PIPERACILLIN AND TAZOBACTAM
count, cholestatic jaundice, circulatory arrest, Clostridium
difficile associated diarrhea, confusion, convulsions,
decreased hematocrit, decreased hemoglobin,
decreased serum albumin, depression, dysgeusia, dysuria, electrolyte disturbance, eosinophilia, epistaxis, erythema multiforme, gastritis, genital pruritus, hallucination,
hematuria, hemolytic anemia, hemorrhage, hepatitis, hiccups, hyperglycemia, hypersensitivity reaction, hypoglycemia, increased blood glucose, increased blood urea
nitrogen, increased gamma-glutamyl transferase,
increased serum alkaline phosphatase, increased serum
ALT, increased serum AST, increased serum bilirubin,
increased serum creatinine, increased thirst, inflammation, interstitial nephritis, intestinal obstruction, leukopenia, leukorrhea, melena, mesenteric embolism, myalgia,
myocardial infarction, neutropenia, oliguria, pancytopenia, photophobia, positive direct Coombs test, prolonged
partial thromboplastin time, prolonged prothrombin time,
pulmonary edema, pulmonary embolism, purpura, renal
failure, rigors, Stevens-Johnson syndrome, supraventricular tachycardia, syncope, thrombocythemia, thrombocytopenia, thrombophlebitis, toxic epidermal necrolysis,
urinary incontinence, urinary retention, vaginitis, ventricular fibrillation, ventricular tachycardia
Drug Interactions
Metabolism/Transport Effects None known.
Avoid Concomitant Use
Avoid concomitant use of Piperacillin and Tazobactam
with any of the following: BCG; BCG (Intravesical);
Probenecid
Increased Effect/Toxicity
Piperacillin and Tazobactam may increase the levels/
effects of: Flucloxacillin [Floxacillin]; Methotrexate; Vancomycin; Vecuronium; Vitamin K Antagonists
The levels/effects of Piperacillin and Tazobactam may be
increased by: Probenecid
Decreased Effect
Piperacillin and Tazobactam may decrease the levels/
effects of: Aminoglycosides; BCG; BCG (Intravesical);
BCG Vaccine (Immunization); Mycophenolate; Sodium
Picosulfate; Typhoid Vaccine
The levels/effects of Piperacillin and Tazobactam may be
decreased by: Tetracycline Derivatives
Storage/Stability
Vials: Store at 20°C to 25°C (68°F to 77°F) prior to
reconstitution. Use single-dose or bulk vials immediately
after reconstitution. Discard any unused portion after 24
hours if stored at 20°C to 25°C (68°F to 77°F) or after 48
hours if stored refrigerated (2°C to 8°C [36°F to 46°F]).
Do not freeze vials after reconstitution. Stability in IV
bags has been demonstrated for up to 24 hours at room
temperature and up to 1 week at refrigerated temperature. Stability in an ambulatory IV infusion pump has
been demonstrated for a period of 12 hours at room
temperature.
Galaxy containers: Store at or below -20°C (-4°F). The
thawed solution is stable for 14 days under refrigeration
(2°C to 8°C [36°F to 46°F]) or 24 hours at 20°C to 25°C
(68°F to 77°F). Do not refreeze.
Mechanism of Action Piperacillin inhibits bacterial cell
wall synthesis by binding to one or more of the penicillinbinding proteins (PBPs); which in turn inhibits the final
transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria
eventually lyse due to ongoing activity of cell wall autolytic
enzymes (autolysins and murein hydrolases) while cell
wall assembly is arrested. Piperacillin exhibits timedependent killing. Tazobactam inhibits many beta-lactamases, including staphylococcal penicillinase and Richmond-Sykes types 2, 3, 4, and 5, including extended
1707
spectrum enzymes; it has only limited activity against class
1 beta-lactamases other than class 1C types.
