tazobactum-Piperacillin/tazoboctam





TAZOCIN  EF
      Piperacillin/tazoboctam



TAZOCIN EF ; Piperacillin sodium + Tazobzctam

DESCRIPION
TAZOCIN EF is an injectable antibacterial combination , consisting of the semisynthetic antibiotic piperacillin sodium and the     lactamase inhibitor tazobactam sodium , for intravenous administration.
Piperacillin sodium is derived from D(-)-<-aminobenzylpenicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R) -6-[®-2-(4-ethy1-2,3-dioxo-1—piperazine –carboxamid)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.

 Piperacillin sodium
Tazobactam sodium is a derivative of the penicillin nucleus. Chemically , tazobactam is a penicillanic acid sulfone, its chemical name is sodium (2S-(2<,3   5<)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethy1)-4-thai-1azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide. The chemical structure of tazobactam sodium is:-
Tazobactam sodium
TAZOCIN EF is available as a white to off-white sterile, cryodesiccated powder of piperacillin and tazobactam as the sodium salts packaged in glass vials. The product contains citric acid and disodium edetate (EDTA).

PHARMACOLOGY
Piperacillin ,a broad spectrum , semisyntheic penicillin active against many Gram-positive and Gram-negative aerobic and anaerobic bacteria , exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triszolylmethy1 penicillanic acid sulfone , is a potent inhibitor of many     lactamases, including the plasmid and chromosomally mediated enzymes that commonly cause resistance to penicillins. The presence of tazobactam in the TAZOCIN EF formulation enhances and extends the antibiotic spectrum of piperacilln to include many    lactamase producing bacteria normally resistant to it. Thus , TAZOCIN EF combines the porperties of a broad-spectrum antibiotic and a      lactamase inhibitor.

Microbiology
TAZOCIN EF is active against most strains of the following  lactamase producing and non  lactamase producing microorganisms;

Gram-negative bacteria
Escherichia coli , Citrobacter app.,Klebsiella app. (including K. pneumonia),Enterobacter spp.,(including E.cloacae), Proteus vulgaris , Proteus mirabilis, serratia spp. (including S. marcescens ), pseudomonas aeruginosa and other pseudomonas spp, Neisseria gonorrhoeae ,Neisseria meningitides , Moraxella catarrhalis , acinetobacter spp., haemophilus influenza.

Gram-positive bacteria
Streptococci (S.pneumoniae , S. pyogenes, S. agalatiae, S.viridans ), Enterococci (E.faecalis, E.faecium ) , staphylococcus aureus (not methicillin-resistant S.aureus)  , S. epidermidis (coagulase-negative staphylococci).

Anaerobic bacteria
Bacteroides spp. Including bacteroides fragilis group, peptostreptococcus spp. Fusobacterim spp. Eubacterium group, clostridia ., veillonella ssp.
Susceptibility
Local information of resistance is desirable, particularly when treating severe infection. This information provides guidance on micro-organisms susceptible to piperacillin/Tazobactam. The following MIC 90values were reported in 1996 for clinical isolates collected in 3 Australian states

Table1 MIC 90 for 1,952 clinically significant isolates

Organism- (number )

MIC90 (mg/L)
E.coli (528)
2.0
Klebsiella spp. (180)
4.0
Klebsiella spp. (ESBL 44)
64.0
Enterobacter spp. (142)
16.0
Citrobacter/Serratia spp. (84)
8.0
Morganella/Proteus/Providencia spp. (45)
2.0
Proteus mirablis spp. (104)

Pseudomonas aeruginosa (88)
32.2
Acinetobacter calcoaceticus(40)
32.2
Staphyloccus aureus (433)
4.0
Coagulase-negative Staphylococcal (28)
16.0


The latest NCCL referneces are
Methods for Dilution antimicrobial susceptibility tests for bacteria that grow aerobicall; approved standard-seventh edition, NCCLS document M7-a5,2006.  NCCLS, wayne,pa for anaerobes:
Methods for antimicrobial susceptibility testing of anaerobic bacteria ; approved standard sixth edition. NCCLS document M11-a,2006 . NCCLS , wayne , pa

Phaemacokinetics

Distribution and plasma levels
Mean plasma concentrations of piperacillin and TAzobactam at steady state of the combination appear in tables 2. Peak piperacillin and Tazobactam plasma concentrations are attained immediately after completion of an intravenous infusion. When given with Tazobactam, piperacillin p;asma levels are similar to those attained when equivalent doses of piperacillin are administered alone.

