Piperacillin/ tazobactam

Piperacillin/ tazobactam belonging to the penicillin antibiotic and a β-lactamase inhibitor. respectively, used to treat Bloodstream infection, Cystic fibrosis, Diabetic foot infection, Intra-abdominal infection, Malignant external otitis, Neutropenic fever, Pneumonia ,Sepsis and septic shock, Skin and soft tissue infection ,Urinary tract infection.

Piperacillin and sulbactam are both beta-lactam antibiotics that are administered intravenously in combination to treat various infections. After intravenous administration, piperacillin and sulbactam are rapidly distributed to various tissues and body fluids. The volume of distribution for piperacillin is approximately 0.2 L/kg, and for sulbactam, it is approximately 0.14 L/kg. Both drugs are highly bound to plasma proteins, with piperacillin being approximately 20% protein-bound and sulbactam being approximately 38% protein-bound. The combination of piperacillin and sulbactam is metabolized in the liver and excreted in the urine. The half-life of piperacillin is approximately one hour, while the half-life of sulbactam is approximately 1.5 hours. In patients with impaired renal function, the elimination half-life of both drugs is prolonged.

Piperacillin/ tazobactam is available in the form of injection, lyophilized powder for reconstitution and premixed bag.

Piperacillin/ tazobactam is available in United States, Canada, United Kingdom, Australia, Germany, France, Italy, Spain, Japan, South Korea, and many others.

Piperacillin Sodium/Tazobactam Sodium Powder for Injection is a sterile injectable antibacterial combination that contains piperacillin sodium and tazobactam sodium for intravenous administration. It is a broad-spectrum antibiotic combined with a β-lactamase inhibitor. The bactericidal activity of piperacillin sodium is due to its ability to inhibit septum formation and cell wall synthesis by blocking the terminal transpeptidation step of cell wall peptidoglycan biosynthesis in susceptible organisms through interaction with the penicillin binding proteins. Piperacillin is effective against various gram-positive and gram-negative aerobic and anaerobic bacteria, as demonstrated in vitro.

Cmax (maximum concentration in blood plasma) of piperacillin is achieved within 30 minutes of intravenous infusion, while tazobactam Cmax is achieved within 1 hour of infusion.

The onset of action is relatively fast, with noticeable antibacterial effects occurring within a few hours of administration.

The duration of action varies depending on the dosage administered, ranging from 4 to 6 hours for lower doses and up to 8 hours for higher doses.

Piperacillin/ tazobactam is available in the form of injection, lyophilized powder for reconstitution and premixed bag.

Piperacillin/ tazobactam is a combination antibiotic medication that is used to treat a variety of Bloodstream infection, Cystic fibrosis, Diabetic foot infection, Intra-abdominal infection, Malignant external otitis, Neutropenic fever, Pneumonia ,Sepsis and septic shock, Skin and soft tissue infection ,Urinary tract infection.

Piperacillin/ tazobactam has several benefits, including:

1. Broad-spectrum coverage: It covers a wide range of bacteria, including both gram-positive and gram-negative organisms.
2. Synergistic effect: Tazobactam enhances the activity of piperacillin against beta-lactamase-producing bacteria.
3. Effective against resistant strains: It is effective against many antibiotic-resistant bacteria, including Pseudomonas aeruginosa.
4. Well-tolerated: It is generally well-tolerated, with a low incidence of side effects.
5. Versatile: It can be administered by intravenous infusion or injection and is available in a variety of dosages to treat different infections.
6. Rapid onset of action: It has a fast onset of action, making it a useful treatment option for serious infections.
7. Cost-effective: It is a cost-effective treatment option compared to other broad-spectrum antibiotics.

