Ceftolozane/ Tazobactam

Ceftolozane/ Tazobactam belongs to the pharmacological class of Fifth-generation cephalosporin antibiotics.

Ceftolozane/ Tazobactam has been approved to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infection, Pneumonia, Serious diseases due to multidrug-resistant P. aeruginosa, and Urinary tract infection.

After intravenous infusion, Ceftolozane plasma concentrations increase in a dose-dependent manner. The mean maximum concentration (Cmax) occurs at the end of infusion and ranges from 61 to 183 mg/L after single doses of 250 to 2,000 mg.The mean steady-state volume of distribution (Vss) is approximately 20 liters, indicating that Ceftolozane distributes widely throughout the body tissues. Ceftolozane protein binding is approximately 20%. Ceftolozane is not metabolized in humans. The mean elimination half-life is approximately 2.5 hours, and clearance ranges from 186 to 245 mL/min. Ceftolozane is primarily excreted unchanged in the urine, with approximately 80% of the dose recovered in the urine within 24 hours.

The common side effects involved in using Ceftolozane/ Tazobactam are Diarrhea, Nausea, Vomiting, Abdominal pain, Headache, Dizziness, Rash, Itching,.

Ceftolozane/ Tazobactam is available in the form of Ceftolozane/ Tazobactam is available in the form of Injectable.

Ceftolozane/ Tazobactam is approved in Germany, Japan, Malaysia, India, the U.K., U.S., and China.

Ceftolozane/ Tazobactam belongs to the pharmacological class of Fifth-generation cephalosporin antibiotics.

Ceftolozane works by interfering with bacterial cell wall synthesis, which leads to the death of susceptible gram-negative and gram-positive bacteria. Tazobactam, on the other hand, inhibits the beta-lactamase enzyme produced by bacteria, which makes them resistant to beta-lactam antibiotics. By combining ceftolozane and tazobactam, the therapeutic response is strengthened, as it provides activity against beta-lactamase enzyme-producing bacteria and a broader range of bacterial infections.

Ceftolozane/ Tazobactam has been approved to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infection,Pneumonia,Serious infections due to multidrug-resistant P. aeruginosa,Urinary tract infection.

The maximum plasma concentration (Cmax) of ceftolozane occurs approximately 1 hour after intravenous administration. The time to reach Cmax (Tmax) is also around 1 hour. The onset of action of ceftolozane is rapid, with therapeutic effects observed within a few hours after administration. The duration of action of ceftolozane varies depending on the indication being treated and the patient's clinical status. In general, the drug is administered every 8 hours for 5 to 14 days for the treatment of infections, with the duration of therapy depending on the clinical response.

Ceftolozane/ Tazobactam is found to be available in the form of Injectable.

Ceftolozane/ Tazobactam can be used in the following treatment:

• Intra-abdominal infection
• Pneumonia
• Serious infections due to multidrug-resistant P. aeruginosa
• Urinary tract infection

Ceftolozane/ Tazobactam can help to relieve symptoms and also for the treatment and maintenance of Intra-abdominal infection, Pneumonia,Serious infections due to multidrug-resistant P. aeruginosa, Urinary tract infection.

Ceftolozane/ Tazobactam is approved for use in the following clinical indications:

• Intra-abdominal infection
• Pneumonia
• Serious infections due to multidrug-resistant P. aeruginosa
• Urinary tract infection

• Intra-abdominal infection (alternative agent):

For adults, the recommended dose of Ceftolozane is 1.5 to 3 g every 8 hours intravenously in combination with metronidazole. The total duration of therapy, including transition to oral antibiotics, is 4 to 5 days after adequate source control.

• Pneumonia, hospital-acquired or ventilator-associated (alternative agent):

For adults, the recommended dose of Ceftolozane is 3 g every 8 hours intravenously. The duration of therapy varies based on disease severity and response to therapy, but it is typically given for 7 days.

• Serious infections due to multidrug-resistant P. aeruginosa (off-label use):

For adults, the recommended dose of Ceftolozane is 1.5 to 3 g every 8 hours intravenously for serious infections caused by multi drug-resistant P. aeruginosa, such as bloodstream infections, skin and soft tissue infections, and pulmonary infections.

• Urinary tract infection, complicated (pyelonephritis or urinary tract infection with systemic signs/symptoms):

For adults, the recommended dose of Ceftolozane is 1.5 g every 8 hours intravenously. Once symptoms improve, switch to an appropriate oral regimen, if culture and susceptibility results allow. The total duration of therapy ranges from 5 to 14 days, depending on clinical response and the antimicrobial chosen to complete the regimen.