Table 2plama levels in adults after a thirty-minute intravenous infusion of piperacillin/Tazobactam(steady stete)
PIPERACILLIN PLASMA LEVELS (μg/mL)
Peperacillin/Tazobactam

Dose
4g/500mg


30*min

298


1 hr

141


1.5 hr

87
2 hr

47
3 hr

16



4 hr

7



TAZOBACTAM  PLASMA LEVELS (μg/mL)
Peperacillin/Tazobactam

Dose
4g/500mg


30*min

33.8


1 hr

17.3


1.5 hr

11.5
2 hr

6.8
3 hr

2.8



4 hr

1.3


*Comletion of 30 minute infusion

In healthy subjects piperacillin/Tazobactam plasma elimination half lives range from 0.7 to 1.2 hours following single or multiple doses .these half-lives are unaffected by dose or duration of infusion. Piperacillin and Tazobactam are 21% and 23% respectively , bound to plasma proteins the protein binding of either piperacillin or tazobactam is unaffected by the presence of either compound. Piperacillin and Tazobactam are widely distributed in tissues and body fluids including intestinal mucosa ,gall bladder , bladder lung and bile.

Biotransformation
Piperacillin does not undergo biotransformation in humans. Approximately 20% of a dose of Tazobactam  is metabolized to a single metabolite that has been found to microbiologically inactive.

Excretion
Piperaciiln and Tazobactam are eliminated by the kidney via glomerular filtration and tubular secretion. Pipercillin is excreted rapidly as unchanged drug,with 69% of the dose appearing in the urine. Piperacillin is also secreted into bile. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80%of the dose appearing as unchanged drug and the remainder of the dose appearing as the metabolite.


Impaired renal function
The half life of piperacillin and Tazobactam incrases with decresing creatinine clearance. The increase is two-fold for piperacillin and Tazobactam, respectively,at creatinine clearance below 20 mL/min compared to patients with normal renal function. Dosage adjustments are recommended when creatinine  clearance is below 40mL/min, see DOSAGE AND ADMINISTRATION.

Piperacillin and Tazobactam are removed from the body during haemodialysis with 31% and 39%of the dosage  of piperacillin and Tazobactam,respectively, recovered in the dialysis fluid. Piperacillin and Tazobactam are removed from the body by peritoneal dialysis with 5%and 12% of the dose ,respectively , appearing in the dialysate. For dosage recommendations in patients undergoing haemodilalysis,see DOSEGE AND ADMINISTEATION.



Impaired liver function
Piperacillin half-life and AUC were increased by 25% and 40% respectively and tazobactum half-life and AUC by 18% and 23% respectively in patients with hepatic impairment. However, dosage adjustment in patients with hepatic impairment are not necessary.

Children
The pharmacokinetics of piperacillin and Tazobictam have been examined in 24 paediatric patients aged 2 months to 12 years receiving 100 mg/kg piperacillin/2.5mg/kg Tazobatam (table 4). The maximum concentration (cmax)forboth piperacillin and  Tazobactam is increased relative to the maximum adult dose but predicted time above the minimum inhibitory concentration is slightly decreased. The dosage of 100mg/kg piperacillin/12.5/kg Tazobactam administered every 8 hours is predicted to provide conerage 31% to 61% of the time for the range of MIC values of 2     g/mL commonly found in intra-abdminal infections in children.

Table 3 piperacillin  and Tazobactam pharmacokinetics in children (cv%) following single doses

Dose
Patient age
Cmax
(mg/L)
AUC
(mg.h/L)
CL
(mL/min/kg)
Vss
(L/kg)
T1/2
(h)
Piperacillin
100mg/kg
2-5 mo
6-23 mo
2-5 y
6-12 y
382(15)
344(15)
408(80)
394(24)
539(29)
373(27)
331(21)
404(17)
3.3(24)
4.8(29)
5.2(19)
4.2(21)
0.28(32)
0.25(27)
0.23(36)
0.24(42)
1.3(16)
1.0(24)
0.9(26)
0.8(27)
Tazobactam
12.5mg/kg
2-5 mo
6-23 mo
2-5 y
6-12 y
43(49)
35(22)
45(42)
45(25)
63(32)
42(23)
37(24)
57(27)
3.6(28)
5.2(24)
5.8(19)
3.9(36)
0.32(31)
0.33(29)
0.27(33)
0.28(36)
1.3(15)
1.1(23)
0.9(29)
1.3(57)

