Piperacillin-Tazobactam (piperacillin sodium/tazobactam sodium)

Piperacillin/tazobactam is a fixed combination of piperacillin sodium and tazobactam sodium; potency of each component is expressed in terms of the base. The commercially available fixed combination contains an 8:1 ratio of piperacillin to tazobactam.

Dosage of piperacillin/tazobactam usually is expressed as the total (sum) of the dosage of each of the 2 components (i.e., dosage of piperacillin plus dosage of tazobactam). However, dosage of piperacillin/tazobactam for pediatric patients often is expressed in terms of the piperacillin component.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Penicillins/Methotrexate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Penicillins may compete with the renal tubular secretion of methotrexate.

CLINICAL EFFECTS: The concurrent use of methotrexate and penicillins may result in elevated levels of methotrexate and methotrexate toxicity, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: Patients receiving concurrent therapy with methotrexate and penicillins should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The dose and duration of leucovorin rescue therapy may need to be increased.

DISCUSSION: Elevated methotrexate levels, signs of methotrexate toxicity, and death have been reported following the concurrent use of methotrexate (both low dose and high dose) and penicillin derivatives. In a patient being treated with high-dose methotrexate (8 G/m2), the concurrent use of amoxicillin resulted in a 56% decrease in the clearance of methotrexate and signs of methotrexate toxicity.(1) There are two cases of methotrexate toxicity following the addition of amoxicillin to low-dose methotrexate therapy (7.5 mg-10 mg weekly) for psoriasis. In another case, a patient was found to have a toxic methotrexate level 12 days after her last dose of weekly methotrexate (7.5 mg). The patient had been treated with amoxicillin followed by flucloxacillin.(2) In a case report, dicloxacillin decreased methotrexate clearance 93%.(4) Flucloxacillin was shown to increase the area-under-curve (AUC) of methotrexate by 7.3% in a study in 10 subjects.(5) In a case report, a patient on low-dose methotrexate (5 mg) developed methotrexate pneumonia following the addition of flucloxacillin to his regimen.(5) In a patient being treated with high-dose methotrexate (12 G/m2), the concurrent use of mezlocillin increased the half-life of methotrexate from 10.1 to 27.2 hours.(6) In a case report, a patient developed methotrexate toxicity following the addition of penicillin V potassium to his methotrexate (50 mg weekly).(7) In a case report, penicillin decreased methotrexate clearance 36%.(4) In one report, leucovorin rescue therapy had to be continued for 192 hours following the concurrent use of methotrexate (3 G/m2) and piperacillin. During cycles without concurrent piperacillin, leucovorin rescue therapy was only required for 72 hours.(8) There are two reports of neutropenia and death following the concurrent use of piperacillin and low-dose methotrexate (2.5 mg three times weekly in one patient, 5 mg weekly in another) for psoriasis. One of these patients also received flucloxacillin. (3) In another case report, the concurrent use of piperacillin decreased methotrexate clearance by 67%.(4) In a case report, ticarcillin decreased methotrexate clearance by 60%.(4)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Penicillins/Oral Contraceptives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens and progesterones are extensively excreted in bile, principally as glycuronide conjugates. Subsequently, they undergo enterohepatic circulation where bacterial hydrolysis occurs, allowing for reabsorption of the oral contraceptives through the bowel wall and eventual urinary excretion. Treatment with antibiotics destroys the gut flora and prevents steroid reabsorption, resulting in lower than normal concentrations of the contraceptive and excretion via the feces rather than the urine.

CLINICAL EFFECTS: May observe reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy. Reduced effects may be seen for several days after discontinuation of antibiotic therapy.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception.

DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Reports of breakthrough bleeding and loss of contraceptive protection leading to unwanted pregnancies have occurred in women taking oral contraceptive agents who received concurrent ampicillin, amoxicillin, penicillin G, or oxacillin. Several studies have shown that the administration of ampicillin or penicillin to pregnant and nonpregnant women resulted in lowered urinary estrogen excretion, in some women as soon as three days after ampicillin therapy began. However in one small prospective study, plasma ethinyl estradiol concentrations showed a tendency to decrease during ampicillin administration on the third, fourth, and fifth morning of ampicillin administration, but were never lower than pretreatment values. In another small prospective study of women taking low dose combination contraceptives, concurrent ampicillin therapy neither altered the plasma levels nor the AUC of norethisterone and ethinyl estradiol. In addition, progesterone levels were in an anovulatory range. In another prospective study of 13 women taking long term oral contraceptive steroids, concurrent ampicillin was not associated with any significant changes in plasma concentrations of ethinyl estradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyl estradiol were noted in two women.

