Ceftazidime + Avibactam

Ceftazidime + Avibactam Uses, Dosage, Side Effects, Food Interaction and all others data.

Avibactam is a non-β-lactam β-lactamase inhibitor that is available in combination with ceftazidime (Avycaz). This combination was approved by the FDA on February 25, 2015 for the treatment of complicated intra-abdominal infections in combination with metronidazole, and the treatment of complicated urinary tract infections, including pyelonephritis caused by antibiotic resistant-pathogens, including those caused by multi-drug resistant gram-negative bacterial pathogens. As there is limited clinical safety and efficacy data, Avycaz should be reserved for patients over 18 years old who have limited or not alternative treatment options.

Ceftazidime is a semisynthetic, broad-spectrum, beta-lactam antibiotic for parenteral administration. Ceftazidime is bactericidal in action exerting its effect by inhibition of enzymes responsible for cell-wall synthesis. A wide range of gram-negative organisms is susceptible to ceftazidime in vitro, including strains resistant to gentamicin and other aminoglycosides. In addition, ceftazidime has been shown to be active against gram-positive organisms. It is highly stable to most clinically important beta-lactamases, plasmid or chromosomal, which are produced by both gram-negative and gram-positive organisms and, consequently, is active against many strains resistant to ampicillin and other cephalosporins.

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. 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.

Ceftazidime + Avibactam
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Ceftazidime + Avibactam
Generic	Ceftazidime + Avibactam
Type
Therapeutic Class
Manufacturer
Available Country	Bangladesh
Last Updated:	September 24, 2024 at 5:38 am

Uses

This is indicated in adults and paediatric patients aged 3 months and older for the treatment of the following infections: Complicated intra-abdominal infection (cIAI) Complicated urinary tract infection (cUTI), including pyelonephritis Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP) ... Read more

Ceftazidime + Avibactam is also used to associated treatment for these conditions: Bacterial Infections, Complicated Intra-Abdominal Infections, Complicated Urinary Tract Infection, Complicated PyelonephritisBacteremia, 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 microorganism

How Ceftazidime + Avibactam works

Avibactam is a non-β lactam β-lactamase inhibitor that inactivates some β-lactamases (Ambler class A β-lactamases, including Klebsiella pneumoniae carbapenemases, Ambler class C and some Ambler class D β-lactamases) by a unique covalent and reversible mechanism, and protects ceftazidime from degradation by certain β-lactamases. Avibactam rapidly reaches the periplasm of bacteria at high enough concentrations to restore activity of ceftazidime against ceftazidime-resistant, β-lactamase-producing strains. Avibactam does not decrease the activity of ceftazidime against ceftazidime susceptible organisms.

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.

Dosage

Ceftazidime + Avibactam dosage

It is recommended that this should be used to treat infections due to aerobic Gram-negative organisms in adults and paediatric patients aged 3 months and older with limited treatment options only after consultation with a physician with appropriate experience in the management of infectious diseases. Complicated intra-abdominal infection: 2 g/0.5 g, every 8 hours for 5-14 days. Complicated urinary tract infection (cUTI), including pyelonephritis: 2 g/0.5 g every 8 hours for 5-10 days. Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP): 2 g/0.5 g Every 8 hours for 7-14 days. Bacteraemia associated with, or suspected to be associated with any of the above infections: 2 g/0.5 g Every 8 hours. Duration of treatment should be in accordance with the site of infection. Infections due to aerobic Gram-negative organisms in patients with limited treatment options: 2 g/0.5 g Every 8 hours. Guided by the severity of the infection, the pathogen(s) and the patient’s clinical and bacteriological progress.

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

severe allergic reactions: signs include sudden swelling of your lips, face, throat or tongue, a severe rash or other severe skin reactions, difficulty swallowing or breathing. This reaction may be life-threatening. diarrhoea that keeps getting worse or does not go away, or stools that contains blood or mucus-this may happen during or after treatment is stopped with this combination. If this happens do not take medicines that stop or slow bowel movement.

Toxicity

Avycaz is contraindicated in patients with known serious hypersensitivity to avibactam-containing products, ceftazidime or other members of the cephalosporin class.

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.

Precaution

This medicinal product does not require any special storage conditions. Store in the original package in order to protect from light.

Interaction

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

Volume of Distribution

The steady state volumes of distribution of avibactam and ceftazidime is 22.2L and 17L respectively.

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

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.

Half Life

Ceftazidime-avibactam has a half life of ~2.7-3.0 hours.

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.

Clearance

Avibactam and ceftazidime has a clearance of ~12L/h and ~7L/h respectively.

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.

Elimination Route

Avibactam and ceftazidime are excreted mainly by the kidneys.

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.

Pregnancy & Breastfeeding use

Animal studies with ceftazidime do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Animal studies with avibactam have shown reproductive toxicity without evidence of teratogenic effects. Ceftazidime/avibactam should only be used during pregnancy if the potential benefit outweighs the possible risk. Ceftazidime is excreted in human milk in small quantities. It is unknown whether avibactam is excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast feeding or to discontinue/abstain from ceftazidime/avibactam therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Contraindication

Hypersensitivity to the active substances or to any of the excipients. Hypersensitivity to any cephalosporin antibacterial agent. Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).

Special Warning

Elderly: No dosage adjustment is required in elderly patients.Renal impairment: No dosage adjustment is required in patients with mild renal impairment.

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.