Clinical Trials

Paediatric
A study was performed to compare the safety, tolerance, and efficacy of 100 mg/kg piperacillin/12.5mg/kg Tazobactam  with those of 50mg/kg cefotaxime plus 7.5 mg/kg metronidazole administered intravenously (iv) every 8hours for the treatment of hospitalized paediatric  patients (aged 2 to 12 of age ) with clinically or bacteriologically diagnosed intra-abdominal infection (IAI).the cure rates in the efficacy evaluable (EE) population at the follow-up visit were 90% and 91%for piperacillin/Tazobactam and cefotaxime plus metronidazole, respectively. The result of the clinicaland microbiological analyses in 521 patients showed that pipercillin/TAzobactam (TAZOCIN EF) administered intravenously was at least as effective as cefotaxime plus metronidazole in the treatment of children aged 2 to 12 years with severe IAIs.
INDICATIONS
TAZOCIN EF is indicated for the treatment of the following systemic and /or local bacterial infections in which susceptible organisms have been detected or are suspected:

1.      lower respiratory tract infection
2.      Urinary tract infections (complicated and uncomplicated)
3.      Intra-abdominal infection
4.      Skin and skin structure infection
5.      Bacterial septicemia
6.      Gynaecological infection
7.      Bacterial infection in neutropenic patient. Full therapeutic doses of TAZOCIN EF plus an aminoglycoside should be used.
8.      bone and joint infection
9.      polymicrobio infection: TAZOCIN EF is indicated for polymicrobio infections including those where aerobic and anaerobic organism are suspected (intra-abdominal, skin and skin structure , upper and lower respiratory tract,gynaecological).


While TAZOCIN EF is indicated only for the conditions listed above ,infection caused by piperacillin susceptible organisms are also amenable to TAZOCIN EF treatment due to its piperacilllin content. Therefore, the treatment of mixed infection caused by piperacillin susceptible organisms and     lactamase producing organisms susceptible to TAZOCIN EF should not require the addition of another antibiotic.

Appropriate culture and susceptibility tests should be performed before treatment in order to identify organisms causing infection and to determine their susceptibilities to TAZOCIN EF. Because of its broad-spectrum of activity against Gram-positive and Gram-nagative aerobic
and anaerobic organisms as listed above, TAZOCIN EF is particulary useful in the treatment of mixed infections and presumptive therapy prior to  the availability of the result of sensitivity tests.
Therapy with TAZOCIN EF may, howevr, be initiated before result of such tests are known.
Modification of the treatment may be required once these results become available or if there is no clinical response.

In serious infections, presumptive therapy with TAZOCIN EF may be initiated before susceptibility test results are available.

TAZOCIN EF acts synergistically with aminoglycosides against certain strains of Pseudomonas aeruginosa. Combined therapy has been successful, especially in patients with impaired host defences. Both drugs should be used in full therapeutic doses. As soon as results of culture and susceptibility tests become available, antimicrobial therapy should be adjusted.

Children under the age of 12 years

In hospitalised children aged 2 to 12 years, TAZOCIN EF is indicated for the treatment of serious
intra-abdominal infections. It has not been evaluated in this indication for paediatric patients
below the age of 2 years.

CONTRAINDICATIONS
The use of TAZOCIN EF is contraindicated in patients with a history of allergic reactions to any
of the penicillins and/or cephalosporins or - lactamase inhibitors.

PRECAUTIONS
Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients on penicillin/cephalosporin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins/cephalosporins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin/cephalosporin hypersensitivity who have experienced severe reactions when treated with either a penicillin or cephalosporin. Past history of a severe allergic reaction to penicillin/cephalosporin is a contraindication to the use of TAZOCIN EF. Before initiating therapy with any penicillin/cephalosporin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. If an allergic reaction occurs, TAZOCIN EF should be discontinued and the appropriate therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including
intubation, should also be administered as indicated.

TAZOCIN EF may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and TAZOCIN EF discontinued if lesions progress.

Antibiotic-associated pseudomembranous colitis has been reported with many antibiotics including piperacillin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs that delay peristalsis eg: opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.

Leucopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic
assessment of haematopoietic function should be performed.

