Extended-infusion Piperacillin-Tazobactam Versus Intermittent-Infusion Dosing Strategy in Critically Ill Patients With Suspected or Confirmed Bacterial Infections.
Phase: PHASE4
Conditions: Gram-Negative Infections
Sponsor: Ain Shams University

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Extended-infusion Piperacillin–tazobactam 
versus Intermittent-Infusion Dosing Strategy 
in Critically Ill Patients with suspected or 
confirmed bacterial Infections. 
 
Date: 24/7/2018 
 
 
 

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Extended-infusion Piperacillin–tazobactam versus Intermittent-
Infusion Dosing Strategy in Critically Ill Patients with suspected or 
confirmed bacterial Infections. 
 
Presented By 
Christina Medhat Naiim  
Teaching Assistant in Clinical Pharmacy Department 
Faculty of Pharmacy 
British University in Egypt (BUE)  
 
Supervised By 
Dr. Nagwaa Sabry 
Head of Clinical Pharmacy Department 
Ain Shams University  
 
Prof.Dr. Mohey Elmazar  
Head of Clinical Toxicology & Pharmacology Department 
 Dean of Faculty of Pharmacy 
 The British University in Egypt (BUE)  
 
                                                       Dr.Naglaa Bazan 
Fellow (Lecturer) and Head of Clinical Pharmacy 
Critical Care Medicine Department 
Cairo University Hospitals 

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Introduction 
Treating gram-negative infections is becoming increasingly difficult due to the emergence of 
resistant pathogens. Studies have demonstrated worse outcomes for patients with resistant 
pathogens based on the premise of inappropriate antimicrobial therapy. The use of currently 
available antimicrobial agents can be optimized through pharmacodynamic parameters to improve 
treatment efficacy and patient outcomes (Winstead et al., 2016). 
 
Piperacillin–tazobactam, is a beta-lactam beta-lactamase inhibitor combination antibiotic widely 
used in the treatment of complicated and hospital-acquired infections. It’s a time-dependent 
antibiotic, that is widely used in the treatment of serious gram-negative healthcare-associated 
infections (Winstead et al., 2016). 
 
The authorized mode of administration described in the product insert is by 30-min intermittent 
infusions. Nonetheless, some authors recommended continuous infusion to optimize treatment of 
infections due to multiresistant bacteria and those for which the minimum inhibitory concentration 
(MIC) of antibiotic is high (effectiveness has direct relationship with the percentage of time that 
the antibiotic levels are above the MIC). MIC is the lowest concentration of an antimicrobial that 
will inhibit the visible growth of a microorganism after overnight incubation (Luque et al., 2015) 
 
Therefore, Continuous infusions of beta-lactam antibiotics have been employed in an attempt to 
maximize the time that free drug concentrations exceed the bacterial MIC. Several studies have 
shown beneficial outcomes associated with continuous infusion piperacillin–tazobactam, 
including higher antibiotic concentrations, improvement in clinical cure rates, and quicker time to 
defervescence (Grant et al., 2002). 
 
One retrospective cohort study comparing extended versus intermittent infusions of piperacillin–
tazobactam in Pseudomonas aeruginosa infections found the 14-day mortality rate to be 
significantly lower among patients who received extended-infusion therapy (4-h infusion of 
piperacillin–tazobactam 3.375 g administered IV every 8 h) compared with patients who received 

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intermittent-infusions (infused over 30 min), but this reduction in 14-day mortality was only 
observed in patients with Acute Physiological and Chronic Health Evaluation-II (APACHE-II) 
scores of 17 or more (Lodise et al., 2007). 
 
A separate retrospective, two-site trial was conducted in an attempt to replicate these results 
using extended-infusion piperacillin–tazobactamin gram-negative infections and found no 
difference in 30-day mortality or length of stay (Patel et al., 2009). 
 
A multicenter, retrospective trial was conducted in 14 hospitals to compare 4-h extended-
infusion piperacillin–tazobactam to intermittent infusions of comparator antibiotics in gram-
negative infections (Patel et al., 2009). In-hospital mortality was significantly reduced in the 
extended-infusion piperacillin–tazobactamarm compared with intermittent- infusion piperacillin–
tazobactam (Yost et al., 2011). Additional retrospective studies have been conducted using 4-h 
infusions of piperacillin–tazobactam 3.375 g administered IV every 8 h and have demonstrated 
reductions in both mortality and length of stay (Lee et al., 2012). 
 
Continuous infusion of other beta-lactam drugs has been successfully used (clinical cure was 
achieved) in several clinical situations, such as neutropenia, cystic fibrosis, Pseudomonas 
aeruginosa infection in which intermittent administration failed. (Dulhunty et al., 2013). There 
are, however, few randomized studies comparing the efficacy of intermittent versus continuous 
infusion in this group of antibiotics (Ashima Lal et al., 2016).  
 
Findings from meta-analyses and reviews have not provided conclusive data on the comparative 
effectiveness of the two modes of administration intermittent versus continuous. (Roberts et al., 
2007) although one prospective, open-label controlled study reported a significantly shorter time 
to defervescence, higher clinical cure rate, and lower cost with continuous administration. The 
lower dose continuous regimen has been shown to provide serum concentrations above the levels 
reached by intermittent infusion in the steady-state (Grant et al., 2002). 
 
 

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Aim of the study 
Evaluating the effectiveness and safety of extended-infusion piperacillin–tazobactam dosing 
strategy versus intermittent-infusion dosing in critically ill patients with suspected or proved 
bacterial infections. 
 
