ZAVICEFTA 2g/0.5g

Indications

• Complicated intra-abdominal infections
• Complicated urinary tract infections
• Nosocomial pneumonia
• Infections caused by resistant strains of bacteria

Dosage

Children: Refer to BNF for Children for appropriate paediatric dosing information, tailored to the child's age, weight, and specific clinical condition.

Adults: Refer to BNF for specific adult dosing guidelines based on the type of infection and patient factors. Typically, it is used in conjunction with ceftazidime, following specific protocols.

Mechanism of action

Avibactam inactivates specific β-lactamases, including Ambler class A β-lactamases, class C, and some class D β-lactamases, through a unique covalent and reversible mechanism. This action protects ceftazidime from degradation, allowing it to remain effective against β-lactamase-producing strains. Avibactam effectively reaches the bacterial periplasm, achieving concentrations sufficient to restore the activity of ceftazidime against resistant strains.

Pharmacodynamics

Avibactam works synergistically with ceftazidime to enhance its antibacterial effect against β-lactamase-producing organisms. Its ability to inhibit β-lactamases increases the overall efficacy of treatment regimens involving ceftazidime, particularly in infections caused by multidrug-resistant bacteria.

Pharmacokinetics

Avibactam is administered intravenously and reaches therapeutic concentrations in the bloodstream and in the periplasm of bacteria. It exhibits a linear pharmacokinetic profile, with a volume of distribution and clearance that support its use in combination therapy. The half-life and elimination pathways are consistent with its classification and therapeutic use.

Pregnancy

There is limited data on the use of avibactam in pregnancy. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is unknown whether avibactam is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at 20 to 25 degrees Celsius. Protect from light and moisture.

Indications

• Bacterial infections
• Complicated urinary tract infections
• Hospital-acquired pneumonia
• Sepsis
• Febrile neutropenia
• Prophylaxis for transurethral resection of the prostate
• Intra-abdominal infections
• Acute exacerbations of chronic obstructive pulmonary disease

Dosage

Children: Child: 1 g

Adults: 1 g every 8 hours, or 2 g once daily for severe infections, with a maximum of 9 g per day depending on the clinical scenario.

Mechanism of action

Ceftazidime works by inhibiting the synthesis of the bacterial cell wall. Specifically, it binds to penicillin-binding proteins (PBPs), predominantly PBP3, thus interfering with the cross-linking of peptidoglycan layers in the bacterial cell wall. This disruption leads to cell lysis and death, making ceftazidime bactericidal against susceptible organisms.

Pharmacodynamics

As a semisynthetic cephalosporin, ceftazidime is particularly resistant to certain beta-lactamases, which enhances its effectiveness against a range of Gram-negative bacteria. Its bactericidal action is primarily due to the inhibition of cell wall synthesis, particularly against bacteria such as Escherichia coli and Pseudomonas aeruginosa. While it is effective against many Gram-negative pathogens, it is less effective against Gram-positive bacteria.

Pharmacokinetics

Ceftazidime is well absorbed when administered intravenously, with a distribution volume of approximately 0.3 to 0.5 L/kg. It is primarily eliminated by the kidneys, with a half-life of about 1.5 to 2 hours in individuals with normal renal function. Dosing adjustments are necessary in patients with renal impairment to prevent accumulation.

Adverse effects

• Thrombocytosis
• Cellulitis
• Erysipelas
• Thrombophlebitis
• Fungal infection
• Acute kidney injury
• Coma
• Encephalopathy
• Jaundice
• Lymphocytosis
• Myoclonus
• Neurological effects
• Paraesthesia
• Seizure
• Taste altered
• Tremor

Precautions

• Caution in patients with severe hepatic impairment
• Caution in renal impairment, dose adjustments may be necessary

Pregnancy

Not known to be harmful.

Breast-feeding

Present in milk in low concentration, but appropriate to use.

Storage

Store at room temperature, protect from light. Reconstituted solutions should be used promptly.

Formulations

• 500 mg powder for solution for injection
• 1 g powder for solution for injection
• 2 g powder for solution for injection

Mechanism of action

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.

Mechanism of action

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.

Pharmacodynamics

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.