As with treatment with other penicillins, neurological complications in the form of convulsions
may occur when high doses are administered, especially in patients with impaired renal function.

As with other antibiotic preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.


Use with caution in the following circumstances
Bleeding manifestations have occurred in some patients receiving 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. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate
therapy instituted.

The possibility of the emergence of resistant organisms that might cause superinfections should be
kept in mind, particularly during prolonged treatment. If this occurs, appropriate measures should
be taken.
As with other penicillins, patients may experience neuromuscular excitability or convulsions if
higher than recommended doses are given intravenously.

Repeated use of lignocaine as diluent should be avoided in patients with severe liver disease or
decreased hepatic blood flow due to the possibility of lignocaine toxicity (resulting from
decreased metabolism and accumulation).

Combined administration of  lactamase inhibitors and  lactam antibiotics may be associated
with a slightly increased risk of hepatic adverse reactions. The incidence of increased liver
enzymes in patients treated with TAZOCIN EF was slightly higher than has been reported
previously with the use of piperacillin alone. The potential for increased hepatic adverse reactions
should be borne in mind when using TAZOCIN EF.

Check the following before use
Periodical assessment of organ system functions including renal, hepatic and haematopoietic
during prolonged therapy (>21 days) is advisable.

For patients with renal impairment and/or hepatic insufficiency, measurement of serum levels of
piperacillin will provide guidance for adjusting dosage.

The theoretical sodium content of each vial of TAZOCIN EF

2.25 g vial:
128mg
Sodium(5.58mmol)
4.5 g vial:
256 mg
Sodium(11.6 mmol)

which may increase a patient’s overall sodium intake.
Periodical electrolyte determinations should be made in patients with low potassium reserves and
the possibility of hypokalaemia should be kept in mind with patients who have potentially low
potassium reserves and who are receiving cytotoxic therapy or diuretics.

Because of its poor penetration into the CSF, piperacillin is not advised in the treatment of
meningitis and brain abscess.

Antimicrobials used in high doses for short periods to treat gonorrhoea may mask or delay
symptoms of incubating syphilis. Therefore, prior to treatment, patients with gonorrhoea should
also be evaluated for syphilis. Specimens for darkfield examination should be obtained from
patients with any suspected primary lesion and serological tests should be made for a minimum of
months.

Use in pregnancy
Pregnancy Category B1.

Adequate human studies on the use of TAZOCIN EF during pregnancy are not available. Limited
studies with piperacillin alone in rats and mice revealed no teratogenic effects or harm to the
foetus. Studies with tazobactam (doses up to 3000 mg/kg IV) or tazobactam and piperacillin
(doses up to 750 mg/kg and 3000 mg/kg IV) in mice showed no evidence of teratogenicity or
harm to the foetus. Studies in rats at these dose levels showed no evidence of teratogenicity
though maternal toxicity, in the form of decreased weight gain, was noted at the dose levels
tested. Piperacillin has been found to cross the placenta in rats. Pregnant women should be
treated only if the expected benefit outweighs the possible risks to the pregnant woman and
foetus.

Use in lactation
Adequate clinical studies on the use of TAZOCIN EF during pregnancy are not available.
Piperacillin is excreted in low concentrations in milk. In animal studies, both piperacillin and
tazobactam were excreted in the milk of lactating rats. Women who are breast-feeding should be
treated only if the expected benefit outweighs the possible risks to the woman and child.

Use in children
Safety and efficacy of the use of TAZOCIN EF in children under the age of 2 years has not yet
been established.

Carcinogenicity, mutagenicity and impairment of fertility
Long term carcinogenicity studies of TAZOCIN EF in animals have not been performed.
Mutagenicity studies with piperacillin and tazobactam showed no evidence of genotoxicity in
assays for chromosomal and DNA damage. One assay for gene mutations (Mouse lymphoma
assay) was weakly positive at tazobactam and piperacillin concentrations ≥g/ml and 2500g/ml respectively. Piperacillin and tazobactam did not affect the fertility of male or female rats.

Interactions with other drugs
Concurrent administration of probenecid and TAZOCIN EF produced a longer half-life and lower
renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of
neither drug are affected. No kinetic interaction is found between TAZOCIN EF and
vancomycin.

Concurrent administration of piperacillin and tobramycin in patients with severe renal dysfunction
(ie chronic haemodialysis patients) has been reported to reduce the elimination half life and
significantly increase the total body clearance of tobramycin.