Injection: Ceftolozane/ Tazobactam powder for solution for infusion in vials or pre-filled syringes with various strengths, including 1.5 g, 3 g, and 4.5 g.

Injectable

• Dosage Adjustments in Kidney Patients:

For the treatment of complicated intra-abdominal infections (cIAI) or complicated urinary tract infections (cUTI), the recommended dosages of ceftolozane- tazobactam depend on the patient's creatinine clearance (CrCl) levels. In patients with CrCl levels of 30-50 mL/min, the recommended dose is 750 mg (500 mg/250 mg) administered intravenously every 8 hours.

For patients with CrCl levels of 15-29 mL/min, the recommended dose is 375 mg (250 mg/125 mg) administered intravenously every 8 hours.

For end-stage renal disease (ESRD) patients who are on hemodialysis, a single loading dose of 750 mg (500 mg/250 mg) is given, followed by a maintenance dose of 150 mg (100 mg/50 mg) every 8 hours for the rest of the treatment period. On hemodialysis days, the dose should be given as soon as possible after completion of dialysis.

For the treatment of hospital-acquired and ventilator-associated pneumonia (HABP/VABP), the recommended dosages of ceftolozane- tazobactam also depend on the patient's CrCl levels. In patients with CrCl levels of 30-50 mL/min, the recommended dose is 1.5 g (1 g/0.5 g) administered intravenously every 8 hours.

For patients with CrCl levels of 15-29 mL/min, the recommended dose is 750 mg (500 mg/250 mg) administered intravenously every 8 hours.

For ESRD patients who are on hemodialysis, a single loading dose of 2.25 g (1.5 g/0.75 g) is given, followed by a maintenance dose of 450 mg (300 mg/150 mg) every 8 hours for the rest of the treatment period. On hemodialysis days, the dose should be given as soon as possible after completion of dialysis.

• Dosage Adjustments in Pediatric Patients:

Intra-abdominal infection:

Infants, Children, and Adolescents <18 years: IV: 20 mg ceftolozane/kg/dose every 8 hours in combination with metronidazole for 5 to 14 days; maximum dose: 1,000 mg ceftolozane per dose.

Adolescents ≥18 years: IV: 1,000 mg ceftolozane every 8 hours in combination with metronidazole for 4 to 14 days.

Pneumonia, hospital-acquired or ventilator-associated:

Adolescents ≥18 years: IV: 2,000 mg ceftolozane every 8 hours for 8 to 14 days.

Urinary tract infection, complicated:

Infants, Children, and Adolescents <18 years: IV: 20 mg ceftolozane/kg/dose every 8 hours for 7 to 14 days; maximum dose: 1,000 mg ceftolozane per dose.

Adolescents ≥18 years: IV: 1,000 mg ceftolozane every 8 hours for 7 days.

There are no specific dietary restrictions related to the use of Ceftolozane/Tazobactam. However, it is important to note that certain foods or beverages may interact with the medication or worsen certain side effects. For example, consuming alcohol may increase the risk of liver damage and should be avoided during treatment with Ceftolozane/Tazobactam. Additionally, some patients may experience gastrointestinal side effects such as nausea and vomiting, which may be aggravated by certain foods or spices.

Ceftolozane/ Tazobactam may be contraindicated under the following conditions:

• In patients with known hypersensitivity to Ceftolozane/ Tazobactam, cephalosporin, penicillin, or any component of the formulation.

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

Decreased Efficacy in the Patients with Baseline Creatinine Clearance of 30 to ≤50 mL/min

In a Phase 3 clinical trial for complicated intra-abdominal infections (cIAI), patients with baseline creatinine clearance (CrCl) of 30 to ≤50 mL/min had lower clinical cure rates compared to those with CrCl >50 mL/min. The reduction in the clinical cure rates was more significant in patients receiving Ceftolozane/ Tazobactam plus metronidazole than in those receiving meropenem. A similar trend was observed in the clinical trial for complicated urinary tract infections (cUTI). Therefore, patients' CrCl should be monitored at least daily, especially those with changing renal function, and the dosage of Ceftolozane/ Tazobactam should be adjusted accordingly.

Hypersensitivity Reactions

Beta-lactam antibiotics have been associated with serious and occasionally fatal hypersensitivity (anaphylactic) reactions. Before starting therapy with Ceftolozane/ Tazobactam, a careful inquiry about previous hypersensitivity reactions to cephalosporin, penicillin, or other beta-lactams should be made. Caution should be exercised when giving the drug to patients with a history of cephalosporin, penicillin, or other beta-lactam allergy since cross-sensitivity has been established. If an anaphylactic reaction occurs, Ceftolozane/ Tazobactam should be discontinued, and appropriate therapy should be initiated.