Piperacillin/ tazobactam is approved for use in the following clinical indications:

• Bloodstream infection
• Cystic fibrosis
• Diabetic foot infection
• Intra-abdominal infection
• Malignant external otitis
• Neutropenic fever
• Pneumonia
• Sepsis and septic shock
• Skin and soft tissue infection
• Urinary tract infection

Bite wound infection, treatment: 3.375g (3g/375mg) IV every 6 hours

Bloodstream infection: 3.375g (3g/375mg) IV every 6 hours

Cystic fibrosis, severe acute pulmonary exacerbation or failure of oral therapy, for coverage of P. aeruginosa: 4.5g (4g/500mg) IV every 6 hours

Diabetic foot infection, moderate to severe: 3.375g (3g/375mg) IV every 6 hours

Intra-abdominal infection: 4.5g (4g/500mg) IV every 6 hours

Malignant external otitis, hospitalized patients: 4.5g (4g/500mg) IV every 6 hours

Neutropenic fever, high-risk cancer patients: 4.5g (4g/500mg) IV every 8 hours

Pneumonia: 4.5g (4g/500mg) IV every 6 hours

Sepsis and septic shock: 4.5g (4g/500mg) IV every 6 hours

Skin and soft tissue infection, moderate to severe: 4.5g (4g/500mg) IV every 6 hours

Urinary tract infection, complicated: 3.375g (3g/375mg) IV every 6 hours.

The combination of Piperacillin/ tazobactam is available as following strengths:

• Injection, lyophilized powder for reconstitution available in various strengths and quantities:
• (2g/250mg)/vial: 2.25g
• (3g/375mg)/vial: 3.375g
• (4g/500mg)/vial: 4.5g
• (36g/4.5g)/vial: 40.5g
• Premix bags available in the following strengths and quantities:
• 2.25g/50mL
• 3.375g/50mL
• 4.5g/100mL

The available dosage forms for Piperacillin/ tazobactam include injection, lyophilized powder for reconstitution and premixed bag.

• Dosage Adjustment in Kidney Patient

Dosage adjustments are necessary for patients with renal impairment who are using Piperacillin/ tazobactam combination. The dose of Piperacillin/ tazobactam should be reduced in patients with creatinine clearance (CrCl) of less than 40 mL/min. In patients with severe renal impairment, the dose should be reduced to 2.25 g every 12 hours. For patients undergoing hemodialysis, a supplemental dose of 2.25 g should be given at the end of each dialysis session. It is important to monitor renal function in patients receiving Piperacillin/ tazobactam, especially those with pre-existing renal disease, as the drug can cause nephrotoxicity. Dosage adjustment is not necessary in patients with mild to moderate renal impairment (CrCl greater than 40 mL/min).

There are no specific dietary restrictions associated with the use of the tazobactam/piperacillin combination in the US.

Piperacillin/ tazobactam is contraindicated in patients with

• Piperacillin/ tazobactam should not be administered to patients who have a past record of hypersensitivity reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors, as it is considered contraindicated.

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

Hypersensitivity Adverse Reactions

• Patients who are undergoing treatment with Piperacillin/ tazobactam may experience serious and potentially fatal hypersensitivity reactions, including anaphylactic or anaphylactoid reactions leading to shock. These reactions are more likely to occur in individuals who have a history of hypersensitivity to penicillins, cephalosporins, carbapenems, or multiple allergens.
• Prior to starting treatment with Piperacillin/ tazobactam, it is important to carefully investigate the patient's medical history for any prior instances of hypersensitivity reactions.
• In the event of an allergic reaction, Piperacillin/ tazobactam should be discontinued immediately, and the patient should receive appropriate medical treatment.

Severe Cutaneous Adverse Reactions

• Piperacillin/ tazobactam has the potential to cause severe cutaneous adverse reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms. Patients should be closely monitored if a skin rash develops, and Piperacillin/ tazobactam should be discontinued immediately if the lesions progress.
• Bleeding manifestations, including abnormalities of coagulation tests such as platelet aggregation, clotting time, and prothrombin time, have been reported in some patients receiving β-lactam drugs, including piperacillin. These reactions are more common in patients with renal failure.
• If bleeding manifestations occur, appropriate therapy should be instituted, and Piperacillin/ tazobactam should be discontinued.
• The leukopenia/neutropenia associated with Piperacillin/ tazobactam treatment appears to be reversible and is usually associated with prolonged administration.
• Regular assessment of hematopoietic function should be performed, especially with prolonged therapy, i.e., ≥ 21 days.

Central Nervous System Adverse Reactions

• Intravenous administration of higher than recommended doses of Piperacillin/ tazobactam may lead to neuromuscular excitability or convulsions, particularly in the presence of renal failure, similar to other penicillins.