The alteration of tobramycin pharmacokinetics in patients with mild to moderate renal dysfunction
who are taking piperacillin concomitantly is unknown. However, reports suggest that the
aminoglycoside inactivation in patients concomitantly taking an aminoglycoside with a broad
spectrum beta-lactam penicillin is only clinically significant in patients with severe renal
dysfunction.

The inactivation of aminoglycosides in the presence of penicillin class drugs has been recognised.
It has been postulated that penicillin-aminoglycoside complexes form; these complexes are
microbiologically inactive and of unknown toxicity.

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of
the neuromuscular blockade of vecuronium. TAZOCIN EF (piperacillin/tazobactam) could
produce the same phenomenon if given along with vecuronium. Due to their similar mechanism
of action, it is expected that the neuromuscular blockade produced by any of the non-depolarising
muscle relaxants could be prolonged in the presence of piperacillin.

Piperacillin may reduce the excretion of methotrexate; therefore, serum levels of methotrexate
should be monitored in patients to avoid drug toxicity.

If TAZOCIN EF is used concurrently with another antibiotic, especially an aminoglycoside, the
drugs must not be mixed in intravenous solutions or administered concurrently due to physical
incompatibility.

During simultaneous administration of high doses of heparin, oral anticoagulants and other drugs
that may affect the blood coagulation system and/or the thrombocyte function, the coagulation
parameters should be tested more frequently and monitored regularly.

Effects on laboratory tests
As with other penicillins, the administration of piperacillin/tazobactam may result in a false-
positive reaction for glucose in the urine using a copper-reduction method. It is recommended
that glucose tests based on enzymatic glucose oxidase reactions be used.

There have been reports of positive test results using Bio-Rad Laboratories Platelia Aspergillus
EIA test in patients receiving TAZOCIN EF injection, who were subsequently found to be free of
Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses
with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive
test results in patients receiving TAZOCIN EF should be interpreted cautiously and confirmed by
other diagnostic methods.

ADVERSE REACTIONS
TAZOCIN EF is generally well tolerated. The overall incidence of adverse events was 15.7%
although a cause/effect relationship was not established in all cases. This incidence was
comparable to that observed with other agents used in the clinical studies. Treatment had to be
discontinued in only 2.9% of cases due to adverse reactions.

The most frequently reported adverse clinical reactions were diarrhoea, rash, erythema, pruritis,
vomiting, allergic reactions, nausea, urticaria, superinfection, phlebitis, thrombophlebitis,
dyspepsia, and insomnia.

Adverse reactions are listed in the Table in CIOMS frequency categories:


Very Common:                       ≥
Common                                 ≥
Uncommon                             ≥and <1%
Rare                                         ≥and <0.1%
Very rare:                                < 0.01%
Not known:                             frequency could not be accurately estimated from clinical studies

The following table of suspected undesirable effects is based on clinical trials and/or spontaneous
postmarketing reporting rates:


Body System               Adverse Reaction

Infections and infestations

Common:                    Candidal superinfection


Blood and lymphatic system disorders

Common:                    Thrombocytopenia, anaemia , Coombs direct test positive, activated partial
thromboplastin time prolonged

Uncommon:                Leucopenia, prothrombin time prolonged

Rare:                            Agranulocytosis, epistaxis

Not known:                 Pancytopenia , neutropenia, purpura, bleeding time prolonged, haemolytic
anaemia , eosinophilia , thrombocytosis

Immune system disorders

Not known:                 Hypersensitivity , anaphylactic reaction , anaphylactoid reaction ,
anaphylactic shock , anaphylactoid shock


Metabolism and Nutrition Disorders

Common:                                Blood albumin decreased, blood total protein decreased

Uncommon:                            Hypokalaemia, blood glucose decreased


Nervous system disorders

Common:                                Headache, insomnia

Not known:                             Dizziness


Vascular disorders

Uncommon:                            Hypotension, phlebitis, thrombophlebitis, flushing


Gastrointestinal disorders

Very common:                                    Diarrhoea

Common:                                Abdominal pain , nausea, vomiting, constipation, dyspepsia


Body System                           Adverse Reaction

Rare:                                        Pseudomembranous colitis, stomatitis

Not known:                             Bloody diarrhoea, dry mouth



Hepatobiliary disorders

Common:                                Alanine aminotransferase increased, aspartate aminotransferase increased,
blood alkaline phosphatase increased

