An Expert Monograph on Ceftazidime (DB00438)

1.0 Executive Summary

Ceftazidime is a parenteral, third-generation cephalosporin antibiotic that has been a significant component of the antimicrobial armamentarium since its patenting in 1978 and subsequent commercial introduction in 1984.[1] Classified as a small molecule drug, it is recognized for its essential role in medicine and is included on the World Health Organization's List of Essential Medicines.[1] The bactericidal action of Ceftazidime is achieved through the inhibition of bacterial cell wall synthesis, which it accomplishes by binding to and inactivating essential penicillin-binding proteins (PBPs), with a particularly high affinity for PBP3 in Gram-negative organisms.[3]

The drug possesses a broad spectrum of activity, but its clinical value is most pronounced in its potent efficacy against a wide range of Gram-negative pathogens. It is especially noted for its activity against Pseudomonas aeruginosa, an opportunistic pathogen frequently associated with multi-drug resistance.[1] This makes Ceftazidime a critical agent for the treatment of severe, life-threatening infections, including hospital-acquired and ventilator-associated pneumonia (HAP/VABP), meningitis, sepsis, complicated urinary tract infections (cUTIs), and bone and joint infections.[1] Furthermore, it holds the status of a first-line therapy for melioidosis, a serious infection endemic to tropical regions.[1]

The pharmacokinetic profile of Ceftazidime is characterized by its parenteral route of administration (intravenous or intramuscular), minimal plasma protein binding of less than 10%, and excellent penetration into a wide variety of body tissues and fluids, including inflamed cerebrospinal fluid.[5] It undergoes no significant metabolism and is eliminated almost entirely unchanged via renal glomerular filtration.[5]

This reliance on renal clearance, however, constitutes its most significant liability. Dose adjustments in patients with any degree of renal impairment are mandatory and must be executed with care to prevent drug accumulation. Failure to do so can lead to severe neurological adverse events, including nonconvulsive status epilepticus, encephalopathy, myoclonus, and coma.[1] The second major safety concern is the risk of

Clostridioides difficile-associated diarrhea (CDAD). As a broad-spectrum antibiotic, Ceftazidime can significantly alter the normal gut flora, creating an environment for C. difficile overgrowth, which can lead to conditions ranging from mild diarrhea to life-threatening pseudomembranous colitis.[1]

In response to the growing challenge of beta-lactamase-mediated resistance, the combination product ceftazidime-avibactam (marketed as Avycaz® and Zavicefta®) was developed. Avibactam, a beta-lactamase inhibitor, protects Ceftazidime from degradation by a wide range of enzymes, including Extended-Spectrum Beta-Lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs). This combination restores and expands Ceftazidime's spectrum of activity, making it a vital tool for treating infections caused by many multi-drug resistant Gram-negative bacteria.[3]

2.0 Drug Identification and Physicochemical Properties

2.1 Nomenclature, Classification, and Regulatory Status

Ceftazidime is a well-established antibiotic belonging to the third generation of cephalosporins, a subclass of beta-lactam antibiotics.[1] It is classified as a small molecule drug and is produced via semi-synthesis from a 7-aminocephalosporanic acid (7-ACA) precursor.[6]

Its unique identity is cataloged across numerous international databases. Key identifiers include DrugBank ID DB00438 and Chemical Abstracts Service (CAS) Number 72558-82-8.[1] It is marketed globally under several brand names, with the most prominent being Fortaz®, Tazicef®, and Tazidime®.[1] The combination product with the beta-lactamase inhibitor avibactam is marketed as Avycaz® in the United States and Zavicefta® in the European Union and other regions.[6]

Ceftazidime's development and approval timeline reflects its long-standing clinical importance. It was first patented in 1978, received approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA) in 1983, and came into widespread commercial use following its approval by the U.S. Food and Drug Administration (FDA) on July 19, 1985.[1]

2.2 Chemical Structure and Formulation Characteristics

The chemical structure of Ceftazidime is central to its antibacterial activity and stability. Its formal IUPAC name is (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.[1]

The molecule is built upon a cephem nucleus, a bicyclic system comprising a four-membered beta-lactam ring fused to a six-membered dihydrothiazine ring.[7] The specific properties of Ceftazidime are determined by the side chains attached at positions 3 and 7 of this nucleus.

• Position 3 (C3) Side Chain: Ceftazidime features a positively charged methylpyridinium group at this position. This moiety is critically important for two reasons: it confers potent intrinsic activity against P. aeruginosa, and its zwitterionic (dipolar ion) nature significantly enhances the molecule's water solubility, facilitating its formulation for parenteral use.[7]
• Position 7 (C7) Side Chain: The acylamino side chain at C7 is complex and provides both its broad Gram-negative spectrum and its resistance to many beta-lactamases. It consists of an aminothiadiazole ring, a feature common to extended-spectrum cephalosporins that boosts activity against Gram-negative bacilli, and a distinctive carboxypropyl-oxyimino group. This latter group, an oxime O-ether with a syn-configuration, provides steric hindrance that protects the core beta-lactam ring from hydrolysis by many common bacterial beta-lactamase enzymes. This structural feature is a key advancement over earlier-generation cephalosporins and is fundamental to Ceftazidime's clinical utility.[1]

For clinical use, Ceftazidime is supplied as a sterile, dry, crystalline powder that is white to cream-colored.[5] It is typically formulated as a pentahydrate salt to improve stability.[3] To facilitate dissolution upon reconstitution, the powder is often admixed with an excipient, most commonly sodium carbonate (approximately 118 mg per gram of ceftazidime) or, in some formulations, L-arginine to provide a sodium-free option.[5] Once reconstituted with a suitable diluent, the resulting solution ranges in color from light yellow to amber and has a pH between 5.0 and 7.5.[22]

