial strains. 12,

Ceftazidime is a semisynthetic, broad-spectrum, third-generation cephalosporin antibiotic that is bactericidal through inhibition of enzymes responsible for cell-wall synthesis, primarily penicillin-binding protein 3 (PBP3).

Among cephalosporins, ceftazidime is notable for its resistance to numerous β-lactamases and its broad spectrum of activity against Gram-negative bacteria, including Pseudomonas aeruginosa.

However, it is less active than first.

• and second-generation cephalosporins against Staphylococcus aureus and other Gram-positive bacteria and also has low activity against anaerobes. 4, 9 Ceftazidime has confirmed activity against clinically relevant Gram-negative bacteria including Citrobacter spp., Enterobacter spp., Klebsiella spp., Proteus spp., Serratia spp., _Escherichia coli, Haemophilus influenzae, Neisseria meningitidis, Pseudomonas aeruginosa, and some Gram-positive bacteria including Staphylococcus spp. and Streptococcus spp.

There are also in vitro data for ceftazidime efficacy against a wide variety of other bacteria, such as Acinetobacter baumannii and Neisseria gonorrhoeae, but no clear clinical studies to support the use of ceftazidime for infections caused by these bacteria.

Although β-lactam antibiotics like ceftazidime are generally well tolerated, there remains a risk of serious acute hypersensitivity reactions, which is higher in patients with a known allergy to ceftazidime or any other β-lactam antibiotic.

As with all antibiotics, ceftazidime may result in the overgrowth of non-susceptible organisms and potentially serious effects including Clostridium difficile -associated diarrhea (CDAD); CDAD should be considered in patients who develop diarrhea and, in confirmed cases, supportive care initiated immediately.

Ceftazidime is primarily renally excreted such that high and prolonged serum concentrations can occur in patients with renal insufficiency, leading to seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia.

Treatment may lead to the development or induction of resistance with a risk of treatment failure.

Periodic susceptibility testing should be considered, and monotherapy failure may necessitate the addition of another antibiotic such as an aminoglycoside.

Cephalosporin use may decrease prothrombin activity, which may be improved by exogenous vitamin K. Inadvertent intra-arterial administration of ceftazidime may result in distal necrosis.

D,D-transpeptidase FtsI (Escherichia coli (strain K12)) Inhibitor Penicillin-binding protein 1A (Escherichia coli (strain K12)) Inhibitor Penicillin-binding protein 1B (Escherichia coli (strain K12)) Inhibitor + 1 more target.

Ceftazidime administered Intravenous in healthy males produced mean C max values of between and 170 μg/mL for doses between 500 mg and 2 g, and are reached immediately following the end of the infusion period.

C max for 1 g of ceftazidime administered Intramuscular is attained approximately one hour following injection and is between 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. 4, 12 In individuals with normal renal function, ceftazidime given Intravenous every eight hours for 10 days as either 1 or 2 g doses showed no accumulation.

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

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

Intravenous, 50% of the dose appears in the urine within two hours, with another 32% of the dose appearing by eight hours post-administration.

Ceftazidime has an elimination half-life of 1.5-2.8 hours in healthy subjects. 4, 12 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 and 30 hours.

The mean renal clearance of ceftazidime in healthy subjects ranges from 72-141 mL/min while the calculated plasma clearance is approximately 115 mL/min. 4, 12.

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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.

10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY.

IF AN ALLERGIC REACTION TO CEFTAZIDIME FOR INJECTION OCCURS, DISCONTINUE THE DRUG.

SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ceftazidime for injection, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of

C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial drug use.

Careful medical history is necessary since

CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Elevated levels of ceftazidime in patients with renal insufficiency can lead to seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia.

Ceftazidime for injection is contraindicated in patients who have shown hypersensitivity to ceftazidime or the cephalosporin group of antibacterial drugs.

The usual adult dosage is 1 gram administered intravenously or intramuscularly every 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.

The guidelines for dosage of ceftazidime for injection are listed in Table 3.

The following dosage schedule is recommended.

Table 3.

Schedule Although clinical improvement has been shown, bacteriologic cures cannot be expected in patients with chronic respiratory disease and cystic fibrosis. *The higher dose should be reserved for immunocompromised pediatric patients or pediatric patients with cystic fibrosis or meningitis.

Usual recommended dosage 1 gram intravenous or intramuscular every to 12 hours Uncomplicated urinary tract infection 250 mg intravenous or intramuscular every 12 hours Bone and joint infections 2 grams intravenous every 12 hours Complicated urinary tract infections 500 mg intravenous or intramuscular every to 12 hours Uncomplicated pneumonia; mild skin and skin-structure infections 500 mg to 1 gram intravenous or intramuscular every 8 hours Serious gynecological and intra-abdominal infections 2 grams intravenous every 8 hours Meningitis 2 grams intravenous every 8 hours Very severe life-threatening infections, especially in immunocompromised patients 2 grams intravenous every 8 hours Lung infections caused by Pseudomonas spp. in patients with cystic fibrosis with normal renal function 30 to 50 mg/kg intravenous to a maximum of 6 grams per day every 8 hours Neonates (0 to 4 weeks) 30 mg/kg intravenous every 12 hours Infants and children (1 month to 12 years) 30 to 50 mg/kg intravenous to a maximum of 6 grams per day* every 8 hours Impaired Hepatic Function No adjustment in dosage is required for patients with hepatic dysfunction.

Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration.

Therefore, 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.

An estimate of

GFR should be made to determine the appropriate maintenance dosage.

The recommended dosage is presented in

Table 4.

Recommended Maintenance Dosages of Ceftazidime for Injection in Renal Insufficiency NOTE: If the dose recommended in Table 3 above is lower than that recommended for patients with renal insufficiency as outlined in Table 4, the lower dose should be used.

Clearance (mL/min) Recommended Unit Dose of Ceftazidime for Injection Frequency of Dosing to 31 1 gram every 12 hours to 16 1 gram every 24 hours to 6 500 mg every 24 hours less than 5 500 mg every 48 hours When only serum creatinine is available, the following formula (Cockcroft's equation) 1 may be used to estimate creatinine clearance.

The serum creatinine should represent a steady state of renal function: Males: Creatinine clearance (mL/min) = Weight (kg) x (140 - age) 72 x serum creatinine (mg/dL) Females: 0.85 x male value In patients with severe infections who would normally receive 6 grams of ceftazidime for injection daily were it not for renal insufficiency, the unit dose given in the table above may be increased by 50% or the dosing frequency may be increased appropriately.

Further dosing should be determined by therapeutic monitoring, severity of the infection, and susceptibility of the causative organism.

In pediatric patients as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass, and the dosing frequency should be reduced in cases of renal insufficiency.

In patients undergoing hemodialysis, a loading dose of 1 gram is recommended, followed by 1 gram after each hemodialysis period.

Ceftazidime for injection can also be used in patients undergoing intraperitoneal dialysis and continuous ambulatory peritoneal dialysis.

In such patients, a loading dose of 1 gram of ceftazidime for injection may be given, followed by 500 mg every 24 hours.

In addition to

IV use, ceftazidime for injection can be incorporated in the dialysis fluid at a concentration of 250 mg for 2 L of dialysis fluid.

Generally, ceftazidime for injection should be continued for 2 days after the signs and symptoms of infection have disappeared, but in complicated infections longer therapy may be required.

Ceftazidime for injection 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 part of the thigh.

Intra-arterial administration should be avoided.

IM administration, ceftazidime for injection should be constituted with one of the following diluents: Sterile Water for Injection, Bacteriostatic Water for Injection, or 0.5% or 1% Lidocaine Hydrochloride Injection.

Refer to

Table 5.

IV route is preferable for patients with bacterial septicemia, bacterial meningitis, peritonitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or pending.

For direct intermittent

IV administration, constitute ceftazidime for injection as directed in Table with Sterile Water for Injection.

Slowly inject directly into the vein over a period of to 5 minutes or give through the tubing of an administration set while the patient is also receiving one of the compatible IV fluids.

IV infusion, constitute the 1 gram, or 2 gram vial and add an appropriate quantity of the resulting solution to an IV container with one of the compatible IV fluids listed under the COMPATIBILITY AND STABILITY section.

Intermittent IV infusion with a

Y-type administration set can be accomplished with compatible solutions.

However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution.

Preparation of Solutions of Ceftazidime for

Injection To obtain a dose of 1 g, withdraw 10 mL from the vial following reconstitution. * To obtain a dose of 2 g, withdraw 11.5 mL from the vial following reconstitution.

Size Amount of Diluent to be

Added (mL) Approximate Available Volume (mL) Approximate Ceftazidime Concentration (mg/mL) Intramuscular 1 gram vial 3 3.6 280 Intravenous 1 gram vial 10 10.8 100 2 gram vial 10 11.5* 170 Discard unused portion.

All vials of ceftazidime for injection as supplied are under reduced pressure.

When ceftazidime for injection is dissolved, carbon dioxide is released and a positive pressure develops.

For ease of use please follow the recommended techniques of constitution described on the detachable Instructions for Constitution section of this insert.

Solutions of ceftazidime for injection, like those of most beta-lactam antibacterial drugs, should not be added to solutions of aminoglycoside antibacterial drugs because of potential interaction.

However, if concurrent therapy with ceftazidime for injection and an aminoglycoside is indicated, each of these antibacterial drugs can be administered separately to the same patient.

Ceftazidime for injection, USP in the dry state should be stored at 20°C to 25°C (68°F to 77°F) and protected from light.

Ceftazidime for injection, USP is a white to cream-colored crystalline powder supplied in vials as follows: NDC Ceftazidime for Injection, USP Package Factor 25021-127-20 1 g Single-Dose Vial 25 vials per carton 25021-128-50 2 g Single-Dose Vial 10 vials per carton *Equivalent to anhydrous ceftazidime.

The container closure is not made with natural rubber latex.

Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ceftazidime for injection.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Ceftazidime is excreted in human milk in low concentrations.

Caution should be exercised when ceftazidime is administered to a nursing woman.

Of the 2,221 subjects who received ceftazidime in 11 clinical studies, 824 (37%) were and older while 391 (18%) were and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater susceptibility of some older individuals to drug effects cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function See DOSAGE AND ADMINISTRATION.