Pharmacokinetics (Adult data unless noted) Both
AUC and peak concentrations are dose proportional
Distribution: Widely distributed into tissues and body fluids
including lungs, intestinal mucosa, female reproductive
tissues, interstitial fluid, gallbladder, and bile; penetration
into CSF is poor when meninges are uninflamed
Vd: Children and Adults: 0.243 L/kg
Protein binding:
Piperacillin: ~26% to 33%
Tazobactam: 31% to 32%
Metabolism:
Piperacillin: 6% to 9% to desethyl metabolite (weak
activity)
Tazobactam: ~22% to inactive metabolite
Bioavailability: IM:
Piperacillin: 71%
Tazobactam: 84%
Half-life (Pediatric data: Reed 1994):
Piperacillin:
Infants 2 to 5 months: 1.4 hours
Children 6 to 23 months: 0.9 hour
Children 2 to 12 years: 0.7 hour
Adults: 0.7 to 1.2 hours
Metabolite: 1 to 1.5 hours
Tazobactam:
Infants 2 to 5 months: 1.6 hours
Children 6 to 23 months: 1 hour
Children 2 to 12 years: 0.8-0.9 hour
Adults: 0.7 to 0.9 hour
Elimination: Piperacillin and tazobactam are both eliminated by renal tubular secretion and glomerular filtration.
Piperacillin, tazobactam, and desethylpiperacillin are also
secreted into bile.
Piperacillin: 50% to 70% eliminated unchanged in urine
Tazobactam: Found in urine at 24 hours, with 20% as the
inactive metabolite and 80% as unchanged drug
Clearance: Children 9 months to 12 years: 5.64 mL/
minute/kg
Dosing: Neonatal Note: Zosyn (piperacillin and tazobactam) is a combination product; each 3.375 g vial contains
3 g piperacillin sodium and 0.375 g tazobactam sodium in
an 8:1 ratio. Dosage recommendations are based on the
piperacillin component.
General dosing, susceptible infection:
Weight-directed dosing (Red Book, 2012): IV:
Body weight <1 kg:
PNA ≤14 days: 100 mg piperacillin/kg/dose every 12
hours
PNA 15 to 28 days: 100 mg piperacillin/kg/dose every
8 hours
Body weight ≥1 kg:
PNA ≤7 days: 100 mg piperacillin/kg/dose every 12
hours
PNA 8 to 28 days: 100 mg piperacillin/kg/dose every 8
hours
Age-directed dosing: Note: Limited data available, positive efficacy results, dosage regimens variable, dosing
partially extrapolated from piperacillin data (Kacet 1992)
GA <36 weeks:
PNA 0 to 7 days: 75 mg piperacillin/kg/dose every 12
hours
PNA 8 to 28 days: 75 mg piperacillin/kg/dose every 8
hours
Meningitis: PNA 0 to 7 days: 200 mg piperacillin/kg/
dose every 12 hours was used in two neonates (GA:
31, 35 weeks) (Placzek 1983)
GA ≥36 weeks:
PNA 0 to 7 days: 75 mg piperacillin/kg/dose every 8
hours
PNA 8 to 28 days: 75 mg piperacillin/kg/dose every 6
hours
PIPERACILLIN AND TAZOBACTAM
Dosing: Usual
Pediatric: Note: Zosyn (piperacillin and tazobactam) is a
combination product; each 3.375 g vial contains 3 g
piperacillin sodium and 0.375 g tazobactam sodium in
an 8:1 ratio. Dosage recommendations are based on the
piperacillin component. Note: Some centers divide
doses every 6 hours for enhanced pharmacodynamic
profile. Unless otherwise specified, dosing presented is
based on traditional infusion method (IV infusion over 30
minutes). Dosing is presented in mg/kg/dose and mg/kg/
day; use precaution.