Nephrotoxicity in Critically Ill Patients

• In a randomized, multicenter, controlled trial involving critically ill patients, Piperacillin/ tazobactam was identified as an independent risk factor for renal failure and was linked to slower recovery of renal function compared to other beta-lactam antibacterial drugs.
• Therefore, in critically ill patients, other treatment options should be considered instead of Piperacillin/ tazobactam.

• If other treatment options are insufficient or unavailable, monitoring of renal function is recommended during the use of Piperacillin/ tazobactam.

Electrolyte Effects

• Piperacillin/ tazobactam combination product has a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin
• Clinicians should take this into account when treating patients who require limited salt intake.
• Patients with low potassium reserves should undergo periodic electrolyte determinations, and healthcare providers should consider the possibility of hypokalemia in patients who have potentially low potassium reserves and are receiving diuretics or cytotoxic therapy.

Clostridium difficile Associated Diarrhea

• The incidence of Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of most antibacterial agents, including Piperacillin/ tazobactam.
• Therefore, in patients who present with diarrhea following the use of antibacterial drugs, CDAD should be considered, and a careful medical history is necessary as CDAD may occur up to 2 months after the administration of antibacterial agents.
• If CDAD is suspected or confirmed, ongoing antibacterial drug use that is not directed against C. difficile may need to be discontinued, and appropriate management should be instituted, including fluid as well as electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and also surgical evaluation, as clinically indicated.

There is no known interaction between alcohol and the use of Piperacillin/ tazobactam combination. However, it is generally recommended to avoid alcohol while taking antibiotics as it may interfere with the effectiveness of the medication and can also increase the risk of side effects such as gastrointestinal upset and liver damage.

Small amounts of piperacillin are eliminated in breast milk while there is no information available on tazobactam levels in breast milk. It is advised to exercise caution when administering Piperacillin/ tazobactam (piperacillin and tazobactam for injection, USP) to lactating mothers.

Pregnancy Category B

Animal studies have demonstrated that Piperacillin/ tazobactam does not impair fertility or cause harm to the fetus. In mice and rats, piperacillin and tazobactam were both found to be safe at doses up to 2 to 3 times and 3 times the maximum recommended human daily dose based on body-surface area (mg/m2), respectively. Although tazobactam was found to cross the placenta in rats, the concentration in the fetus was only up to 10% of that found in maternal plasma.

Limited data is available on the use of Piperacillin/ tazobactam in pregnant women, and there are no adequate and well-controlled studies on its use during pregnancy. As animal studies may not accurately predict the effects on humans, the drug should only be used during pregnancy if the benefits clearly outweigh the potential risks.

There is a potential for food-drug interactions with the Piperacillin/ tazobactam combination, as certain foods may affect the absorption or metabolism of the drug. It is recommended to take the medication on an empty stomach, at least one hour before or two hours after a meal, to minimize the risk of food-drug interactions. However, if gastrointestinal upset occurs, the medication may be taken with food.

The adverse reactions related to Piperacillin/ tazobactam can be categorized as follows:

Common

• Diarrhea
• Nausea
• Rash
• Injection site reactions
• Vomiting
• Abdominal pain

Less common

• Headache
• Dizziness
• Fever
• Itching
• Joint pain
• Muscle pain
• Vaginal discharge or itching
• Changes in taste
• Yeast infection
• Thrush (oral yeast infection)

Rare

• Allergic reactions (including anaphylaxis)
• Blood disorders (such as anemia, thrombocytopenia)
• Liver problems (including hepatitis, jaundice)
• Kidney problems (including interstitial nephritis)
• Seizures (particularly with high doses or in patients with kidney problems)
• Clostridium difficile-associated diarrhea (a potentially life-threatening infection of the colon)

The clinically relevant drug interactions of Piperacillin/ tazobactam are briefly summarized here:

Aminoglycosides Inactivation:

When given with piperacillin, aminoglycosides may be converted into microbiologically inert amides, leading to reduced concentrations in the body, especially in patients with end-stage renal disease requiring hemodialysis. Thus, monitoring is necessary.

In Vitro Inactivation:

Piperacillin can also inactivate aminoglycosides in vitro. Therefore, Piperacillin/ tazobactam (a combination of piperacillin and tazobactam) and aminoglycosides should be administered separately. However, amikacin and gentamicin can be given simultaneously with Piperacillin/ tazobactam in certain diluents and at specific concentrations, but not tobramycin.