Piperacillin-Tazobactam/Vancomycin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The nephrotoxic effects of piperacillin-tazobactam may be additive with those of vancomycin.(1-5)

CLINICAL EFFECTS: The concurrent administration of piperacillin-tazobactam with vancomycin may result in additive nephrotoxic effects.(1-5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of piperacillin-tazobactam states that the concurrent use of piperacillin-tazobactam and vancomycin warrants routine monitoring of kidney function.(1) The manufacturer of vancomycin states renal function monitoring is warranted when used concurrently and/or sequentially with other potentially nephrotoxic drugs.(2) Area-under-the curve (AUC) based dosing of vancomycin when used concurrently with piperacillin-tazobactam may reduce the risk of acute kidney injury (AKI). Routine monitoring of kidney function is warranted.(3)

DISCUSSION: A systematic review and metaanalysis found the concomitant use of vancomycin and piperacillin-tazobactam was associated with acute kidney injury in unadjusted odds ratio (OR 3.12; 95% confidence interval (CI) 2.04 - 4.78, p<0.001) and in adjusted OR (aOR 3.11; 95% CI 1.77 - 5.47, p<0.001) analysis. For adults only, results were similar for unadjusted (OR 2.71; 95% CI 1.72 - 4.27, p<0.001) and adjusted (aOR 3.15; 95% CI 1.72 - 5.76, p<0.001) analysis. For children only, concurrent use was associated with increased risk in unadjusted (OR 5.26; 95% CI 2.71 - 10.21, p<0.001) analysis.(4) A retrospective matched cohort study in patients receiving concurrent vancomycin and piperacillin-tazobactam for a minimum of 48 hours had significantly higher rates of acute kidney injury than patients receiving vancomycin and cefepime (29% vs 11%, respectively; hazard ratio (HR) = 4, p<0.001). Results of a multivariate analysis found vancomycin and piperacillin-tazobactam combination therapy was an independent risk factor for RIFLE (Risk, Injury, Failure, Loss, End Stage Renal Disease) -defined acute kidney injury (HR = 4.3; 95% CI 2.7 - 6.7; p<0.0001). The onset of acute kidney injury was more rapid in patients receiving vancomycin and piperacillin-tazobactam than in patients receiving vancomycin and cefepime (3 days vs 5 days, p<0.001).(5) A retrospective cohort analysis evaluated RIFLE-defined acute kidney injury in patients receiving combination vancomycin and piperacillin-tazobactam, vancomycin monotherapy, and piperacillin-tazobactam monotherapy. RIFLE-defined acute kidney injury occurred in 14.1% of patients across the cohort. The therapy specific acute kidney injury occurred in combination vancomycin and piperacillin-tazobactam, vancomycin monotherapy and piperacillin-tazobactam monotherapy in 21%, 8.3%, and 7.8% of patients (p<0.0001), respectively. In a multivariate analysis, vancomycin monotherapy and piperacillin-tazobactam monotherapy were associated with decreased odds of acute kidney injury compared to combination vancomycin and piperacillin-tazobactam therapy (Vancomycin Monotherapy - aOR 0.48; 95% CI 0.41 - 0.57; Piperacillin-Tazobactam Monotherapy - aOR 0.43; 95% CI 0.37 - 0.5). In a univariate analysis the following factors were associated with acute kidney injury: combination vancomycin and piperacillin-tazobactam therapy, days of therapy, baseline creatinine clearance, transfer from outside hospitals, Charlson Comorbidity Index, admission type, length of hospitalization, dehydration exposure, and hypotension exposure.(6) A retrospective cohort study evaluated the incidence of AKI with Vancomycin AUC based dosing with concomitant piperacillin-tazobactam (VPT) compared to meropenem or cefepime (VMC). AKI occurred in 13.68% of patients with VPT compared to 4.8% of patients who received VMC. Patients in other VPT studies utilizing traditional trough based vancomycin dosing experienced AKI 21.4 to 34.8%.(3)

Piperacillin/Nondepolarizing Muscle Relaxants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Piperacillin may prolong the neuromuscular blockade of the nondepolarizing muscle relaxants.(1,2)

CLINICAL EFFECTS: Concurrent use of nondepolarizing muscle relaxants and piperacillin may result in prolonged neuromuscular blockade including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should be monitored for increased or unexpected prolongation of neuromuscular blockade when using piperacillin with nondepolarizing muscle relaxants. Assure monitoring protocols are in place for patients receiving neuromuscular blocking agents. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Concurrent use of nondepolarizing muscle relaxants and piperacillin may result in increased or prolonged neuromuscular blockage.(1,2) If these agents are used together, patients should be monitored closely for increased neuromuscular blockage.