General dosing, susceptible infection (Red Book
[AAP] 2012): IV: Severe infection:
Infants <2 months: 100 mg piperacillin/kg/dose every 6
hours (Bradley 2014)
Infants 2 to 9 months: 80 mg piperacillin/kg/dose every
8 hours
Infants >9 months, Children, and Adolescents: 100 mg
piperacillin/kg/dose every 8 hours; maximum daily
dose: 16 g piperacillin/day
Appendicitis and/or peritonitis: IV:
Infants 2 to 9 months: 80 mg of piperacillin/kg/dose
every 8 hours
Infants >9 months and Children weighing ≤40 kg:
100 mg piperacillin/kg/dose every 8 hours; maximum
dose: 3,000 mg piperacillin/dose
Children weighing >40 kg and Adolescents: 3,000 mg
piperacillin every 6 hours; maximum daily dose: 16 g
piperacillin/day
Cystic fibrosis, pseudomonal lung infection: Infants,
Children, and Adolescents: Note: Multiple dosing
approaches have been evaluated; optimal dose may
vary based on disease severity, susceptibility patterns
(eg, MIC), or patient tolerability:
Standard dosing range: IV: 240 to 400 mg piperacillin/
kg/day divided every 8 hours (Kliegman 2011); others
have used 350 to 400 mg/kg/day divided every 4
hours in early piperacillin trials (Zobell 2013)
High-dose: Limited data available: IV: 450 mg piperacillin/kg/day every 4 to 6 hours or 600 mg piperacillin/
kg/day divided every 4 hours has been described from
early studies of piperacillin alone; usual maximum
daily dose: 18 to 24 g piperacillin/day. Note: Piperacillin doses >600 mg/kg/day or an extended duration
of therapy (>14 days) have been associated with
dose-related adverse effects including serum sickness, immune-mediated hemolytic anemia and bone
marrow suppression (Zobell 2013).
Intra-abdominal infection, complicated: Infants, Children, and Adolescents: IV: 200 to 300 mg piperacillin/
kg/day divided every 6 to 8 hours; maximum daily dose:
12 g piperacillin/day (Solomkin 2010)
Surgical antimicrobial prophylaxis (Bratzler, 2013): IV:
Infants 2 to 9 months: 80 mg piperacillin/kg 30 to 60
minutes prior to procedure; may repeat in 2 hours
Infants >9 months, Children, and Adolescents weighing
≤40 kg: 100 mg piperacillin/kg 30 to 60 minutes prior
to procedure; may repeat in 2 hours. Maximum dose:
3,000 mg piperacillin/dose
Adolescents weighing >40 kg: 3000 mg piperacillin 30
to 60 minutes prior to procedure; may repeat in 2
hours
Extended-infusion method: Limited data available:
Children and Adolescents: IV: 100 mg piperacillin/kg/
dose infused over 4 hours 3 times daily. Dosing based
on a prospective, observational study (n=332) in a
single children's hospital comparing the extended interval method to traditional dosing (Nichols 2012).
Adult: Note: Dosing expressed as total dose of combination product (piperacillin/tazobactam); dosing presented
is based on traditional infusion method (IV infusion over
30 minutes) unless otherwise specified as the extended
infusion method (IV infusion over 4 hours)
1708
General dosing, susceptible infection: IV: 3.375 g
(3,000 mg piperacillin/375 mg tazobactam) every 6
hours or 4.5 g (4,000 mg piperacillin/500 mg tazobactam) every 6 to 8 hours; maximum: 16 g piperacillin/day
Diverticulitis, intra-abdominal abscess, peritonitis:
IV: 3.375 g every 6 hours; Note: Some clinicians use
4.5 g every 8 hours for empiric coverage since the %
time>MIC is similar between the regimens for most
pathogens; however, this regimen is not recommended
for nosocomial pneumonia or Pseudomonas coverage.
Pneumonia, nosocomial: IV: 4.5 g every 6 hours for 7 to
14 days (when used empirically, combination with an
aminoglycoside or antipseudomonal fluoroquinolone is
recommended; consider discontinuation of additional
agent if P. aeruginosa is not isolated)
Skin and soft tissue infection: IV: 3.375 g every 6 to 8
hours for 7 to 14 days. Notes: When used for necrotizing infection of skin, fascia, or muscle, combination
with clindamycin and ciprofloxacin is recommended
(Stevens 2005); for severe diabetic foot infections,
recommended treatment duration is up to 4 weeks
depending on severity of infection and response to
therapy (Lipsky, 2012).
Dosing adjustment in renal impairment:
Infants, Children, and Adolescents: There are no dosage
adjustments provided in the manufacturer's labeling;
however, the following have been used by some clinicians (Aronoff 2007): Note: Dosage recommendations
are based on the piperacillin component. Dosing based
on a usual dose of 200 to 300 mg piperacillin kg/day in
divided doses every 6 hours.