Probenecid:

When given concomitantly with Piperacillin/ tazobactam, probenecid inhibits the tubular renal secretion of piperacillin and tazobactam, leading to an increased half-life of both drugs. Thus, co-administration should be avoided unless the benefits outweigh the risks.

Vancomycin:

Increased incidence of acute kidney injury has been reported in patients administered with both Piperacillin/ tazobactam and vancomycin, as compared to vancomycin alone. Therefore, kidney function should be monitored in patients receiving this combination therapy.

Anticoagulants:

When high doses of heparin, oral anticoagulants, or other drugs that affect the blood coagulation system or the thrombocyte function are used concomitantly with Piperacillin/ tazobactam, coagulation parameters should be tested more frequently and monitored regularly.

Vecuronium:

Concomitant use of piperacillin and vecuronium may prolong the neuromuscular blockade of vecuronium, and thus monitoring for adverse reactions related to neuromuscular blockade is necessary.

Methotrexate:

Limited data suggest that concurrent use of piperacillin and methotrexate may reduce the clearance of methotrexate due to competition for renal secretion. Therefore, serum concentrations of methotrexate and signs and symptoms of methotrexate the toxicity should be frequently monitored if concurrent therapy is necessary.

The common side effects of Piperacillin/ tazobactam include the following:

• Diarrhea
• Nausea
• Vomiting
• Rash
• Itching
• Swelling
• Hives
• Fever
• Chills
• Joint pain
• Dizziness
• Headache
• Confusion
• Seizures
• Abdominal pain
• Dark urine
• Yellowing of the skin or eyes (jaundice)
• Easy bruising or bleeding
• Unusual tiredness or weakness

• Pregnancy

Pregnancy Category B

Animal studies have demonstrated that Piperacillin/ tazobactam does not impair fertility or cause harm to the fetus. In mice and rats, piperacillin and tazobactam were both found to be safe at doses up to 2 to 3 times and 3 times the maximum recommended human daily dose based on body-surface area (mg/m2), respectively. Although tazobactam was found to cross the placenta in rats, the concentration in the fetus was only up to 10% of that found in maternal plasma.

Limited data is available on the use of Piperacillin/ tazobactam in pregnant women, and there are no adequate and well-controlled studies on its use during pregnancy. As animal studies may not accurately predict the effects on humans, the drug should only be used during pregnancy if the benefits clearly outweigh the potential risks.

• Nursing Mothers

Small amounts of piperacillin are eliminated in breast milk while there is no information available on tazobactam levels in breast milk. It is advised to exercise caution when administering Piperacillin/ tazobactam (piperacillin and tazobactam for injection, USP) to lactating mothers.

• Pediatric Use

There is evidence from well-controlled and pharmacokinetic studies in adults and pediatric patients to support the use of Piperacillin/ tazobactam in pediatric patients who are at least 2 months of age and have appendicitis and/or peritonitis. Among these studies is a clinical trial involving 542 pediatric patients between 2-12 years old with complicated intra-abdominal infections, in which 273 patients received Piperacillin/ tazobactam. However, the safety and efficacy of this drug in pediatric patients aged less than 2 months is unknown and requires further research. Dosage recommendations for Piperacillin/ tazobactam in pediatric patients with impaired renal function are not available.

• Geriatric Use

Advanced age alone does not increase the risk of adverse effects in patients over 65 years old. However, dosage adjustments should be made for those with renal insufficiency. When selecting a dose for elderly patients, caution should be exercised by starting at the lower end of the dosing range due to the higher likelihood of decreased hepatic, renal, or cardiac function, as well as concomitant disease or drug therapy.

Piperacillin/ tazobactam contains 64 mg (2.79 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients might receive between 768 and 1024 mg/day (33.5 and 44.6 mEq) of sodium. Geriatric patients may have a reduced ability to excrete sodium and may therefore be more susceptible to sodium-associated conditions such as congestive heart failure.

Since this drug is significantly eliminated through the kidneys, the risk of toxic reactions may be higher in patients with renal impairment. Elderly patients are more likely to have impaired renal function, so care should be taken when selecting a dose, and renal function monitoring may be beneficial.