Selected Cephalosporins & Penicillins/Probenecid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Probenecid impairs the clearance of some cephalosporins and penicillins via inhibition of renal anion transporters in the proximal tubule.(49) It has also been hypothesized that probenecid may affect tissue distribution of cephalosporins.(1-5)

CLINICAL EFFECTS: The concurrent administration of probenecid may result in increased maximum concentration (Cmax), area-under-curve (AUC), and half-life of the cephalosporin or penicillin.(49) While this may improve antibiotic efficacy,(46-48) increased levels may also increase the risk for antibiotic-associated nephrotoxicity.(4)

PREDISPOSING FACTORS: Underlying renal dysfunction may increase the risk for nephrotoxicity.

PATIENT MANAGEMENT: In patients receiving the combination to improve antibiotic efficacy, monitor for antibiotic adverse effects and consider monitoring renal function. In patients receiving probenecid therapy to prevent or treat hyperuricemia, exposure to the antibiotic will be increased. A decrease in antibiotic dose or frequency may be required. The US manufacturer of piperacillin-tazobactam states probenecid should not be coadministered with piperacillin-tazobactam unless the benefit outweighs the risk.(50)

DISCUSSION: Concurrent use of probenecid with a cephalosporin or penicillin may cause an increase in the Cmax, AUC, and an increased elimination half life of the antibiotic.(6-8,49) This may be beneficial or necessary in difficult to treat infections,(46-48) but an increased risk for adverse effects should be expected. Antibiotics not dose adjusted for concurrent use with probenecid may be associated with an increased risk for adverse effects, such as nephrotoxicity. Probenecid administered concurrently with piperacillin-tazobactam prolongs the half-life of piperacillin by 21% and tazobactam by 71%. In a study in 8 healthy males, concurrent administration of probenecid (1 g) with piperacillin (1 g IM) increased piperacillin's Cmax and AUC by 30% and 60%. Renal clearance was reduced by 40%.(51) The cephalosporins affected by probenecid include cefazolin,(9-11) cephacetrile,(12,13) cephaloglycin,(14,15) cephalexin,(16-21) cephradine, (22-23) cefoxitin,(24-28) cefadroxil(29), cefaclor,(23) cefamandole,(30) ceftizoxime,(31,32) cefuroxime,(33,34) cefprozil,(35) cefonicid,(36) cefmetazole,(37) cefmenoxime,(38) and cefditoren.(39) Probenecid has been shown not to affect moxalactam,(4,40,41) ceforanide, (4,42), cefoperazone, ceftazidime(4,34,43) or ceftriaxone.(4)

Selected Penicillins/Selected Anticoagulants (Vit K Antag)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Large doses of parenterally administered penicillins and oral amoxicillin appear to increase the risk of bleeding during concurrent administration of anticoagulants.

