ceftolozane/tazobactam (Rx)

>10% (HABP/VABP)

Increased hepatic transaminase (11.9%)

1-10% (cIAI or cUTI)

Nausea (2.8-7.9%)

Headache (2.5-5.8%)

Diarrhea (1.9-6.2%)

Pyrexia (1.7-5.6%)

Constipation (1.9-3.9%)

Insomnia (1.3-3.5%)

Vomiting (1.1-3.3%)

Hypokalemia (0.8-3.3%)

ALT increased (1.7-1.5%)

AST increased (1-1.7%)

Anemia (0.4-1.5%)

Thrombocytosis (0.4-1.9%)

Abdominal pain (0.8-1.2%)

Anxiety (0.2-1.9%)

Dizziness (0.8-1.1%)

Hypotension (0.4-1.7%)

Atrial fibrillation (0.2-1.2%)

Rash (0.9-1.7%)

1-10% (HABP/VABP)

Renal impairment/failure (8.9%)

Diarrhea (6.4%)

Intracranial hemorrhage (4.4%)

Vomiting (3.3%)

Clostridium difficile colitis (2.8%)

<1%

Cardiac disorders: Tachycardia, angina pectoris

Gastrointestinal disorders: Ileus, gastritis, abdominal distension, dyspepsia, flatulence, paralytic ileus

General disorders and administration site conditions: Infusion site reactions

Infections and infestations: Candidiasis candidiasis (including oropharyngeal and vulvovaginal), fungal urinary tract infection

Investigations: Increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, positive Coombs test

Metabolism and nutrition disorders: Hyperglycemia, hypomagnesemia, hypophosphatemia

Nervous system disorders: Ischemic stroke

Renal and urinary system: Renal impairment, renal failure

Respiratory, thoracic, and mediastinal disorders: Dyspnea

Skin and subcutaneous tissue disorders: Urticaria

Vascular disorders: Venous thrombosis

Contraindications

Hypersensitivity to any of the components

Cautions

Clinical cure rates lower in patients with baseline CrCl of 30 to ≤50 mL/min when compared with other antibiotics in clinical trials

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions reported with beta-lactam antibacterial agents

As with all antibiotics, Clostridium difficile-associated diarrhea (CDAD) has been reported; if suspected, discontinue and initiate prompt treatment for CDAD

Prescribing antibiotics in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria

Pregnancy

There are no data available on ceftolozane/tazobactam or its individual components regarding use in pregnant women to assess drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes

Human data: Although available studies with multiple cephalosporins cannot definitively establish absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association of cephalosporin use during pregnancy with major birth defects, miscarriage, or other adverse maternal or fetal outcomes

Lactation

There are no data on presence of either drug component in human milk; there are no data on effects of either drug component on breastfed infant, or on milk production

Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or from underlying maternal conditions

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Ceftolozane: Cephalosporin that has demonstrated potent in vitro activity against Pseudomonas aeruginosa

Tazobactam: Beta-lactamase inhibitor

Absorption

Day 1 measurements

Peak plasma time: 1.02 hr

Peak plasma concentration: 65.7/17.8 mcg/mL (cIAI, cUTI); 105/26.4 mcg/mL (HABP/VABP)

AUC: 186/35.8 mcg•h/mL (cIAI, cUTI); 392/73.3 mcg•h/mL (HABP/VABP)

Distribution

Protein bound: 16-21/30%

Vd: 13.5/18.2 L

Metabolism

Ceftolozane: Not metabolized to any appreciable extent

Tazobactam: The beta-lactam ring is hydrolyzed to form the pharmacologically inactive tazobactam metabolite M1

Elimination

Half-life: 2.77/0.91 hr

Renal clearance (ceftolozane): 3.41-5.59 L/hr

Excretion

• Ceftolozane: >95% excreted unchanged in urine
• Tazobactam: >80% excreted as the parent compound with the remainder excreted as the M1 metabolite

IV Compatibilities

Not established

IV Preparation

Reconstitute vial with 10 mL of sterile water for injection or 10 mL 0.9% NaCl and gently shake to dissolve

Final volume is ~11.4 mL

Must be further diluted; reconstituted solution is NOT for direct injection

Withdraw appropriate volume for dose (see list below) and add to 100 mL of 0.9% NaCl or D5W

Inspect for particulate matter and discoloration; color ranges from clear, colorless solutions to solutions that are clear and slightly yellow

Dose volume

• 3 g (2 g/1 g): 2 vials of 11.4 mL each (entire contents from 2 vials)
• 2.25 g (1.5 g/0.5 g): 11.4 mL from 1 vial (entire contents) and 5.7 mL from a second vial
• 1.5 g (1 g/0.5 g): 11.4 mL (entire vial contents)
• 750 mg (500 mg/250 mg): 5.7 mL
• 450 mg (300 mg/150 mg): 3.5 mL
• 375 mg (250 mg/125 mg): 2.9 mL
• 150 mg (100 mg/50 mg): 1.2 mL

IV Administration

Infuse IV over 1 hr

Storage

Unreconstituted vials: Store refrigerated 2-8°C (36-46°F); protect from light

Reconstituted vials: May keep at room temperature for 1 hr before transfer and dilution in infusion bag

Diluted solution (IV bag): Stable for 24 hr when stored at room temperature or 7 days when refrigerated at 2-8°C (36-46°F)

Do not freeze