2.3 Physical and Chemical Properties

The chemical and physical properties of Ceftazidime dictate its formulation, stability, and pharmacokinetic behavior. The anhydrous form has a molecular formula of C22​H22​N6​O7​S2​ and a corresponding molecular weight of 546.57 g/mol.[1] The more common pentahydrate form has the formula

C22​H32​N6​O12​S2​ and a molecular weight of 636.6 g/mol.[5]

Despite its formulation for injection, the base molecule has very low intrinsic water solubility (approximately 0.00573 g/L).[3] Its hydrophilic nature is confirmed by its octanol-water partition coefficient (LogP) of -1.6, indicating that it preferentially resides in aqueous environments over lipid ones, a property consistent with its distribution in body fluids and its reliance on renal excretion.[3]

Table 1: Key Identifiers and Physicochemical Properties of Ceftazidime

Property Category	Parameter	Value / Identifier	Source(s)
Identifiers	DrugBank ID	DB00438	1
	CAS Number	72558-82-8	1
	PubChem CID	5481173	1
	ChEBI ID	CHEBI:3508	1
	UNII	DZR1ENT301	1
	ATC Code	J01DD02	1
Nomenclature	IUPAC Name	(6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	2
	Common Synonyms	Fortaz, Fortum, Tazicef, Tazidime	1
Chemical Formula	Anhydrous	C22​H22​N6​O7​S2​	1
	Pentahydrate	C22​H32​N6​O12​S2​	5
Molecular Weight	Anhydrous	546.57 g/mol	1
	Pentahydrate	636.6 g/mol	5
Structural Codes	SMILES	CC(C)(C(=O)O)O/N=C(/C1=CSC(=N1)N)\C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C[N+]4=CC=CC=C4)C(=O)[O-]	2
	InChIKey	ORFOPKXBNMVMKC-DWVKKRMSSA-N	3
Physical Properties	Physical Description	White to cream-colored crystalline solid	3
	Water Solubility	0.00573 g/L (low)	3
	LogP	-1.6	3
Druglikeness	H-bond Acceptors	10	2
	H-bond Donors	3	2
	Rotatable Bonds	10	2
	TPSA	244.76 A˚2	2

3.0 Comprehensive Pharmacological Profile

3.1 Mechanism of Action and Pharmacodynamics

3.1.1 Core Bactericidal Action

Ceftazidime exerts its potent antibacterial effect through a bactericidal mechanism, meaning it actively kills bacteria rather than merely inhibiting their growth.[5] The fundamental action is the disruption of bacterial cell wall synthesis.[5] Bacteria, particularly Gram-negative organisms, rely on a rigid outer cell wall composed of peptidoglycan to maintain their structural integrity and survive osmotic stress. By interfering with the construction of this essential structure, Ceftazidime causes the bacterial cell wall to become defective, leading to a loss of homeostasis, cell lysis, and ultimately, bacterial death.[3]

3.1.2 Molecular Target Specificity

The molecular targets of all beta-lactam antibiotics, including Ceftazidime, are the Penicillin-Binding Proteins (PBPs). PBPs are a group of bacterial enzymes, such as transpeptidases and carboxypeptidases, that catalyze the final steps of peptidoglycan synthesis, specifically the cross-linking of peptide side chains.[3] Ceftazidime covalently binds to the active site of these enzymes, inactivating them and halting cell wall construction.

While it inhibits several PBPs—including PBP1A, PBP1B, and Peptidoglycan D,D-transpeptidases FtsI and MrdA—Ceftazidime exhibits a particularly high binding affinity for PBP3 in Gram-negative bacteria.[4] This specific affinity is clinically significant, as inhibition of PBP3 is primarily associated with the formation of long, filamentous bacterial forms that are unable to divide, a key step leading to cell death.

3.1.3 Structural Basis for Beta-Lactamase Stability

A defining pharmacodynamic characteristic of Ceftazidime is its enhanced stability against many common beta-lactamase enzymes.[1] These bacterial enzymes are a primary mechanism of resistance, as they hydrolyze the amide bond in the beta-lactam ring, rendering the antibiotic inactive. The chemical structure of Ceftazidime, specifically the complex carboxypropyl-oxyimino side chain at the C7 position, provides a high degree of steric hindrance. This bulkiness physically obstructs the access of many plasmid- and chromosomally-mediated penicillinases and cephalosporinases to the beta-lactam ring, thus protecting the drug from degradation and allowing it to reach its PBP targets intact.[1]

3.2 Spectrum of Antimicrobial Activity

As a third-generation cephalosporin, Ceftazidime's spectrum of activity is broad but is distinctly skewed towards potent coverage of Gram-negative bacteria, a hallmark of its class.[1] Its activity against Gram-positive cocci and anaerobic bacteria is comparatively limited.[10]

Clinically Relevant Gram-Negative Activity: Ceftazidime has demonstrated both in vitro and clinical efficacy against a wide array of clinically significant Gram-negative pathogens.[5]

• Pseudomonas aeruginosa: This is the key pathogen for which Ceftazidime is renowned. Its potent and reliable activity against P. aeruginosa, including some strains resistant to other antibiotics, has been a cornerstone of its therapeutic use since its introduction.[1]
• Enterobacteriaceae: It is highly active against most species within this family, including Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Citrobacter freundii complex, Serratia spp., Salmonella spp., and Shigella spp..[5]
• Other Gram-Negative Organisms: It provides excellent coverage for Haemophilus influenzae (including ampicillin-resistant, beta-lactamase-producing strains), Neisseria meningitidis, Neisseria gonorrhoeae, and Moraxella catarrhalis.[5]
• Burkholderia pseudomallei: Ceftazidime is the treatment of choice for melioidosis, the severe infection caused by this organism.[1]

Gram-Positive Activity: The activity against Gram-positive bacteria is modest.

