Piperacillin/Tazobactam in Sepsis

Management
Speaker

SP.21.11.BRO01
 Sepsis

 Sepsis is life-threatening organ dysfunction caused by

a dysregulated host response to infection. Sepsis and
the inflammatory response that ensues can lead to
multiple organ dysfunction syndrome and death.
 Sepsis and septic shock are major healthcare
problems, impacting millions of people around the
world each year and killing between one in three and
one in six of those it affects.
 Early identification and appropriate management in
the initial hours after the development of sepsis
improve outcomes.

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (nih.gov)
 Epidemiology

 For the first time in 2020, the Global Burden of Disease program
provided a comprehensive assessment of the burden of sepsis
which demonstrated much higher sepsis incidence than previously
reported.
 The global burden of sepsis is difficult to ascertain, although a
recent scientific publication estimated that in 2017 there were 48.9
million cases and 11 million sepsis-related deaths worldwide,
which accounted for almost 20% of all global deaths.
 In 2017, almost half of all global sepsis cases occurred among
children, with an estimated 20 million cases and 2.9 million global
deaths in children under five years of age.
 Significant regional disparities in sepsis incidence and mortality
exist; approximately 85.0% of sepsis cases and sepsis-related
deaths worldwide occurred in low- and middle-income countries.
Ref: https://www.who.int/news-room/fact-sheets/detail/sepsis
 Risk Factors

Anyone affected by an infection, severe injury, or serious non-communicable disease

can progress to sepsis but vulnerable populations are at higher risk including:

 older persons,
 pregnant or recently pregnant women,
 neonates,
 hospitalized patients,
 patients in intensive care units,
 people with HIV/AIDS,
 people with liver cirrhosis,
 people with cancer,
 people with kidney disease,
 people with autoimmune diseases,
 and people with no spleen.

Ref: https://www.who.int/news-room/fact-sheets/detail/sepsis
 Signs and symptoms
Sepsis is a medical emergency and can present with various signs and
symptoms at different times. Warning signs and symptoms include:

 fever or low temperature and shivering,

 altered mental status,
 difficulty breathing/rapid breathing,
 increased heart rate,
 weak pulse/low blood pressure,
 low urine output,
 cyanotic or mottled skin,
 cold extremities,
 and extreme body pain or discomfort.

Suspecting sepsis is a first major step towards early recognition and diagnosis.
Ref: https://www.who.int/news-room/fact-sheets/detail/sepsis
 Causes
 In 2017, the largest contributors to sepsis cases and sepsis-related
mortality across all ages were diarrheal diseases (9.2 to 15 million
annual cases) and lower respiratory infections (1.8-2.8 million annually)
 However, non-communicable diseases are on the rise; one-third of
sepsis cases and nearly half of all sepsis-related deaths in 2017 were
due to an underlying injury or chronic disease.
 Maternal disorders were the most common non-communicable
disease complicated by sepsis.
 Among children, the most common causes of sepsis-related deaths
were neonatal disorders, lower respiratory infections, and diarrheal
diseases.
 Group B streptococcus is the leading cause of both neonatal and
maternal sepsis, though Escherichia coli is an emerging threat. Both
pathogens have displayed considerable resistance to treatment and
are considered priority pathogens for research and development (R&D)
of new antibiotics.
Ref: https://www.who.int/news-room/fact-sheets/detail/sepsis
 Prevention
There are two main steps to preventing sepsis:
 Prevention of microbial transmission and infection
 Prevention of an infection evolving into sepsis
Prevention of infection in the community involves using effective hygiene
practices, such as hand washing, and safe preparation of food, improving
sanitation and water quality and availability, providing access to vaccines,
particularly for those at high risk, as well as appropriate nutrition, including
breastfeeding for newborns.
Prevention of infection in health care facilities mainly relies on having
functioning infection prevention and control (IPC) programmes and teams,
effective hygiene practices and precautions, including hand hygiene, along with a
clean, well-functioning environment and equipment.
Prevention of the evolution to sepsis in both community and health care facilities
requires the appropriate antibiotic treatment of infection, including
reassessment for optimization, prompt seeking of medical care, and early
detection of sepsis signs and symptoms.
Ref: https://www.who.int/news-room/fact-sheets/detail/sepsis
 Prevention