PREDISPOSING FACTORS: Renal failure may predispose patients to penicillin-induced coagulation abnormalities. A study suggests that various inflammatory syndromes or the nature of the infection can affect INR levels. The risk for bleeding episodes may be greater in patients with additional disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor patient INR for an increase in the hypoprothrombinemic response to anticoagulants during concomitant administration of penicillins. Adjust the dose of warfarin accordingly. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: High dose parenteral administration of penicillins and oral amoxicillin have been reported to cause an increase in the hypoprothrombinemic effects of warfarin producing bleeding. Significant clinical effects have been reported with combined administration of warfarin and either carbenicillin or penicillin G. There have been several case reports and retrospective reviews documenting increased acenocoumarol and warfarin effects, including bleeding, following the addition of amoxicillin, with and without clavulanic acid, to therapy. In a randomized controlled trial, adult ambulatory patients that had no recent and ongoing infectious or inflammatory conditions received warfarin to a target INR between 2 and 3 with amoxicillin-clavulanic acid (1 gram twice daily for seven days) or placebo. The results showed the mean maximum INR increase from baseline to day 10 did not differ between amoxicillin/clavulanic acid (0.22 +/- 0.3) and the placebo period (0.24 +/- 0.6, p = 0.94). No patient experienced an INR of greater than 3.5. No bleeding events were reported during the entire study. A prospective cross-sectional observational study in 120 patients evaluated warfarin drug interactions, particularly with high-dose amoxicillin/clavulanate. The study found that patients on amoxicillin/clavulanate had a relative risk of having an INR >=4 of 4.8 compared to patients not on amoxicillin/clavulanate (95% CI 2.1-11.3, p < 0.001). This risk was primarily driven by patients on high-dose amoxicillin/clavulanate, who were 5.8 times more likely to have INR >=4 (95% CI 3.5-9.6, p<0.001). Significantly more patients on high-dose than normal dose amoxicillin/clavulanate had an INR value >= 4 (87.5% v. 28.9%, respectively). Nine out of ten patients who experienced bleeding during hospitalization were prescribed amoxicillin/clavulanate. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with penicillins (OR=1.59; 95% CI 1.14-2.20) and amoxicillin (OR=1.78; 95% CI 1.14-2.79). A case-control nested cohort study of Medicare beneficiaries with warfarin prescriptions was evaluated for antibiotic use and warfarin toxicity in older adults. An increased risk of bleeding was associated with penicillins with an adjusted odds ratio of 1.92. Parenteral penicillins linked to this monograph include: almecillin, amdinocillin, amoxicillin, ampicillin, azlocillin, bacampicillin, carbenicillin, cyclacillin, hetacillin, mezlocillin, penicillin, penicillin G, penicillin V, phenethicillin, piperacillin, and ticarcillin. Oral penicillins linked to this monograph include: amoxicillin and penicillin.

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There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Clostridioides difficile infection
• Severe neutropenic disorder

• Hypokalemia
• Increased risk of bleeding due to coagulation disorder
• Seizure disorder

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Less Frequent

• Anaphylaxis
• Phlebitis after infusion
• Pruritus of skin
• Skin rash
• Urticaria

Rare or Very Rare

• Acute generalized exanthematous pustulosis
• Agranulocytosis
• Anemia
• Clostridioides difficile infection
• DRESS syndrome
• Eosinophilia
• Eosinophilic pneumonia
• Erythema multiforme
• Exfoliative dermatitis
• Hemolytic anemia
• Hemophagocytic lymphohistiocytosis
• Hepatitis
• Hyperbilirubinemia
• Hypersensitivity drug reaction
• Hypoglycemic disorder
• Hypotension
• Increased alanine transaminase
• Increased alkaline phosphatase
• Increased aspartate transaminase
• Increased risk of bleeding due to coagulation disorder
• Interstitial nephritis
• Jaundice
• Leukopenia
• Linear immunoglobulin A bullous dermatosis
• Muscle relaxation
• Neutropenic disorder
• Pancytopenia
• Qualitative platelet disorder
• Renal failure
• Rhabdomyolysis
• Seizure disorder
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Thrombocytosis
• Thrombophlebitis
• Toxic epidermal necrolysis

More Frequent

• Constipation
• Diarrhea
• Headache disorder
• Insomnia
• Nausea

Less Frequent

• Acute abdominal pain
• Candidiasis
• Fever
• Vomiting

Rare or Very Rare

• Anticholinergic toxicity
• Arthralgia
• Chills
• Delirium
• Dyspepsia
• Epistaxis
• Flushing
• Injection site sequelae
• Myalgia
• Purpura
• Stomatitis

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Available human data regarding use of piperacillin/tazobactam during pregnancy are inadequate to inform a drug-associated risk for major birth defects and miscarriage. Piperacillin and tazobactam both cross the human placenta.

Reproduction studies in pregnant mice and rats using IV piperacillin/tazobactam (up to 1-2 times the human dosage of piperacillin and 2-3 times the human dosage of tazobactam based on body surface area) did not reveal evidence of teratogenicity or fetal structural abnormalities; however, intraperitoneal administration in rats at doses less than the maximum recommended human daily dosage based on body surface area given prior to mating and throughout gestation or from gestation day 17 through lactation day 21 resulted in maternal toxicity, reduced litter size, and effects on peri- and postnatal development (e.g., reduced pup weights, increased stillbirths, increased pup mortality, ossification delays, rib variations).

Piperacillin is distributed into human milk; it is not known whether tazobactam is distributed into human milk. Effects of the drugs on breast-fed infants or milk production are not known.

The developmental and health benefits of breast-feeding should be considered along with the woman's clinical need for piperacillin/tazobactam and potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

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