• It is active against methicillin-susceptible Staphylococcus aureus (MSSA) and coagulase-negative staphylococci like Staphylococcus epidermidis.[5] It is clinically inactive against methicillin-resistant Staphylococcus aureus (MRSA).[10]
• It covers susceptible strains of Streptococcus pneumoniae, Streptococcus pyogenes (Group A Strep), and Streptococcus agalactiae (Group B Strep).[5]
• It is inactive against Enterococcus species (e.g., E. faecalis) and Listeria monocytogenes.[10]

Anaerobic Activity: Coverage is generally poor and unreliable. While it shows some in vitro activity against Prevotella melaninogenica and some Clostridium species (excluding C. difficile), many clinically important anaerobes, most notably Bacteroides fragilis, are resistant.[5] For this reason, in mixed infections where anaerobes are suspected (e.g., intra-abdominal infections), Ceftazidime must be combined with an agent with specific anti-anaerobic activity, such as metronidazole.

Table 2: In Vitro Spectrum of Activity of Ceftazidime Against Key Pathogens

Organism Group	Species	Typical Susceptibility	Clinical Notes
Gram-Positive Cocci	Staphylococcus aureus (MSSA)	Susceptible / Intermediate	Active against methicillin-susceptible strains.9
	Staphylococcus aureus (MRSA)	Resistant	Clinically ineffective against MRSA.10
	Streptococcus pneumoniae	Susceptible	Effective against penicillin-susceptible strains.5
	Streptococcus pyogenes (Group A)	Susceptible	.5
	Enterococcus spp.	Resistant	Clinically ineffective.10
Gram-Negative Bacilli	Pseudomonas aeruginosa	Susceptible	Key indication; potent activity.1
(Enterobacteriaceae)	Escherichia coli	Susceptible	.9
	Klebsiella spp.	Susceptible	Susceptible, but resistance via ESBL/KPC is common.12
	Enterobacter spp.	Susceptible	Risk of inducible AmpC resistance during therapy.12
	Serratia spp.	Susceptible	.9
	Proteus mirabilis	Susceptible	.9
Other Gram-Negatives	Haemophilus influenzae	Susceptible	Active against ampicillin-resistant strains.5
	Neisseria meningitidis	Susceptible	.6
	Burkholderia pseudomallei	Susceptible	First-line treatment for melioidosis.1
Anaerobes	Bacteroides fragilis	Resistant	Most isolates are resistant; requires combination therapy.5
	Clostridium difficile	Resistant	Not active; use can lead to C. difficile colitis.1

3.3 Mechanisms of Bacterial Resistance

Despite its inherent stability, bacteria have evolved several mechanisms to overcome the action of Ceftazidime [5]:

1. Hydrolysis by Advanced Beta-Lactamases: The most significant mechanism of acquired resistance is the production of beta-lactamase enzymes that are capable of hydrolyzing Ceftazidime. These include Extended-Spectrum Beta-Lactamases (ESBLs), which are common in E. coli and Klebsiella species, and carbapenemases such as Klebsiella pneumoniae carbapenemase (KPC), which confer resistance to a very broad range of beta-lactams.[1]
2. Alteration of Penicillin-Binding Proteins (PBPs): Bacteria can develop mutations in the genes (e.g., ftsI) that encode for PBPs. These mutations can alter the structure of the protein's active site, thereby reducing the binding affinity of Ceftazidime and rendering it less effective.[5]
3. Decreased Permeability and Efflux: Gram-negative bacteria can limit the intracellular concentration of Ceftazidime by modifying their outer membrane. This can involve the down-regulation or mutation of porin channels, which are the primary entry gates for the antibiotic, or the up-regulation of multidrug efflux pumps that actively expel the drug from the periplasmic space before it can reach its PBP targets.[5]
4. Inducible Resistance: A particularly challenging form of resistance is seen with organisms that possess inducible AmpC beta-lactamases, such as Enterobacter spp., Serratia spp., and Pseudomonas spp. These bacteria may initially test as susceptible in vitro, but exposure to the antibiotic during therapy can induce high-level expression of the AmpC enzyme, leading to the emergence of resistance and subsequent clinical failure. This phenomenon underscores the importance of cautious use in infections caused by these organisms.[12]

3.4 Pharmacokinetics: A Detailed Analysis of ADME

The clinical use of Ceftazidime is profoundly influenced by its pharmacokinetic profile, which is characterized by parenteral administration, wide distribution, lack of metabolism, and near-complete renal elimination.

3.4.1 Absorption

Ceftazidime is not absorbed from the gastrointestinal tract and must be administered parenterally, either via intravenous (IV) or intramuscular (IM) injection.[1]

• Intravenous (IV) Administration: Following IV administration, Ceftazidime achieves rapid, high peak serum concentrations (Cmax​) that are directly proportional to the administered dose. A 1 g IV dose results in a Cmax​ of approximately 60-69 mcg/mL, while a 2 g dose can produce a Cmax​ of 129-170 mcg/mL.[5]
• Intramuscular (IM) Administration: The drug is well-absorbed from the muscle, with peak serum concentrations occurring approximately one hour after injection (Tmax​). A 500 mg IM dose yields a Cmax​ of about 17 mcg/mL, and a 1 g IM dose yields a Cmax​ of about 39 mcg/mL.[5]

3.4.2 Distribution

Ceftazidime distributes extensively throughout the body.