Ref: https://www.who.int/news-room/fact-sheets/detail/sepsis
 Diagnosis and Clinical Management

 Identifying and not underestimating the signs and symptoms along with
the detection of some biomarkers (such as C reactive protein and
procalcitonin), are crucial elements for early diagnosis of sepsis and the
timely establishment of its appropriate clinical management.
 After early recognition, diagnostics to help identify a causal pathogen of
infection leading to sepsis are important to guide targeted antimicrobial
treatment.
 Once the source of infection is determined, source control, such as
drainage of an abscess, is critical.
 Antimicrobial resistance (AMR) can jeopardize clinical management of
sepsis because empirical antibiotic treatment is often required. Early fluid
resuscitation to improve volume status is also important in the initial
phase of sepsis management. In addition, vasopressors may be required to
improve and maintain tissue perfusion.
 Repeated exams and assessments, including monitoring vital signs, guide
the appropriate management of sepsis over time.
Ref: https://www.who.int/news-room/fact-sheets/detail/sepsis
 Surviving Sepsis
Campaign:
International
Guidelines for
Management of
Sepsis and Septic
Shock 2021

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (springer.com)
 Surviving Sepsis
Campaign:
International
Guidelines for
Management of
Sepsis and Septic
Shock 2021

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (springer.com)
 Surviving Sepsis
Campaign:
International
Guidelines for
Management of
Sepsis and Septic
Shock 2021

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (springer.com)
 Surviving Sepsis
Campaign:
International
Guidelines for
Management of
Sepsis and Septic
Shock 2021

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (springer.com)
 Surviving Sepsis
Campaign:
International
Guidelines for
Management of
Sepsis and Septic
Shock 2021

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (springer.com)
 Surviving Sepsis
Campaign:
International
Guidelines for
Management of
Sepsis and Septic
Shock 2021

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (springer.com)
 Surviving Sepsis
Campaign:
International
Guidelines for
Management of
Sepsis and Septic
Shock 2021

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (springer.com)
 Surviving Sepsis
Campaign:
International
Guidelines for
Management of
Sepsis and Septic
Shock 2021

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (springer.com)
 Antibiotics

 Early administration of appropriate antimicrobials is one of the most effective

interventions to reduce mortality in patients with sepsis. Delivering
antimicrobials to patients with sepsis or septic shock should therefore be
treated as an emergency.
 According to “Surviving Sepsis Campaign: International Guidelines
for Management of Sepsis and Septic Shock 2021” For adults with possible
septic shock or a high likelihood for sepsis, it is recommended administering
antimicrobials immediately, ideally within 1 h of recognition.
 For adults with possible sepsis without shock, rapid assessment of the
likelihood of infectious versus non-infectious causes of acute illness is
recommended.
 Rapid assessment includes history and clinical examination, tests for both
infectious and non-infectious causes of acute illness and immediate treatment
for acute conditions that can mimic sepsis. Whenever possible this should be
completed within 3 h of presentation so that a decision can be made as to the
likelihood of an infectious cause of the patient’s presentation and timely
antimicrobial therapy provided if the likelihood of sepsis is thought to be high.
Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (nih.gov)
Antibiotics

Ref: Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (nih.gov)
 Diagnosis and Clinical Management

Ref: https://www.researchgate.net/figure/Different-antibiotic-classes-at-a-glance-https-wwwcompoundchemcom-2014-09-08_fig1_330337388
 Severe Sepsis and Septic Shock Antibiotic Guide

Ref: https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/clinicalpathways/SHC-Sepsis-ABX-Guideline.pdf
 Severe Sepsis and Septic Shock Antibiotic Guide

Ref: https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/clinicalpathways/SHC-Sepsis-ABX-Guideline.pdf
 Severe Sepsis and Septic Shock Antibiotic Guide

Ref: https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/clinicalpathways/SHC-Sepsis-ABX-Guideline.pdf
 Severe Sepsis and Septic Shock Antibiotic Guide

Ref: https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/clinicalpathways/SHC-Sepsis-ABX-Guideline.pdf
 Severe Sepsis and Septic Shock Antibiotic Guide

Ref: https://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/clinicalpathways/SHC-Sepsis-ABX-Guideline.pdf
Microbiology of commonly used
Antibiotics