Uncommon:                            Blood bilirubin increased

Not known:                             Jaundice, gamma-glutamyltransferase increased, hepatitis



Skin and subcutaneous tissue disorders

Common:                    Rash, pruritis

Uncommon:                Erythema multiforme , urticaria, rash maculopapular

Rare:                            Toxic epidermal necrolysis

Not known:                 Dermatitis bullous, Stevens-Johnson Syndrome , hyperhidrosis, eczema,
drug reaction with eosinophilia and systemic symptoms (DRESS) , acute
generalised exanthematous pustulosis (AGEP)


Musculoskeletal, Connective tissue and bone disorders

Uncommon:                Arthralgia, myalgia

Not known:                 Muscular weakness, prolonged muscle relaxation


Renal and urinary disorders

Common:                    Blood creatinine increased, blood urea increased

Not known:                 Tubulointerstitial nephritis , renal failure

General disorders and administration site conditions

Common:                    Pyrexia, injection site reaction

Uncommon:                Chills

Not known:                 Oedema, fatigue


Psychiatric Disorders

Not known:                 Hallucinations


Piperacillin therapy has been associated with an increased incidence of pyrexia and rash in cystic
fibrosis patients.
† Adverse event identified post-marketing.


DOSAGE AND ADMINISTRATION

Dosage
TAZOCIN EF may be given by slow intravenous injection, by infusion (20-30 minutes).


Adults and children 12 years and older
The usual intravenous dosage for adults and children with normal renal function is 4 g
piperacillin/0.5 g tazobactam (TAZOCIN EF) given every eight hours.

The total daily dose depends on the severity and localisation of the infection and can vary from 2
g piperacillin/0.25 g tazobactam to 4g piperacillin /0.5g tazobactam (TAZOCIN EF) administered
every six, eight or twelve hours.

Use in neutropenic patients -adults and children over the age of 12:
In neutropenic patients, the usual intravenous dosage for adults and children with normal renal
function is 4.5 g TAZOCIN EF given every eight hours as a 30 minute infusion, in conjunction with
an aminoglycoside. The total daily dose depends on the severity and localisation of the infection and
can vary from 2.25 g to 4.5 g TAZOCIN EF administered every six or eight hours.

Tazocin EF has been shown to have a synergistic effect with an aminoglycoside against
Pseudomonas infection. Therefore combination therapy is recommended for use in neutropenic
patients, in whom infection is attributed predominantly to Pseudomonas organisms.


Children under the age of 12 years:

Recommended Intravenous Dosage
Hospitalised children with intra-abdominal infection
For children aged 2 to 12 years, weighing up to 40 kg, and with normal renal function, the
recommended dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram every 8 hours.

For children aged 2 to 12 years, weighing over 40 kg, and with normal renal function, follow the
adult dose guidance, ie 4 g piperacillin/0.5 g tazobactam every 8 hours.

The duration of therapy should be guided by the severity of the infection and the patient's clinical
adult dose guidance, ie 4 g piperacillin/0.5 g tazobactam every 8 hours.

The duration of therapy should be guided by the severity of the infection and the patient's clinical
and bacteriological progress. Therapy is recommended to be a minimum of 5 days and a
maximum of 14 days, considering that dose administration should continue at least 48 hours after
the resolution of clinical signs and symptoms.



Renal insufficiency:
In patients with renal insufficiency, the intravenous dose should be adjusted to the degree of
actual renal function impairment. The suggested daily doses are as follows:






Intravenous dosage schedule for adults with impaired renal function


Creatinine Clearance (mL/min)


>40
20-40


<20



Recommended piperacillin / Tazobactam
Dosage

NO DOSAGE ADJUSTMENT NECESSARY
12 g/1.5g/day
Divided Dose
4g piperacillin/0.5g tazobactum q 8 hr
8g /1g/day
Divided Dose
4g piperacillin/0.5g tazobactum q 12 hr


For patients on haemodialysis, the maximum daily dose is 8 g/1 g/day TAZOCIN EF. In addition,
because haemodialysis removes 30%-50% of piperacillin in 4 hours, one additional dose of 2 g
piperacillin/0.25 g tazobactam (TAZOCIN EF) should be administered following each dialysis
period. For patients with renal failure and hepatic insufficiency, measurement of serum levels of
TAZOCIN EF will provide additional guidance for adjusting dosage.