• Protein Binding: It exhibits very low binding to plasma proteins, with less than 10% of the drug bound.[5] This low binding is clinically advantageous, as it means over 90% of the drug in circulation is in its free, unbound, and pharmacologically active form, available to diffuse into tissues.
• Tissue Penetration: It achieves therapeutic concentrations in a wide range of tissues and body fluids, including skin, bone, synovial fluid, peritoneal fluid, bile, sputum, aqueous humor, and muscle tissue.[5] For example, after a 2 g IV dose, average concentrations of 31.1 mcg/g in bone and 25.6 mcg/mL in synovial fluid have been measured.[11]
• Central Nervous System (CNS) Penetration: A crucial feature of Ceftazidime is its ability to penetrate the blood-brain barrier, particularly when the meninges are inflamed. It achieves therapeutic concentrations in the cerebrospinal fluid (CSF) sufficient to treat meningitis caused by susceptible Gram-negative pathogens. With a standard meningitis regimen (2 g IV every 8 hours), CSF concentrations of 9.4-9.8 mcg/mL are typically reached.[5]
• Accumulation: In individuals with normal renal function, there is no evidence of drug accumulation, even after 10 days of repeated high-dose therapy (e.g., 2 g every 8 hours).[5]

3.4.3 Metabolism

Ceftazidime is not metabolized in the body to any significant extent.[10] Its pharmacokinetic profile is unaffected by hepatic dysfunction. Consequently, no dosage adjustment is required for patients with liver disease, provided their renal function is not concurrently impaired.[1]

3.4.4 Excretion

Elimination of Ceftazidime is almost entirely dependent on the kidneys.[1]

• Route and Mechanism: Approximately 80% to 90% of an administered dose is excreted unchanged in the urine over a 24-hour period.[5] The primary mechanism of renal excretion is glomerular filtration. The lack of effect of probenecid (an inhibitor of tubular secretion) on its elimination kinetics confirms that active tubular secretion does not play a significant role.[5]
• Excretion Rate and Half-life: Elimination is rapid in patients with normal renal function. About 50% of an IV dose is excreted in the first 2 hours, with an additional 20% excreted between hours 2 and 4.[5] The mean renal clearance is approximately 100 mL/min.[5] The serum elimination half-life ( t1/2​) in healthy adults is consistently reported to be around 1.9 to 2.0 hours.[5] This short half-life necessitates frequent dosing (typically every 8 or 12 hours) to maintain therapeutic concentrations.

The complete reliance on a single organ for clearance creates a significant clinical vulnerability. Any decline in renal function directly and proportionally impacts Ceftazidime's elimination, leading to a prolonged half-life and elevated serum concentrations. This is not a trivial consideration, as the patient populations most in need of powerful antibiotics like Ceftazidime—such as those with sepsis or in intensive care units—are also the most susceptible to developing acute kidney injury. Because the drug has no alternative metabolic clearance pathway, faltering renal function immediately removes the body's only mechanism for eliminating the drug. This rapid accumulation is directly linked to the drug's most severe toxicity: neurotoxicity. This dynamic establishes a high-stakes clinical scenario where the drug's therapeutic window can shrink precipitously in the very patients it is meant to treat, demanding a level of vigilant monitoring of renal function that exceeds that for drugs with multiple clearance pathways. The absence of metabolism is thus a double-edged sword, preventing the formation of active metabolites but also removing any safety net if the kidneys fail.

Table 3: Summary of Pharmacokinetic Parameters in Adults with Normal Renal Function

Parameter	Value	Source(s)
Administration	Route	IV, IM
Absorption	Bioavailability (IM)	Well absorbed
	Tmax​ (IM)	~1 hour
	Cmax​ (1g IM)	~39 mcg/mL
	Cmax​ (1g IV)	~60-90 mcg/mL
Distribution	Protein Binding	< 10%
	CNS Penetration	Yes, especially with inflamed meninges
Metabolism	Extent of Metabolism	Minimal / None
Excretion	Primary Route	Renal (Glomerular Filtration)
	% Excreted Unchanged in Urine	80-90% within 24 hours
	Elimination Half-life (t1/2​)	1.9 - 2.0 hours
	Renal Clearance	~100 mL/min
	Total Plasma Clearance	~115 mL/min

4.0 Clinical Efficacy and Therapeutic Applications

4.1 Approved Indications and Evidence-Based Clinical Use

Ceftazidime is approved by regulatory authorities for the treatment of a broad spectrum of serious bacterial infections where susceptible organisms are implicated. Its use is well-established and supported by decades of clinical experience.[1] Key licensed indications include:

• Lower Respiratory Tract Infections: This includes community- and hospital-acquired pneumonia (HAP), as well as broncho-pulmonary infections, particularly in patients with cystic fibrosis where P. aeruginosa is a common and problematic pathogen.[1]
• Urinary Tract Infections (UTIs): It is indicated for both uncomplicated and complicated UTIs, including the more severe upper tract infection, pyelonephritis.[1]
• Skin and Skin-Structure Infections: Used for infections caused by susceptible Gram-negative bacilli and S. aureus (MSSA).[1]
• Bacterial Septicemia and Bacteremia: It is a crucial agent for treating bloodstream infections, often used empirically in cases of suspected sepsis.[1]
• Bone and Joint Infections: Its good bone penetration makes it effective for osteomyelitis and septic arthritis caused by susceptible organisms like P. aeruginosa and MSSA.[1]
• Gynecologic Infections: Approved for infections of the female genital tract, such as endometritis and pelvic cellulitis, caused by susceptible E. coli.[6]
• Intra-abdominal Infections: Indicated for peritonitis and other intra-abdominal infections. Due to its limited anaerobic coverage, it is typically used in combination with an agent like metronidazole in this setting.[1]
• Central Nervous System (CNS) Infections: Its ability to cross the blood-brain barrier makes it a valuable option for treating meningitis caused by susceptible strains of H. influenzae, N. meningitidis, and, in some cases, P. aeruginosa.[1]
• Febrile Neutropenia: It is widely used as an empiric monotherapy or in combination regimens for the management of fever in immunocompromised patients with neutropenia.
• Specialized Infections: It is indicated for malignant otitis externa and is considered a first-line, mortality-reducing treatment for melioidosis, a severe infection caused by Burkholderia pseudomallei that is endemic in parts of Asia and Australia.[1]

4.2 Off-Label and Investigational Uses

Beyond its labeled indications, Ceftazidime is used in several off-label clinical scenarios. In the setting of Outpatient Parenteral Antimicrobial Therapy (OPAT), it is employed for treating infective exacerbations of bronchiectasis and other deep-seated Gram-negative infections where the pathogen is known to be susceptible.[28] It has also been used off-label for treating certain types of wound infections and bacterial food poisoning.[8] Investigational studies continue to explore its pharmacokinetics in specialized patient populations, such as critically ill individuals receiving continuous renal replacement therapy (CRRT), to optimize dosing in these complex scenarios.[30]

4.3 The Role of Combination Therapy: A Deep Dive into Ceftazidime-Avibactam

The clinical history of Ceftazidime offers a clear illustration of the evolutionary arms race between antibiotics and bacterial resistance. A drug that was revolutionary in the 1980s for its anti-pseudomonal power saw its utility steadily eroded over the subsequent decades by the global proliferation of beta-lactamase enzymes. This challenge prompted a key strategy in modern antibiotic development: not the discovery of an entirely new molecule, but the "rejuvenation" of an existing, well-understood one by pairing it with a protective agent.

This approach led to the development of the fixed-dose combination ceftazidime-avibactam, marketed as Avycaz® and Zavicefta®.[6]

• Rationale and Mechanism of Avibactam: Avibactam is a novel, non-beta-lactam beta-lactamase inhibitor.[3] Its function is to covalently bind to and inactivate a broad range of serine beta-lactamases, thereby acting as a "shield" for Ceftazidime. The inhibitory spectrum of avibactam is extensive and clinically vital, covering Ambler Class A enzymes (which include ESBLs and KPC), Class C enzymes (like chromosomal AmpC), and some Class D enzymes (oxacillinases).[7] By neutralizing these enzymes, avibactam restores the intrinsic activity of Ceftazidime against many bacteria that had become resistant. It is important to note that avibactam does not inhibit metallo-beta-lactamases (MBLs) and does not enhance Ceftazidime's activity against bacteria where resistance is driven by other mechanisms, such as efflux pumps or altered PBPs. It also does not improve activity against Acinetobacter spp. or most anaerobes.[7]
• Approved Indications and Clinical Efficacy: The ceftazidime-avibactam combination is specifically indicated for more severe and complicated infections where resistant pathogens are likely to be involved [17]:
• Complicated Intra-abdominal Infections (cIAI), used in conjunction with metronidazole.
• Complicated Urinary Tract Infections (cUTI), including pyelonephritis.
• Hospital-Acquired Bacterial Pneumonia (HAP) and Ventilator-Associated Bacterial Pneumonia (VABP).
• It is also reserved as an option for infections caused by aerobic Gram-negative organisms in patients with limited alternative treatment options.

Clinical trials have demonstrated that ceftazidime-avibactam is as effective as carbapenem-based regimens for treating cIAI and cUTI, even when these infections are caused by cephalosporin-resistant isolates.[7]

This evolution effectively creates two distinct therapeutic agents for clinical consideration. "Classic" Ceftazidime remains a valuable, targeted therapy for infections known or strongly suspected to be caused by susceptible organisms. "Ceftazidime-avibactam" is a broader-spectrum agent reserved for the challenge of confirmed or highly suspected multi-drug resistant Gram-negative infections. They have different indications, different spectra of activity, and different places in antimicrobial stewardship protocols, representing a paradigm of how legacy antibiotics can be strategically repurposed to meet the contemporary challenges of resistance.

5.0 Dosing, Administration, and Patient Population Considerations

5.1 Available Formulations and Routes of Administration

Ceftazidime is available exclusively for parenteral use. It is supplied as a powder for injection in vials of various strengths, including 500 mg, 1 g, 2 g, and 6 g pharmacy bulk packages.[12] Premixed, frozen solutions of Ceftazidime in dextrose for IV infusion are also available.[9]

The standard routes of administration are intravenous (IV) and deep intramuscular (IM) injection.[1] For severe or life-threatening infections, such as sepsis or meningitis, the IV route is strongly preferred to ensure rapid and complete bioavailability.[29] Inadvertent intra-arterial administration must be avoided, as it has been associated with distal necrosis.[16]

IV administration can be performed as a slow bolus injection over 3 to 5 minutes or as an intermittent infusion, typically over 30 minutes.[9] In certain clinical settings, particularly in critically ill patients, extended infusions (e.g., over 3 to 4 hours) may be employed. This strategy aims to optimize the pharmacodynamic profile of the drug by maximizing the time that the free drug concentration remains above the minimum inhibitory concentration (MIC) of the target pathogen (

fT>MIC), which can improve efficacy against less susceptible organisms.[35]

5.2 Adult Dosing Regimens by Indication

Dosing for adults with normal renal function varies significantly based on the site and severity of the infection.