Post-marketing reports have shown cases of overdose with Piperacillin/ tazobactam. The symptoms experienced in these cases, such as nausea, vomiting, and diarrhea, are similar to those seen with the recommended dosages. Intravenous administration of higher than recommended doses may cause neuromuscular excitability or convulsions, especially in patients with renal failure. In such cases, treatment should be based on the patient's clinical presentation and symptoms, and supportive measures should be provided. Hemodialysis may be used to reduce excessive serum concentrations of piperacillin or tazobactam. In a study of patients given a single 3.375 g dose of Piperacillin/ tazobactam, approximately 31% and 39% of the piperacillin and tazobactam doses, respectively, were removed by hemodialysis.

• Pharmacodynamic

Tazobactam sodium has limited efficacy in inhibiting bacteria in vitro because it has a reduced affinity for penicillin-binding proteins. Nevertheless, it is a β-lactamase inhibitor of the Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. Its ability to inhibit class II and IV (2a & 4) penicillinases varies. Moreover, Tazobactam does not induce chromosomally-mediated β-lactamases at the recommended dosage regimen's achieved concentrations.

• Pharmacokinetics

Absorption:

The absorption of Piperacillin/ tazobactam combination is rapid, and peak plasma concentrations of both drugs are achieved immediately after completion of an intravenous infusion. When compared to piperacillin administered alone, the plasma concentrations of piperacillin following a 30-minute infusion of Piperacillin/ tazobactam are similar. The mean peak plasma concentrations of Piperacillin/ tazobactam for the 2 g/0.25 g, 3 g/0.375 g, and 4 g/0.5 g doses are approximately 134, 242, and 298 mcg/mL, respectively. Similarly, the corresponding mean peak plasma concentrations of tazobactam are 15, 24, and 34 mcg/mL. Steady-state plasma concentrations of both drugs are similar after multiple 3 g/0.375 g Piperacillin/ tazobactam 30-minute intravenous infusions administered every 6 hours. In healthy individuals, the plasma half-lives of piperacillin and tazobactam range from 0.7 to 1.2 hours and remain unaffected by the dose or duration of infusion, following single or multiple doses of Piperacillin/ tazobactam.

Distribution:

Tazobactam and piperacillin exhibit a wide distribution pattern in various body fluids and tissues including the intestinal mucosa, gallbladder, lung, female reproductive tissues such as the uterus, ovary, and fallopian tubes, interstitial fluid, and bile. Mean tissue concentrations were found to be around 50-100% of those in the plasma. However, distribution of piperacillin and tazobactam into cerebrospinal fluid is low in individuals with non-inflamed meninges, similar to other penicillins.

Metabolism:

Piperacillin undergoes metabolism to form a minor microbiologically active desethyl metabolite, while tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.

Excretion:

Both tazobactam and piperacillin are excreted from the body through the kidney via glomerular filtration and tubular secretion. Tazobactam and its metabolite are primarily excreted through renal excretion with around 80% of the dose as unchanged drug and the remaining amount as the single metabolite. Piperacillin, on the other hand, is rapidly excreted as unchanged drug, with 68% of the dose in the urine. Additionally, piperacillin, tazobactam, and desethyl piperacillin are secreted into the bile.

• Therapeutic Benefits of Piperacillin/ tazobactam Combination

Clinical studies have demonstrated various therapeutic benefits of Piperacillin/ tazobactam combination. Some of the benefits observed in these studies include:

The Piperacillin/ tazobactam combination has several therapeutic benefits, including:

1. Broad Spectrum Activity: Piperacillin/ tazobactam has a broad spectrum of activity against both the Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa, Enterobacter species, and Klebsiella pneumoniae.
2. Enhanced Efficacy: The addition of tazobactam to piperacillin enhances its efficacy by preventing the degradation of piperacillin by bacterial beta-lactamases.
3. Reduced Antibiotic Resistance: The combination of piperacillin and tazobactam reduces the development of antibiotic resistance compared to using piperacillin alone.
4. Lower Risk of Superinfection: The broad-spectrum activity of Piperacillin/ tazobactam reduces the risk of superinfection by eliminating a wide range of bacterial pathogens.

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