Patients and Methods 
Study Design 
A prospective randomized comparative study will be conducted at Critical Care Medicine 
Department - Cairo University Hospitals 
Patients: 
A total of 52 patients will be recruited from ICU- Cairo University Hospitals.  All adult critically 
ill patients admitted to Critical Care Medicine Department with suspected or confirmed bacterial 
infections on admission or during their ICU stay will be assessed for inclusion into the study.  
Inclusion criteria 
 
• 
Adults aged 18-74 years 
• 
Expected ICU stay more than 24 hours 
Exclusion Criteria: 
• 
Allergy or potential allergy to the study medications  
• 
Pregnancy 
• 
Patients with CrCl< 20 ml/min or on dialysis  
• 
Cancer patients 
 
 
 

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Recruited patients will be randomly assigned to either of two groups as follows:  
Group I (n=26) will receive pipracillin/tazobactam as intermittent infusion (over 30min) every 8 
hours. (Kim etal., 2002) 
Group II (n=26) will receive piperacillin/tazobactam as extended infusion (over 4 hours) every 8 
hours. (Kim etal., 2007) . 
Calculation of sample size: 
To achieve a power of 80% and a significant level of 5% based on an effect size conventions of 
0.8 and the expected comparison of the difference between two independent means using G 
power program (3.010). The number of patients per arm was found to be 26. 
Recruited patients' demographics, comorbidities, current medications and laboratory parameters 
will be recorded from patients’ files. APACHE II scores will be determined during the first 24 
hours of inclusion into the study and on day of stopping antibiotic, discharge and/or death of the 
patient. Microbiological cultures from suspected site of infection and blood cultures will be 
withdrawn from all patients before starting antibiotic therapy.   
All patients will be subjected to the following: 
 
A. Patient's full history: 
1) Age 
2) Sex  
3) Medical history 
4) Concurrent diseases 
5) Concurrent medications 
 
B. Patient evaluation and assessment: 
 
The following will be evaluated at baseline and periodically thereafter until day of stopping 
antibiotic, discharge and/or death : 
 
1) Kidney functions (Serum creatinine, blood urea nitrogen) 
2) Liver functions (ALT, AST, Bil D, Bil T, Albumin) 
3) Complete blood count 

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4) Microbiological Evaluation: Cultures and sensitivity tests from suspected site of infection 
will be withdrawn from all patients at baseline (before starting antibiotic) and at end of 
therapy 
5) Clinical signs and symptoms of infection documented by the attending physician on 
patient’s medical record  
6) APACHE II Variables: 
• Partial pressure of O2 in arterial blood (PaO2) 
• Mean arterial pressure (MAP) 
• Temperature 
• Heart rate 
• Respiratory rate 
• Arterial pH 
• Sodium plasma levels 
• Potassium plasma levels. 
• Serum Creatinine 
• Hematocrit 
• White blood count 
• Glasgow coma score (The GCS is the summation of scores for eye, verbal, and motor 
responses. The minimum score is a 3 which indicates deep coma or a brain-dead state. The 
maximum is 15 which indicates a fully awake patient (the original maximum was 14, but 
the score has since been modified) 
• Lactate, serum blood glucose, AST, ALT, BUN will be detected 
Outcomes 
Effectiveness 
• Clinical cure: defined as complete resolution of the clinical signs and symptoms of 
infection (Physical assessment, white blood cells with differential, temperature) 
• Composite endpoint of 30 day mortality or readmission within 30 days of discharge.  
• Length of stay at the ICU  
 

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➢ Safety: 
Any adverse events occurring during study period will be recorded 
 
➢ Pharmacoeconomic Analysis 
A cost-effectiveness analysis will be performed for level-1 and level-2 costs from the health care 
provider perspective, comparing treatment with continuous infusion versus intermittent infusion. 
The level-1 analysis will be limited to acquisition prices of drugs, whereas the level-2 analysis will 
encompass all costs directly related to antibiotic use: supplies, preparation, administration, daily 
hospital stay cost, treatment of adverse events, concomitant antibiotics, and expenditures for 
treating failures. 
A decision tree categorizing each case as a treatment success or failure will be employed to 
compare the cost-effectiveness of intermittent versus continuous infusion with regard to average 
level-1 and level-2 costs. A sensitivity analysis will be performed to determine which study 
conditions or variables, if changed, will alter the economic outcome. One-way sensitivity analyses 
will be performed by varying each treatment arm’s probability of success from 50–95%.  
 
 
 
 
 
 
 
 
 
 
 

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References:  
Winstead EM, Ratliff PD, Hickson RP. Mueller JE, Judd WR. Evaluation of an alternative 
extended-infusion piperacillin–tazobactam dosing strategy for the treatment of gram-negative 
infections. International Journal of Clinical Pharmacy.2016; 38(5): 1087-1093. 
 
Cotrina-Luque J, Gil-Navarro MV, Acosta-García H, Alfaro-Lara ER, Luque-Márquez R, 
Beltrán-García M, Bautista-Paloma FJ.Continuous versus intermittent piperacillin/tazobactam 
infusion in infection due to or suspected pseudomonas aeruginosa. Int J Clin Pharm. 2016; 
38(1):70-9. 
 
Lodise TP Jr, Lomaestro B, Drusano GL. piperacillin–tazobactam for Pseudomonas aeruginosa 
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Patel GW, Patel N, Lat A. Outcomes of extended infusion piperacillin/tazobactam for 
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