Table 4: Recommended Adult Dosing Regimens by Clinical Indication (Normal Renal Function)

Clinical Indication	Recommended Dose	Frequency	Route	Maximum Daily Dose	Source(s)
Usual Recommended Dosage	1 g	Every 8 to 12 hours	IV or IM	6 g	12
Uncomplicated UTI	250 mg	Every 12 hours	IV or IM	500 mg	11
Complicated UTI	500 mg	Every 8 to 12 hours	IV or IM	1.5 g	11
Uncomplicated Pneumonia / Mild Skin Infections	500 mg - 1 g	Every 8 hours	IV or IM	3 g	9
Bone and Joint Infections	2 g	Every 12 hours	IV	4 g	9
Severe Infections (cIAI, Gynecologic)	2 g	Every 8 hours	IV	6 g	9
Very Severe/Life-Threatening Infections (Meningitis, Sepsis, Febrile Neutropenia)	2 g	Every 8 hours	IV	6 g	9
Cystic Fibrosis Lung Infections (P. aeruginosa)	30 - 50 mg/kg	Every 8 hours	IV	6 g	11

5.3 Pediatric and Neonatal Dosing Guidelines

Dosing in pediatric populations requires careful consideration of age and, in neonates, gestational age and weight.

• Infants and Children (1 month to 12 years): The standard dosage is 30 to 50 mg/kg IV every 8 hours.[11] For severe infections such as meningitis, cystic fibrosis exacerbations, or in immunocompromised children, the dose can be increased up to 150 mg/kg/day, divided every 8 hours, not to exceed the maximum adult dose of 6 g/day.[12]
• Neonates (0 to 4 weeks): Dosing in this vulnerable population is complex. The FDA-approved label recommends a conservative dose of 30 mg/kg IV every 12 hours.[11] However, clinical practice guidelines often advocate for more nuanced, age- and weight-based regimens to ensure adequacy while minimizing risk:
• Postnatal Age 0-7 days: 50 mg/kg/dose IV every 12 hours is commonly recommended.[24]
• Postnatal Age >7 days: The dosing interval is typically shortened to every 8 hours (50 mg/kg/dose) for term infants or those weighing over 1200 g.[12]

5.4 Dosage Adjustments in Special Populations: Renal Impairment and Dialysis

Given that Ceftazidime is almost exclusively eliminated by the kidneys, dose modification in patients with renal impairment is mandatory to prevent the accumulation of the drug to toxic levels.[1] An initial loading dose of 1 g is generally recommended for adults to quickly achieve therapeutic concentrations, followed by adjusted maintenance doses.[34]

Table 5: Recommended Dosage Adjustments for Patients with Renal Impairment

Creatinine Clearance (CrCl) (mL/min)	Recommended Maintenance Dose	Dosing Frequency	Notes	Source(s)
> 50	Standard Dose (e.g., 1-2 g)	Every 8-12 hours	No adjustment needed.	34
31 - 50	1 g	Every 12 hours	For severe infections, 2 g every 12 hours may be used.	12
16 - 30	1 g	Every 24 hours	For severe infections, 2 g every 24 hours may be used.	12
6 - 15	500 mg - 1 g	Every 24 hours	Use lower end of range unless infection is severe.	28
< 5 (ESRD, not on dialysis)	500 mg - 1 g	Every 48 hours	Use lower end of range.	12
Hemodialysis (HD)	1 g	After each HD session	Administer a supplemental dose of 1 g post-dialysis.	12
Peritoneal Dialysis (PD/CAPD)	500 mg	Every 24 hours	After a 1 g loading dose. Can be added to dialysis fluid.	12
Continuous Renal Replacement Therapy (CRRT)	2 g	Every 12 hours	Dose may vary based on CRRT modality and intensity. Expert consultation is advised.	24

For pediatric patients with renal impairment, specific guidelines are less established, but the general principle is to extend the dosing interval based on the degree of impairment (e.g., to every 12, 24, or 48 hours) while using an age- and weight-appropriate dose.[12]

6.0 Safety, Tolerability, and Risk Management

6.1 Profile of Adverse Drug Reactions

Although generally considered well-tolerated, Ceftazidime is associated with a range of adverse drug reactions (ADRs), from common and mild to rare but life-threatening.[1]

Table 6: Clinically Significant Adverse Reactions to Ceftazidime by Frequency and System Organ Class

System Organ Class	Frequency	Adverse Reaction(s)	Source(s)
Local Reactions	Common (1% to 10%)	Pain, swelling, redness at injection site; Phlebitis, thrombophlebitis with IV administration.	1
Gastrointestinal	Common (1% to 10%)	Diarrhea.	37
	Uncommon (0.1% to 1%)	Nausea, vomiting, abdominal pain, antibiotic-associated colitis.	1
	Rare / Not Known	Clostridioides difficile-associated diarrhea (CDAD), pseudomembranous colitis.	1
Dermatologic / Hypersensitivity	Common (1% to 10%)	Maculopapular or urticarial rash.	15
	Uncommon (0.1% to 1%)	Pruritus (itching).	24
	Rare (<0.1%) / Very Rare	Angioedema, Anaphylaxis (can be life-threatening), Erythema multiforme, Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN).	12
Hematologic	Common (1% to 10%)	Eosinophilia, Positive direct Coombs' test.	31
	Uncommon (0.1% to 1%)	Thrombocytosis, thrombocytopenia, leukopenia, neutropenia.	12
	Very Rare (<0.01%)	Agranulocytosis, hemolytic anemia.	12
Nervous System	Uncommon (0.1% to 1%)	Headache, dizziness.	37
	Very Rare / Not Known	Neurological sequelae (strongly associated with renal impairment/overdose): Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis (flapping tremor), myoclonus (muscle twitching), neuromuscular excitability, confusion, hallucinations.	8
Hepatic	Common (1% to 10%)	Transient elevations in liver enzymes (ALT, AST, GGT, ALP).	37
	Very Rare (<0.01%)	Jaundice, hyperbilirubinemia.	16
Renal	Not Known	Renal impairment.	16
Infections	Uncommon (0.1% to 1%)	Candidiasis (oral thrush, vulvovaginitis).	31