Children aged 2 to 12 years:

The pharmacokinetics of piperacillin/tazobactam have not been studied in paediatric patients with
renal impairment. Each patient must be monitored closely for signs of drug toxicity. Drug dose
and interval should be adjusted accordingly.


Duration of therapy:

In acute infections, treatment with TAZOCIN EF should be for a minimum of five days and
continued for 48 hours beyond resolution of clinical symptoms or the fever.


Co-administration of piperacillin/tazobactam with aminoglycosides

Due to the in vitro inactivation of the aminoglycoside by the beta-lactam antibiotics,
piperacillin/tazobactam and the aminoglycoside are recommended for separat e administrat ion.
Piperacillin/tazobactam and the aminoglycoside should be reconstituted and diluted separately
when concomitant therapy with aminoglycosides is indicat ed.

The following compatibility information doesnot apply to the piperacillin/tazobactam formulation
not containing EDTA.



In circumstances where co-administrat ion is preferred, the ref ormulat ed piperacillin/tazobactam
containing EDTA (TAZOCIN EF) supplied in vialsiscompatiblefor simultaneousco-
administration viaY-site infusion only with the following aminoglycosidesunder the following
conditions
Aminoglycosides
Piperacillin/tazobactam
(gram) dose
Tazobactum Diluent volume(ml)
Aminoglycosides
Concentration
Range(mg/ml)
Acceptable
Diluent
Amikacin
2.25,3375,45
50,100,150
1.75-7.5
0.9%
Sodium Choloride of
5%
dextrose
Gentamicin
2.25,3375,45
100,150
0.7-3.32
0.9%
Sodium
Chloride

















The dose of aminoglycoside should be based on pat ient weight, status of infection
(serious or life threatening) and renal function (creatinine clearance).

Compatibility of piperacillin/tazobactam with other aminoglycosides has not been established.
Only the concentration and diluents for amikacin and gentamicin with the dosages of
piperacillin/tazobactam listed in the above table have been established as compatible for co-
administration via Y-site infusion. Simultaneous co-administration via Y-site in any manner other
than listed above may result in inactivation of the aminoglycoside by piperacillin/tazobactam


Administration

Reconstitution Directions

For intravenous use

Diluents for Reconstitution:Sterile                 Water for Injections
Sodium Chloride Injection
Dextrose 5% in Water



When swirled constantly, reconstitution generally occurs within 5 to 10 minutes. The reconstituted
solution should be withdrawn from the vial by syringe. When reconstituted as directed, the vial
contents withdrawn by syringe will provide the labelled amount of TAZOCIN EF. Solutions of
TAZOCIN EF prepared in this manner appear clear to slightly yellow in colour.

Vial Size (piperacillin/tazobactam)

4,50 g (4 g/0.5 g)

Minimum volume of diluent to be added
To vial
20 ML
Reconstitute each vial with the volume of diluent shown in the table below, using one of the above
Diluents.






Administration Directons

For intravenous use:
The reconstituted solution may be further diluted to the desired volume (e.g. 50 mL to 150 mL)
with one of the compatible diluents for intravenous use listed below.
Compatible Intravenous Diluents:

1.0.9% Sodium Chloride for Injection.
2. Sterile Water for Injection.
3.Dextrose 5%.
4.Dextran 6% in Saline.
4.Lactated Ringer’s Solution (Only compatible with piperacillin/tazobactam EDTA

reformulation and is compatible for co-administration via a Y-site).
*Maximum recommended volume of Sterile Water for Injection per dose is 50 mL.

Pharmaceutical Incompatibilities
TAZOCIN EF should not be mixed with other drugs in a syringe or infusion bottle since
compatibility has not been established. Whenever TAZOCIN EF is used concurrently with
another antibiotic, the drugs must be administered separately. The mixing of TAZOCIN EF with
an aminoglycoside can result in substantial inactivation of the aminoglycoside. However,
amikacin
and gentamicin were determined to be compatible with

TAZOCIN EF in certain diluents at
specific concentrations (see DOSAGE AND ADMINISTRATION:
Co-administration of piperacillin/tazobactam with Aminoglycosides)
Because of chemical instability, TAZOCIN EF should not be used with solutions containing only
sodium bicarbonate or having a pH in the basic range.
TAZOCIN EF should not be added to blood products or albumin hydrolysates.

