Piperacillin + Tazobactam

ADMINISTRATION ROUTES:

IV

ALTERNATIVE NAMES:

Tazocin, PipTaz-AFT, Piperacillin/Tazobactam Kabi

ICU INDICATIONS:

1. Treatment of infections caused by susceptible organisms
2. Broad spectrum cover of hospital-acquired infections

PRESENTATION AND ADMINISTRATION:

IV:

4.5 g vial of powder (piperacillin 4 g + tazobactam 500 mg)

Note: Piperacillin + tazobactam should be administered by a continuous infusion in ICU. Give a loading dose, then start continuous infusion as indicated below. See DOSAGE below for details.

Reconstitution:

Reconstitute each vial with 17 mL of water for injection to make a total volume of 20 mL (approximate concentration of piperacillin + tazobactam 225 mg/mL). Reconstituted piperacillin + tazobactam is stable for 4 hours at 25 degrees.

Load / Intermittent IV dose:

Inject reconstituted solution over 3 - 5 mins. Alternatively, add dose to 50 – 100 mL of compatible fluid and administer over 20 – 30 mins.

For subsequent continuous infusions:

Make up the dose to 100 mL of compatible IV fluid and administer over 12 hours as per table below.

The diluted solution is stable for 24 hours at room temperature.

Note: Always adjust the volume to be infused (VTBI) on the infusion pump to account for any volume used to prime the IV line, e.g. if priming a line with 25 mL of medicine solution, the VTBI must be set as 75 mL. In this situation, the infusion will finish earlier than expected - do NOT alter the standard infusion rate of 8.3 mL/h. Any subsequent infusions will complete in 12 hours as prescribed.

When changing infusion lines, do NOT flush the remaining medication from the old line. Instead, discard the old line, prime a new line with the medicine solution, and connect it to a new medication bag.

Prescribed dose	Volume to remove from a 100 mL bag	Volume of reconstituted drug solution to add to bag	Final volume	Infusion rate for a 12-hour infusion
9 g	40 mL	40 mL	100 mL	8.3 mL/h
6.75 g	30 mL	30 mL	100 mL	8.3 mL/h
4.5 g	20 mL	20 mL	100 mL	8.3 mL/h

• If the infusion is paused for less than 3 hours, the rate must be increased so it completes within 12 hours of when it was initially commenced. If necessary, any remaining antibiotic that has not been infused at the 12 hour mark can be administered as a bolus.

• If the infusion is paused for 3 hours or more, a loading dose must be administered and the infusion restarted after the appropriate timing interval has passed (see DOSAGE section below).

Compatible with the following IV fluids:

Sodium chloride 0.9%, glucose 5%

Store at room temperature

DOSAGE:

IV:

ICU CONTINUOUS IV INFUSION

4.5 g load

9 g BD via 12-hour infusions

Start 3 hours after loading dose

Convert continuous infusions to intermittent IV doses when patient cleared for discharge from ICU or as appropriate. Give first intermittent dose as soon as the continuous infusion is stopped.

ICU INTERMITTENT IV DOSING

4.5 g TDS

Treatment can be started with intermittent IV dosing for patients who are likely to be discharged from ICU soon after initiation. Intermittent IV dosing can also be considered for patients who have difficult IV access: discuss with a pharmacist first as piperacillin + tazobactam may be compatible for Y-site administration with other infusions.

DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:

Continuous Infusion Dose in Renal Impairment/CRRT

GFR (ml/min)	Load	Continuous infusion (irrespective of indication)
20 - 40 or CVVHDF	4.5 g	6.75 g BD via 12 hour infusions. Start 4 hours after loading dose
< 20	4.5 g	4.5 g BD via 12 hour infusions. Start 6 hours after loading dose

For other modes of renal replacement therapy (intermittent haemodialysis, peritoneal dialysis) see intermittent dosing below.

Intermittent Dosing in Renal Impairment and RRT

GFR (ml/min) / CRRT mode	DOSE
20 - 40 or CVVHDF	4.5 g TDS
< 20	4.5 g BD

Intermittent IV dosing is used in all patients receiving intermittent haemodialysis (HD) or peritoneal dialysis (CAPD) as per table below.

MODALITY	DOSE
CAPD	4.5 g BD
HD	4.5 g BD. On dialysis days, ensure 2nd dose is given after dialysis session

DOSAGE IN PAEDIATRICS:

IV:

50 - 75 mg/kg 6 - 8 hourly

CLINICAL PHARMACOLOGY:

Piperacillin + tazobactam has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.

Aerobes, Gram-Positive:

• Staphylococcus aureus (excluding methicillin and oxacillin-resistant isolates)

Aerobes, Gram-Negative:

• Acinetobacter baumanii
• Escherichia coli
• Haemophilus influenzae (excluding beta-lactamase negative, ampicillin-resistant isolates)
• Klebsiella pneumoniae
• Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible)

Anaerobes, Gram-Negative:

• Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus)

The following in vitro data are available but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin + tazobactam. However, the safety and effectiveness of piperacillin + tazobactam in treating clinical infections due to these bacteria have not been established in adequate and well- controlled clinical trials.

Aerobes, Gram-Positive:

• Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)
• Staphylococcus epidermidis (excluding methicillin and oxacillin resistant isolates)
• Streptococcus agalactiae
• Streptococcus pneumoniae (penicillin-susceptible isolates only)
• Streptococcus pyogenes
• Viridans group streptococci

Aerobes, Gram-Negative:

• Citrobacter koseri
• Moraxella catarrhalis
• Morganella morganii
• Neisseria gonorrhoeae
• Proteus mirabilis
• Proteus vulgaris
• Serratia marcescens
• Providencia stuartii
• Providencia rettgeri
• Salmonella enterica

Anaerobes, Gram-Positive:

• Clostridium perfringens

Anaerobes, Gram-Negative:

• Bacteroides distasonis
• Prevotella melaninogenica

CONTRAINDICATIONS:

1. Hypersensitivity to piperacillin + tazobactam

WARNINGS:

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens.

There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam. Before initiating therapy with tazocin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens.

PRECAUTIONS:

General:

Bleeding manifestations have occurred in some patients receiving beta-lactam antibiotics, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure.

As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

Sodium content (up to 11.3 mmol per vial depending on the brand) should be considered in patients requiring sodium restriction and in those with unexplained hypernatraemia.

Laboratory Tests:

No tests in addition to routine ICU tests are required.

Drug/Laboratory Test Interactions:

None noted

IMPORTANT DRUG INTERACTIONS IN ICU:

None of note

ADVERSE REACTIONS:

General:

Fever, agitation, pain

Gastrointestinal:

Diarrhoea, nausea, vomiting, dyspepsia, constipation, stool changes, abdominal pain

Hepatobiliary:

Hepatic impairment, hepatitis, jaundice

CNS:

Insomnia, headache, anxiety, dizziness, delirium, encephalopathy, tonic-clonic seizures

Respiratory:

Rhinitis, dyspnoea, epistaxis

Cardiovascular:

Hypertension, chest pain, oedema, flushing

Dermatologic:

Pruritis, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis)

Endocrine & Metabolic:

Hypoglycemia

Neuromuscular & Skeletal:

Arthralgia, myalgia

Haematologic & Oncologic:

Agranulocytosis, bone marrow depression, hemolytic anemia, hemophagocytic lymphohistiocytosis, immune thrombocytopenia, pancytopenia, eosinophilia, leukopenia, neutropenia, pancytopenia, thrombocytopenia

Renal:

Acute kidney injury, interstitial nephritis, nephrotoxicity