6.2 Significant Warnings, Precautions, and Contraindications

The safe use of Ceftazidime requires awareness of its contraindications and adherence to several critical warnings and precautions.

Contraindication:

The only absolute contraindication is a history of a documented, severe hypersensitivity reaction (e.g., anaphylaxis) to Ceftazidime, any of its components, or any other cephalosporin antibiotic.1

Major Warnings (Equivalent to Black Box Warnings):

While not always presented in a formal "black box" on all labels, the following warnings are of the highest clinical importance:

1. Clostridioides difficile-Associated Diarrhea (CDAD): As with nearly all broad-spectrum antibacterial agents, Ceftazidime therapy alters the normal flora of the colon, which can lead to the overgrowth of C. difficile. This organism produces toxins A and B, which cause CDAD. The clinical presentation can range from mild, watery diarrhea to severe, fulminant, and potentially fatal colitis. CDAD must be considered in the differential diagnosis of any patient who develops diarrhea during or after antibiotic therapy, as onset can be delayed for up to two months post-treatment. If CDAD is suspected or confirmed, Ceftazidime should be discontinued if possible, and appropriate management (fluid/electrolyte replacement, protein supplementation, specific anti-C. difficile therapy) must be initiated.[14]
2. Neurological Adverse Reactions: This is the most significant dose-related toxicity of Ceftazidime. High and prolonged serum concentrations, which occur in patients with renal insufficiency who do not receive appropriate dose reductions, can lead to severe neurological sequelae. These include seizures, nonconvulsive status epilepticus (NCSE), encephalopathy (confusion, altered consciousness), coma, asterixis, and myoclonus. It is imperative that the dosage be adjusted based on creatinine clearance in all patients with renal impairment.[14]
3. Hypersensitivity Reactions: Serious, acute, and sometimes fatal hypersensitivity reactions, including anaphylaxis, can occur. Before initiating therapy, a careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Due to structural similarities, cross-hypersensitivity between penicillins and cephalosporins can occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction occurs, Ceftazidime must be discontinued immediately and appropriate emergency measures instituted.[1]

Precautions:

• Renal Impairment: Use with extreme caution and strictly follow the established guidelines for dose adjustment.[1]
• History of Gastrointestinal Disease: Prescribe with caution in individuals with a history of GI disease, particularly colitis, due to the increased risk of CDAD.[8]
• Seizure Disorders: Use with caution in patients with a history of seizures, as cephalosporins can lower the seizure threshold, especially when drug levels are elevated due to renal failure.[12]
• Hematologic Effects: Immune-mediated hemolytic anemia has been reported.[12] Cephalosporins can also be associated with a fall in prothrombin activity and hypoprothrombinemia. Prothrombin time (PT/INR) should be monitored in at-risk patients (e.g., those with renal or hepatic impairment, poor nutritional state, or on prolonged therapy), and exogenous vitamin K should be administered as indicated.[16]
• Superinfection: Prolonged or repeated use of Ceftazidime may result in the overgrowth of non-susceptible organisms, such as fungi (e.g., Candida) or Enterococcus species, leading to a secondary infection.[16]

6.3 Management of Overdose

An overdose of Ceftazidime primarily manifests as an exacerbation of its known neurological toxicities. Symptoms may include severe neuromuscular excitability, muscle spasms and twitching (myoclonus), seizures, encephalopathy (confusion, memory problems), and coma.[8] Management is supportive. In cases of significant overdose, particularly in patients with renal failure where the drug cannot be cleared, hemodialysis is an effective intervention to rapidly remove Ceftazidime from the circulation and can be life-saving.[10]

7.0 Drug and Disease Interactions

7.1 Clinically Significant Drug-Drug Interactions

Ceftazidime has several clinically relevant interactions that can affect its efficacy or safety profile.

Table 7: Major and Moderate Drug Interactions with Ceftazidime

Interacting Drug / Class	Severity of Interaction	Potential Effect	Recommended Management	Source(s)
Live Bacterial Vaccines (BCG, Cholera, Typhoid)	Major	Ceftazidime's antibacterial activity can inactivate the live vaccine, leading to vaccination failure.	Avoid co-administration. Separate administration by at least 24-48 hours after completing antibiotic course.	19
Nephrotoxic Agents (e.g., Aminoglycosides, Loop Diuretics like Furosemide)	Moderate	Potential for additive nephrotoxicity, increasing the risk of kidney damage.	Monitor renal function (serum creatinine, BUN) closely, especially with high-dose or prolonged therapy.	24
Warfarin	Moderate	May enhance the anticoagulant effect of warfarin, increasing the risk of bleeding.	Monitor prothrombin time (PT) and International Normalized Ratio (INR) frequently. Dose adjustment of warfarin may be necessary.	19
Oral Contraceptives (Estrogen/Progestin-based)	Moderate	May decrease the efficacy of oral contraceptives by altering gut flora and enterohepatic circulation of estrogens.	Advise patients to use an additional or alternative (non-hormonal) method of contraception during and for a short period after therapy.	8
Chloramphenicol	Moderate	In vitro studies have shown antagonism; chloramphenicol may interfere with the bactericidal activity of beta-lactams.	This combination is generally avoided in clinical practice due to the potential for reduced efficacy.	5