OVERDOSAGE
There have been post-marketing reports of overdose with piperacillin/tazobactam. The majority
of those events experienced including nausea, vomiting, and diarrhoea have also been reported
with the usual recommended dosages. Patients may experience neuromuscular excitability or
convulsions if higher than recommended doses are given intravenously (particularly in the
presence of renal failure).

No specific antidote is known. In the event of an emergency, all required intensive medical
measures are indicated as in the case of piperacillin. In cases of motor excitability or convulsions,
anticonvulsive agents (e.g. diazepam or barbiturates) may be indicated. In cases of anaphylactic
reactions, the usual counter measures are to be initiated (adrenaline, antihistamines,
corticosteroids and, if required, oxygen and airway management).

Excessive serum concentrations of either piperacillin or tazobactam may be reduced by
Haemodialysis.


PRESENTATION
2.25g vial containing piperacillin sodium 2.085 g equivalent to 2 g piperacillin and tazobactam
sodium 0.2683 g equivalent to 250 mg tazobactam..

5 g vial containing piperacillin sodium 4.170 g equivalent to 4 g piperacillin and tazobactam
sodium 0.5366 g equivalent to 500 mg tazobactam.

STORAGE AND STABILITY

Lyophilized
Vials containing sterite TAZOCIN EF lyophilized power may be stored below
30 for to 2year.


Solution:
Diluted solution should be used immediately.

DATE OF PREPARATION
13 Oct 2015

Reference:

1.      Daley.D..Mulgrave L.S. Smith H and Dimech. W .An evalution of the in vitro activity
of piperacillin/tazobactam Pathology 28:167-172. 1996
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4.      Russo J., Thompson M., Russo M.E., et al. Piperacillin Distribution into Bile, Gallbladder Wall, Abdominal Skeletal Muscle and Adipose Tissue in Surgical Patients. Antimicrob Agents Chemother 1982; 22(3):488-492.
5.      Morrison, J., Batra, V. Pharmacokinetics of Piperacillin Sodium in Man. Drugs Exptl Clin Res 1979; 5(2-3):105-110.
6.      Tjandramaga, T., Mullie, A., Verbesselt, R., De Schepper, P., Verbist, L. Piperacillin: Human Pharmacokinetics After Intravenous and Intramuscular Administration. Antimicrob Agents Chemother 1978; 14(6):829-837.
7.      Verbist, L. In vitro activity of piperacillin, a new semisynthetic penicillin with an unusually broad spectrum of activity. Antimicrob Agents Chemother 1978; 13(3):349-357.
8.      Winston, D.J., Murphy, W., Young, L.S., Hewitt, W. Piperacillin therapy for serious bacterial Infections. Am J Med 1980; 69:255-261.
9.      Higashitani, F., Hyodo, A., Ishida, N., Inoue, M., Mitsuhasi, S. Inhibition of Beta-Lactamases by tazobactam and in vitro antibacterial activity of tazobactam combined with piperacillin. J Antimicrob Chemother 1990; 25(4):567-574.
10.  Diver, J.M., Thornber, D., Wise, R. Protection of Piperacillin and Ticarcillin from Beta-Lactamase Hydrolysis by Tazobactam (YTR 830) and Clavulanic Acid. J Antimicrob Chemother 1989; 24(1):89-92.
11.  Jones, R.N., Pfaller, M.A., Fuchs, P.C., Aldridge, K., Allen, S.D., Gerlach, E.H. Piperacillin/Tazobactam (YTR 830) combination. Comparative antimicrobial activity against 5889 recent aerobic clinical isolates and 60 Bacteroides fragilis group strains. Diagn Microbiol Infect Dis 1989; 12(6):489-494.
12.  Wise, R., Gillett, A., Cadge, B., Durham, S., Baker, S. The influence of protein binding upon tissue fluid levels of 6 beta-lactam antibiotics. J Infect Dis 1980; 142:77-82.
13.  Kuck, N.A., Petersen, P.J., Weiss, W.J., Testa, R.T. In Vitro and In Vivo Efficacy of YTR-830H and Piperacillin Combinations Versus Beta-Lactamase Producing Bacteria. J Chemother 1989; 1(3):155-161.
14.  Neu, H.C., Niu, W., Chin, N. Tazobactam Prevention of Emergence of Resistance. Diagn Microbiol Infect Dis 1989; 12:477-480.
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25.  Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, Wayne, PA 2012.
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27.  Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11. Clinical and Laboratory Standards Institute, Wayne, PA 2012.

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