Clostridium difficile-associated Diarrhea

Nearly all systemic antibacterial agents, including Ceftolozane/ Tazobactam, have been associated with Clostridium difficile-associated diarrhea (CDAD), which can range from mild diarrhea to fatal colitis. Treatment with the antibacterial agents alters the normal flora of the colon and may lead to the overgrowth of C. difficile, which produces toxins A and B that contribute to the development of CDAD. Therefore, CDAD should be considered in all patients who present with diarrhea following antibacterial use. A careful medical history is necessary because Clostridium difficile-associated Diarrhea has been reported to occur more than 2 months after the administration of antibacterial agents. If Clostridium difficile-associated Diarrhea is confirmed, antibacterial not directed against C. difficile should be discontinued if possible. Fluid and electrolyte levels should be managed appropriately, protein intake should be supplemented, antibacterial treatment of C. difficile should be monitored, and surgical evaluation should be instituted as clinically indicated.

Development of Drug-Resistant Bacteria

Prescribing Ceftolozane/ Tazobactam in the absence of a proven or strongly suspected bacterial infection is not likely to benefit the patient and risks the development of drug-resistant bacteria.

There is no known interaction between Ceftolozane/ Tazobactam and alcohol. However, as alcohol consumption can impair the immune system and increase the risk of infections, it is generally recommended to avoid excessive alcohol intake during treatment with any antibiotic, including Ceftolozane/ Tazobactam.

The safety and effectiveness of Ceftolozane/ Tazobactam have not been established in pediatric patients.

Pregnancy Category B

Ceftolozane/ Tazobactam (ceftolozane and tazobactam) has not been adequately studied in pregnant women, and animal reproduction studies may not always predict human response. Therefore, Ceftolozane/ Tazobactam should only be used during pregnancy if the potential benefits outweighs the possible risk.

There are no known food interactions with ceftolozane/ tazobactam. However, it is recommended to take this medication with food to improve its absorption and reduce the risk of gastrointestinal side effects.

The adverse reactions related to Ceftolozane/ Tazobactam can be categorized as follows:

Common:

• Nausea
• Diarrhea
• Headache
• Pyrexia (fever)
• Infusion site reactions, such as phlebitis (inflammation of a vein)

Less Common:

• Vomiting
• Constipation
• Rash
• Insomnia
• Dizziness
• Abdominal pain
• Increased liver enzymes

Rare:

• Anaphylaxis (a severe, life-threatening allergic reaction)
• Clostridioides difficile infection (a type of bacterial infection that can cause severe diarrhea and inflammation of the colon)
• Stevens-Johnson syndrome (a rare, serious disorder of the skin and mucous membranes)
• Toxic epidermal necrolysis (a severe, life-threatening skin condition that causes the skin to blister and peel)
• Seizures
• Peripheral neuropathy (nerve damage in the arms and legs)
• Hemolytic anemia (a type of anemia that occurs when red blood cells are destroyed faster than they are produced).

The clinically relevant drug interactions of Ceftolozane/ Tazobactam is briefly summarized here:

Probenecid: Probenecid can increase the plasma concentration of Ceftolozane/ Tazobactam by inhibiting its renal tubular secretion. Therefore, caution should be exercised when administering these drugs together.

Valproic Acid: Ceftolozane/ Tazobactam may decrease the serum concentration of valproic acid. Therefore, it is recommended to monitor the serum concentration of valproic acid when these drugs are co-administered.

Warfarin: Ceftolozane/ Tazobactam may increase the anticoagulant effect of warfarin. Therefore, it is recommended to monitor the prothrombin time or INR when these drugs are co-administered.

Oral Contraceptives: Ceftolozane/ Tazobactam may reduce the efficacy of oral contraceptives. Therefore, patients should be advised to use alternative contraceptive methods during treatment with Ceftolozane/Tazobactam.

Live Vaccines: Ceftolozane/ Tazobactam may interfere with the response to live vaccines. Therefore, it is recommended to avoid live vaccines during treatment with Ceftolozane/Tazobactam.