Unlike many other beta-lactam antibiotics, the pharmacokinetics of Ceftazidime are not significantly affected by probenecid. This confirms that its renal clearance is primarily via glomerular filtration and not active tubular secretion, so this common interaction does not apply.[5]

7.2 Critical Disease State Considerations

The presence of certain underlying medical conditions can significantly impact the safety and efficacy of Ceftazidime.

• Renal Dysfunction: This is the most critical disease interaction. As outlined extensively, failure to adjust the dose in patients with any degree of renal impairment will lead to drug accumulation and a high risk of severe neurotoxicity.[1] Furthermore, in clinical trials of ceftazidime-avibactam for complicated intra-abdominal infections, a decreased clinical response was noted in the subgroup of patients with a baseline CrCl of 30 to 50 mL/min, prompting specific dosing recommendations for that combination product.[13]
• Gastrointestinal Disease (especially Colitis): Patients with a history of colitis are at an increased risk of developing CDAD when treated with Ceftazidime. The drug should be prescribed with caution in this population.[8]
• Seizure Disorders: Cephalosporins, including Ceftazidime, can lower the seizure threshold. This risk is magnified in patients with a pre-existing seizure disorder, especially if the dose is not appropriately reduced for renal function.[12]
• Hepatic Disease: While Ceftazidime itself does not require dose adjustment for hepatic impairment, clinicians must be aware that patients with severe liver disease (e.g., cirrhosis) often have concomitant renal dysfunction (hepatorenal syndrome). Dosing must be based on the patient's renal function, regardless of their hepatic status.[1]
• Conditions Requiring Sodium Restriction: Formulations of Ceftazidime that contain sodium carbonate as an excipient contribute to the patient's total daily sodium load (approximately 54 mg or 2.3 mEq per gram of ceftazidime). This should be taken into account when treating patients with conditions such as congestive heart failure, severe hypertension, or fluid overload. Sodium-free formulations containing L-arginine are available and may be preferred in these patients.[5]

8.0 Concluding Analysis and Expert Recommendations

Ceftazidime remains a cornerstone antibiotic in the management of serious Gram-negative bacterial infections, particularly those caused by Pseudomonas aeruginosa. Its enduring value is anchored in its potent, targeted bactericidal activity and a generally favorable pharmacokinetic profile that includes excellent penetration into challenging sites like the CNS and bone. However, the comprehensive analysis of its properties reveals a critical duality: its high efficacy is counterbalanced by significant, predictable risks that demand a high level of clinical vigilance. The drug's safety profile is inextricably linked to its pharmacokinetic "Achilles' heel"—its near-total and exclusive reliance on renal clearance, with no alternative metabolic pathways.

This singular dependence on the kidneys means that any degree of renal impairment directly translates into a risk of accumulation and severe, dose-dependent neurotoxicity. This characteristic places Ceftazidime in a unique position, where its safe administration is less about the drug itself and more about the physiological state of the patient receiving it. The development of the ceftazidime-avibactam combination has successfully rejuvenated the molecule, restoring its utility against many multi-drug resistant pathogens and highlighting a key strategy in the ongoing fight against antimicrobial resistance.

Based on this comprehensive analysis, the following recommendations are provided to guide the optimal and safe clinical use of Ceftazidime:

1. Mandatory Renal Function Assessment: Ceftazidime should never be prescribed or administered without a recent assessment of the patient's renal function, ideally via a calculated creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR).
2. Strict Adherence to Renal Dosing Guidelines: Dosing must be rigorously adjusted according to established guidelines for any degree of renal impairment. The dosing tables provided in this monograph serve as a critical reference for this purpose. An initial loading dose followed by a reduced maintenance dose is the standard of care.
3. Vigilant Monitoring in High-Risk Patients: In critically ill, elderly, or hemodynamically unstable patients, renal function should be monitored frequently throughout the course of therapy. Clinicians must maintain a low threshold to re-evaluate and further reduce the dose if renal function declines.
4. Recognition of the Neurotoxicity Toxidrome: All healthcare professionals involved in the care of patients receiving Ceftazidime should be educated to recognize the signs of drug-induced neurotoxicity (e.g., new-onset confusion, myoclonus, asterixis, seizures). Ceftazidime toxicity should be high on the differential diagnosis for any patient who develops such symptoms, especially in the setting of renal impairment.
5. Judicious Use of Combination Products: The use of ceftazidime-avibactam should be reserved for the treatment of infections where resistant, beta-lactamase-producing Gram-negative organisms (e.g., ESBL, KPC producers) are confirmed or strongly suspected based on local epidemiology and patient risk factors. Its use for infections known to be susceptible to Ceftazidime alone constitutes poor antimicrobial stewardship, contributing to unnecessary costs and selective pressure.
6. Embrace Antimicrobial Stewardship Principles: To preserve the long-term efficacy of both Ceftazidime and its combination with avibactam, their use should always be guided by the principles of antimicrobial stewardship. This includes de-escalating to a narrower-spectrum agent when susceptibility results are available, using the shortest effective duration of therapy, and aligning prescribing practices with local antibiogram data.

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