Gram +ve Gram –ve Anaerobic Nephro-

Groups Drugs Ototoxicity
coverage coverage coverage toxicity

Ceftriaxone
Cephalosporins Good Good Less No No
Ceftazidim

Ciprofloxacin
Quinolones Less Good Less No No
Levofloxacin

Gentamicin
Aminoglycoside Less Less Less Yes Yes
Amikacin

Glycopeptides Vancomycin Good No Less Yes No

Colistin Polimixin B Less Excellent Less Yes No

B lactam/
Piperacillin/
B lactamase Good Excellent Good No No
tazobactam
combination

Ref: Intensive Care Med. 1994 Jul;20 Suppl 3:S27-34

 Piperacillin/Tazobactam

Most effective beta-lactam/beta-lactamase inhibitor combination.

Piperacillin:
Semisynthetic, broad-spectrum, ampicillin
derived ureidopenicillin antibiotic.

Tazobactam:
Penicillin derivative which inhibits the action of
bacterial beta-lactamases and protects
piperacillin from destruction.

Ref: Drugs. 1999 May;57(5):805-4

Benefits of Combination

• Broadens the activity and antimicrobial coverage

• Covers Gram +ve and Gram –ve aerobic and anaerobic bacteria including
extended-spectrum beta-lactamase (ESBL) producing bacteria
• Active against resistant Enterobacteriaceae
[Salmonella, E.coli, Klebsiella, Shigella, Proteus, Enterobacter]

• Good safety and tolerability profile.

Ref: Expert Rev Anti Infect Ther. 2007 Jun;5(3):365-83

High susceptibility against Pseudomonas sp.

25,460 isolates were tested from 1997 to 2007

Pseudomonas isolates were taken from 10 countries and 27 hospitals

Piperacillin/Tazobactam
83.60%
Meropenem
83%
Imipenem
79.70%
Cefepime
77.50%
Ceftazidin
75.80%
Ciprofloxacin
71.50%

Ref: Diagnostic Microbiology and Infectious Disease 65 (2009) 331–334

Resistance to ‘Superbugs’

Ref: Bangladesh Crit Care J September 2016 Vol. 4 (2): 69-73

Adverse reactions & Precaution

Adverse reaction:
• Phlebitis (1.3%)
• Inflammation at injection site (1.3%)
• Thrombophlebitis (0.2%)

Precaution:
• Caution should be exercised in patients with history of asthma, hay
fever or during pregnancy and breastfeeding

• Caution should be taken if allergic to the drug or to penicillin,

cephalosporin, or other beta-lactam antibiotics.
Dosage and Duration

• Piperacillin/Tazobactam is given intravenously as a bolus injection

over 3 to 5 min or by Infusion over 20-30 minutes.

• Usual adult dose: 4.5g every 6 hours

• Usual duration of treatment is from 7 to 10 days.

Child dose

Child dose:
2-8 month: 80 mg/kg IV every 8 hours

9 month-older:
Weight 40 kg or less: 100 mg/kg IV every 8 hours
Weight greater than 40 kg: Usual adult dose every 6 hours.

Brodactam is approved for children above 2 month of age.

Dose schedule for patients with renal impairment

Renal Function All Indications

Nosocomial
(Creatinine (except nosocomial
pneumonia
clearance)mL/min pneumonia)
> 40 ml/min 3.375 g 6h 4.5 g 6h
20-40 ml/min* 2.25 g 6h 3.375 g 6h
<20 ml/min* 2.25 g 8h 2.25g 6h
Hemodialysis** 2.25 g 12h 2.25 g 8 h
CAPD 2.25 g 12 h 2.25 g 8 h

*Creatinine clearance for patients not receiving hemodialysis

**0.75 g should be administered following each hemodialysis session on hemodialysis days.
Drug Interactions

• Probenecid administered with piperacillin/tazobactam prolongs the

half-life of piperacillin/tazobactam

• Co-administration of methotrexate and piperacillin may reduce the

clearance of methotrexate due to competition for renal secretion.
Reconstitution

Withdraw 20 ml diluent by disposable syringe and push into the

vial containing drug

Mix to become the vial content a complete solution

Withdraw total solution by the syringe and push into the vial of
0.9% Sodium Chloride solution

Vials should be used immediately after reconstitution.

Thank You