GFR >50 mL/minute/1.73 m2: No adjustment required
GFR 30 to 50 mL/minute/1.73 m2: 35 to 50 mg piperacillin/kg/dose every 6 hours
GFR <30 mL/minute/1.73 m2: 35 to 50 mg piperacillin/
kg/dose every 8 hours
Intermittent hemodialysis (IHD): Hemodialysis removes
30% to 40% of a piperacillin/tazobactam dose: 50 to
75 mg piperacillin/kg/dose every 12 hours
Peritoneal dialysis (PD): Peritoneal dialysis removes
21% of tazobactam and 6% of piperacillin: 50 to
75 mg piperacillin/kg/dose every 12 hours
Continuous renal replacement therapy (CRRT): 35 to
50 mg piperacillin kg/dose every 8 hours
Adults: Note: Dosing expressed as total dose of combination product (piperacillin/tazobactam).
Traditional infusion method (ie, IV infusion over 30
minutes): Manufacturer’s labeling:
Nosocomial pneumonia:
CrCl >40 mL/minute: No adjustment needed
CrCl 20 to 40 mL/minute: 3.375 g every 6 hours
CrCl <20 mL/minute: 2.25 g every 6 hours
Hemodialysis: 2.25 g every 8 hours with an additional dose of 0.75 g after each dialysis
CAPD: Adults: 2.25 g every 8 hours
All other indications:
CrCl >40 mL/minute: No adjustment needed
CrCl 20 to 40 mL/minute: 2.25 g every 6 hours
CrCl <20 mL/minute: 2.25 g every 8 hours
Hemodialysis: Hemodialysis removes 30% to 40% of
a piperacillin/tazobactam dose: 2.25 g every 12
hours with an additional dose of 0.75 g after each
dialysis
CAPD: Peritoneal dialysis removes 21% of tazobactam and 6% of piperacillin: 2.25 g every 12 hours
Dosing adjustment in hepatic impairment: No dosing
adjustment required
Preparation for Administration
Parenteral:
Reconstitution:
Single-dose vials: Reconstitute with 5 mL of diluent (NS,
D5W, or SWFI) per 1,000 mg of piperacillin to yield a
PIRBUTEROL
concentration of piperacillin 200 mg/mL and tazobactam 25 mg/mL
Pharmacy bulk vial: Reconstitute with 152 mL of diluent
(NS, D5W or SWFI) to yield a concentration of piperacillin 200 mg/mL and tazobactam 25 mg/mL
Intermittent IV infusion: Further dilute dose in a volume of
50 to 150 mL for a usual final concentration of piperacillin 20 to 80 mg/mL; dilution of doses in volumes as
low 25 or 37.5 mL have been used in ambulatory
infusion pumps
Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult specific
product labeling.
Note: 8:1 ratio of piperacillin sodium/tazobactam sodium
Infusion [premixed iso-osmotic solution]:
Zosyn: 2.25 g: Piperacillin 2 g and tazobactam 0.25 g
(50 mL) [contains edetate disodium, sodium 128 mg
(5.58 mEq)]
Zosyn: 3.375 g: Piperacillin 3 g and tazobactam 0.375 g
(50 mL) [contains edetate disodium, sodium 192 mg
(8.38 mEq)]
Zosyn: 4.5 g: Piperacillin 4 g and tazobactam 0.5 g (100
mL) [contains edetate disodium, sodium 256 mg
(11.17 mEq)]
Injection, powder for reconstitution: 2.25 g: Piperacillin 2 g
and tazobactam 0.25 g; 3.375 g: Piperacillin 3 g and
tazobactam 0.375 g; 4.5 g: Piperacillin 4 g and tazobactam 0.5 g; 40.5 g: Piperacillin 36 g and tazobactam 4.5 g
Zosyn: 2.25 g: Piperacillin 2 g and tazobactam 0.25 g
[contains edetate disodium, sodium 128 mg
(5.58 mEq)]
Zosyn: 3.375 g: Piperacillin 3 g and tazobactam 0.375 g
[contains edetate disodium, sodium 192 mg
(8.38 mEq)]
Zosyn: 4.5 g: Piperacillin 4 g and tazobactam 0.5 g [contains edetate disodium, sodium 256 mg (11.17 mEq)]
Zosyn: 40.5 g: Piperacillin 36 g and tazobactam 4.5 g
[contains edetate disodium, sodium 2304 mg (100.4
mEq); bulk pharmacy vial]
Administration
Parenteral:
Intermittent IV infusion: Administer over 30 minutes
Extended IV infusion: Administration over 3 to 4 hours
has been reported in pediatric and adult patients (Kim
2007; Nichols 2012; Shea 2009).
Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in
vitro. This has been observed to a greater extent with
tobramycin and gentamicin, while amikacin has shown
greater stability against inactivation. Concurrent use of
these agents may pose a risk of reduced antibacterial
efficacy in vivo, particularly in the setting of profound
renal impairment. However, definitive clinical evidence
is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of
aminoglycoside levels, CBC, and clinical response
should be considered. Note: Reformulated Zosyn containing EDTA has been shown to be compatible in vitro
for Y-site infusion with amikacin and gentamicin diluted in
NS or D5W (applies only to specific concentrations and
varies by product; consult manufacturer’s labeling).
Reformulated Zosyn containing EDTA is not compatible
with tobramycin.
Monitoring Parameters Serum electrolytes, bleeding
time especially in patients with renal impairment; periodic
tests of renal, hepatic, and hematologic function; observe
for changes in bowel frequency, CBC with differential;
monitor for signs of anaphylaxis during first dose
Test Interactions Positive Coombs' [direct] test; false
positive reaction for urine glucose using copper-reduction
method (Clinitest); may result in false positive results with
the Platelia Aspergillus enzyme immunoassay (EIA)
Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro, leading to a potential
underestimation of aminoglycoside serum concentration.
Note: Reformulated Zosyn containing EDTA has been
shown to be compatible in vitro for Y-site infusion with
amikacin and gentamicin diluted in NS or D5W (applies
only to specific concentrations and varies by product;
consult manufacturer’s labeling). Reformulated Zosyn
containing EDTA is not compatible with tobramycin.
Additional Information Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a
greater extent with tobramycin and gentamicin, while
amikacin has shown greater stability against inactivation.
Concurrent use of these agents may pose a risk of
reduced antibacterial efficacy in vivo, particularly in the
setting of profound renal impairment. However, definitive
clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine
monitoring of aminoglycoside levels, CBC, and clinical
response should be considered. Note: Reformulated
Zosyn® containing EDTA has been shown to be compatible in vitro for Y-site infusion with amikacin and gentamicin
diluted in NS or D5W (applies only to specific concentrations and varies by product; consult manufacturer’s labeling). Reformulated Zosyn® containing EDTA is not
compatible with tobramycin.
^ Piperacillin and Tazobactam for Injection (Can) see
Piperacillin and Tazobactam on page 1706
^ Piperacillin and Tazobactam Sodium see Piperacillin
and Tazobactam on page 1706
^ Piperacillin Sodium and Tazobactam Sodium see
Piperacillin and Tazobactam on page 1706
Pirbuterol
1709
(peer BYOO ter ole)
Brand Names: US Maxair Autohaler [DSC]
Therapeutic Category Adrenergic Agonist Agent; Antiasthmatic; Beta 2 -Adrenergic Agonist; Bronchodilator;
Sympathomimetic
Generic Availability (US) No
Use Prevention and treatment of bronchospasm in patients
with reversible airway obstruction due to asthma or COPD
Pregnancy Risk Factor C
Pregnancy Considerations Adverse events have been
observed in some animal reproduction studies. Beta-agonists may interfere with uterine contractility if administered
during labor.
Uncontrolled asthma is associated with adverse events on
pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low birth weight infants). Other
beta2-receptor agonists are preferred for the treatment of
asthma during pregnancy (NAEPP, 2005).
Breast-Feeding Considerations It is not known if pirbuterol is excreted into breast milk. The manufacturer recommends that pirbuterol be used in breast-feeding women
only if the potential benefit to the mother outweighs the
possible risk to the infant. The use of beta2-receptor
agonists are not considered a contraindication to breastfeeding (NAEPP, 2005).
Contraindications Hypersensitivity to pirbuterol or any
component of the formulation
Warnings/Precautions Optimize anti-inflammatory treatment before initiating maintenance treatment with pirbuterol. Do not use as a component of chronic therapy
without an anti-inflammatory agent. Only the mildest form
of asthma (Step 1 and/or exercise-induced) would not