The following are the side effects involving Ceftolozane/ Tazobactam:

• Nausea
• Diarrhea
• Headache
• Constipation
• Rash
• Vomiting
• Insomnia
• Increased liver enzymes
• Increased blood creatinine levels
• Anemia
• Hypokalemia
• Hypomagnesemia
• Clostridioides difficile infection
• Hypersensitivity reactions
• Injection site reactions

Pregnancy:

Pregnancy Category B

Ceftolozane/ Tazobactam (ceftolozane and tazobactam) has not been adequately studied in pregnant women, and animal reproduction studies may not always predict human response. Therefore, Ceftolozane/ Tazobactam should only be used during pregnancy if the potential benefit outweighs the possible risk.

• Nursing Mothers

It is not known if ceftolozane or tazobactam is excreted in human milk. Due to the possibility of adverse effects on nursing infants, caution should be exercised when administering Ceftolozane/ Tazobactam to a nursing woman.

• Pediatric Use

The safety and effectiveness of Ceftolozane/ Tazobactam have not been established in pediatric patients.

• Geriatric Use

Of the 1015 patients treated with Ceftolozane/ Tazobactam in the Phase 3 clinical trials, 250 (24.6%) were 65 years or older, including 113 (11.1%) who were 75 years or older. The incidence of adverse events was higher in older subjects (65 years or older) in the trials for both indications. In elderly patients with cIAI, the cure rates were lower in the Ceftolozane/ Tazobactam plus metronidazole arm compared to the comparator arm. Ceftolozane/ Tazobactam is eliminated by the kidney, and the risk of adverse reactions may be higher in patients with impaired renal function, including elderly patients. Dosage adjustment may be necessary for elderly patients based on renal function.

Physicians should be knowledgeable and vigilant about the treatment and identification of over dosage of Ceftolozane/ Tazobactam.

In the event of an overdose of Ceftolozane/ Tazobactam, it is crucial to discontinue the medication and provide general supportive treatment. Prompt medical attention should be sought to prevent potentially life-threatening complications.

Hemodialysis is a potential treatment option for Ceftolozane/ Tazobactam overdose. Studies have shown that approximately 66% of ceftolozane, 56% of tazobactam, and 51% of the tazobactam metabolite M1 can be removed from the body through hemodialysis. However, there is limited information available on the use of hemodialysis specifically for Ceftolozane/ Tazobactam overdose, and it should only be considered on a case-by-case basis by a healthcare professional. Close monitoring and appropriate management are necessary for any patient receiving hemodialysis for a potential Ceftolozane/ Tazobactam overdose.

Pharmacodynamics

The combination of ceftolozane and tazobactam provides therapeutic benefits by increasing the range of bacterial infections that can be treated effectively. This is particularly important in cases where bacterial infections are resistant to beta-lactam antibiotics. The addition of tazobactam allows for the effective treatment of infections caused by these resistant organisms, leading to improved patient outcomes.

Pharmacokinetics

Pharmacokinetic Parameters:

• Absorption

The maximum plasma concentration (Cmax) and area under the curve (AUC) of Ceftolozane/ Tazobactam increase proportionally to the dose. However, repeated intravenous infusions of up to 2 g/1 g (ceftolozane/tazobactam) every 8 hours for 10 days in healthy adults with normal renal function did not significantly increase plasma levels of Ceftolozane/Tazobactam. Furthermore, the elimination half-life (t½) of ceftolozane is dose-independent.

• Distribution

Ceftolozane and tazobactam bind to human plasma proteins at approximately 16-21% and 30%, respectively. The steady-state volume of distribution of Ceftolozane/ Tazobactam in healthy adult males following a single 1 g/0.5 g intravenous dose was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, which is similar to extracellular fluid volume.

• Metabolism

Ceftolozane is found to be eliminated in the urine as unchanged parent drug, indicating that it is not metabolized significantly. On the other hand, the beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive tazobactam metabolite M1.

• Excretion

Ceftolozane and the tazobactam metabolite M1 are eliminated by the kidneys. More than 95% of ceftolozane was excreted in the urine as unchanged parent drug, and more than 80% of tazobactam was excreted as the parent compound, with the remaining amount excreted as the tazobactam M1 metabolite. After a single dose of Ceftolozane/Tazobactam, renal clearance of ceftolozane was similar to plasma clearance, suggesting that ceftolozane is found to be eliminated by the kidney via glomerular filtration.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206829lbl.pdf
• https://www.ema.europa.eu/en/documents/product-information/zerbaxa-epar-product-information_en.pdf
• https://go.drugbank.com/drugs/DB09050
• https://reference.medscape.com/drug/zerbaxa-ceftolozane-tazobactam-999969
• https://pubchem.ncbi.nlm.nih.gov/compound/Ceftolozane