Pharmacokinetic, Pharmacodynamic, and Clinical Efficacy of Continuous or Extended Infusion Regimens of Piperacillin/Tazobactam

Special Feature

By Jessica C. Song, MA, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.

Jessica C. Song reports no financial relationships relevant to this field of study.

Piperacillin/Tazobactam (P/T) offers one of the broadest antimicrobial spectrums, and is equipped with an effective mechanism to maintain its potency in the presence of beta-lactamases. The potent and broad spectrum activity of P/T makes it a viable option for empirical treatment of mixed infections, multidrug-resistant pathogens, and beta-lactamase-producing organisms.1-4 With such a wide spectrum of activity, and potential for many uses, overuse of this agent may account for a sizeable percentage of hospitals' antimicrobial expenditures.4

Time-dependent antimicrobial agents, including ß-lactam/ß-lactamase inhibitor antibiotics such as P/T, rely on the length of time that concentrations are maintained above the pathogen's minimal inhibitory concentration (MIC) to maximize bacterial eradication.5-11 For time-dependent drugs such as P/T, the percentage of time that drug levels exceed the MIC (%T > MIC) required to yield a bactericidal effect can vary to some extent, depending on the pathogen. Adequate drug exposure for Staphylococcus aureus and Streptococcus pneumoniae/Enterobacteriaceae usually is achieved with %T > MIC of at least 40%-50% and 60%-70% of the dosing interval, respectively.12,13

Recent years have witnessed the development of both prolonged- and continuous-infusion P/T regimens in an attempt to maximize efficacy against challenging pathogens such as Pseudomonas aeruginosa, while minimizing acquisition costs associated with P/T.5-11 At present, limited published data exist on the pharmacokinetics/pharmacodynamics and clinical efficacy of prolonged- and continuous-infusion P/T regimens in critically ill patients. The purpose of this review will be to discuss the pharmacokinetic and pharmacodynamic properties of extended- and continuous-infusion P/T regimens in critically ill patients. In addition, a summary of recently published clinical studies of extended- and continuous-infusion P/T regimens used in critically ill patients will be highlighted in this article.

Pharmacokinetics Pharmacodynamics

Attainment of target concentrations of P/T in critically ill, septic patients poses a challenge to clinicians, given the pathophysiological changes seen in this population. Critically ill patients have been shown to display increased volume of distribution and clearance of P/T, which places patients at risk for low plasma concentrations.5 Roberts et al conducted a pharmacokinetic/ pharmacodynamic study of 16 critically ill patients (see Table 1) with known or suspected sepsis.5 Eight patients received continuous infusion P/T (12/1.5 g daily), and eight patients received intermittent bolus P/T, given as 4.5 grams infused every 6 to 8 hours. Monte Carlo simulations were performed using three continuous infusion regimens, four intermittent administration regimens, and two extended infusion regimens.

P/T volume of distribution was approximately 2.5- to nearly four-fold higher in critically ill patients compared with other studies in healthy volunteers. In addition, P/T clearance reported in this study was considerably higher compared with other studies in healthy volunteers. Roberts et al proposed that the disease process led to increased cardiac output and consequent increased renal clearance. The probability of target attainment (PTA) of fT > MIC (free concentration maintained above the MIC for 50% of the dosing interval) ranged from a low of 40% with P/T infused intermittently as 4 g (as piperacillin) every eight hours up to 74% with P/T infused intermittently as 3 g every four hours. Extended-infusions of P/T 4 g every 6 to 8 hours yielded PTAs of 69% to 81%. Continuous infusion of P/T (8/1–16/2 g) yielded PTAs of 89% to 93%.

Table 1 summarizes key findings of other pharmacokinetic/pharmacodynamic studies of continuous-infusion and extended-infusion P/T. Briefly, Patel et al conducted a pharmacodynamic study6 of P/T extended-infusion and intermittent infusion regimens in 105 hospitalized patients, three of whom displayed creatinine clearances below 40 mL/min. The FDA recommends lowering P/T doses from 4.5 g given every six hours to 3.375 g infused every six hours in patients with creatinine clearances of 20-40 mL/min. A Monte Carlo simulation determined PTAs (50% fT > MIC) of intermittent-infusion and extended-infusion P/T regimens in patients with varying degrees of renal impairment. Of note, all P/T regimens yielded suboptimal PTAs at an MIC of 32 mg/L in patients with creatinine clearances ranging from 20 mL/min to 100 mL/min. Based on the PTAs observed in the few patients with creatinine clearances between 20 to 40 mL/min, Patel et al recommended a dose of intermittent P/T 3.375 g infused every six hours or P/T 3.375 g infused over four hours every 12 hours in patients with creatinine clearances at or below 20 mL/min.

Roberts et al measured subcutaneous tissue piperacillin concentrations (used microdialysis technique) in 13 ventilator-associated pneumonia patients who either received P/T 4.5 g infused every 6 to 8 hours or P/T (12/1.5 g) as a continuous infusion on a daily basis.7 The intermittent-infusion group received 235 mg/kg of piperacillin during the first 30 hours, whereas the continuous-infusion group received 164 mg/kg (p = 0.06). Patients who received intermittent-infusion P/T were significantly older (p = 0.04) than patients who received continuous-infusion P/T. Median tissue concentrations did not differ significantly between the two groups on days one and two of therapy.

Boselli et al determined alveolar concentrations of P/T in 40 ventilator-associated pneumonia (VAP) patients with normal/mild renal impairment (n = 20) or moderate-advanced renal impairment (n = 20). Patients in each group underwent randomization to receive P/T 12/1.5 g or 16/2 g daily as a continuous infusion, following a loading dose of P/T (4/0.5 g). Nine of the 20 patients with normal/mild renal impairment had infections caused by Pseudomonas aeruginosa (MICs, 1-4 mg/L). Sixty percent of the patients receiving the lower P/T dose yielded epithelial lining fluid concentrations of piperacillin below 16 mg/L; median epithelial lining fluid concentration/serum concentration ratios for piperacillin were 0.43 and 0.46, respectively, for higher and lower doses of P/T. None of the patients with moderate/advanced renal impairment yielded epithelial lining fluid concentrations of piperacillin below 16 mg/L. Roberts et al cautioned against using the lower dose of P/T (12/1.5 g) as a continuous infusion in VAP patients with normal renal function, since this regimen may not yield sufficiently high epithelial lining fluid concentrations of piperacillin in order to exceed the susceptibility breakpoint (16 mg/L) for both Enterobacteriaceae and nonfermentative gram-negative bacteria.

Studies Of Critically Ill Patients

Table 2 summarizes key points from three recently published clinical studies of continuous-infusion and extended-infusion P/T regimens in critically ill patients. Unfortunately, with the exception of one small study (n = 40), none of the published studies were prospective, randomized, and controlled studies. Lorente et al conducted a historical cohort study of 74 VAP patients during a five-year time period.9 Comparators included P/T (4.5 g given every six hours) and P/T administered as a continuous infusion (4.5 g infused over 6 hours every six hours). Compared with intermittent infusion-treated patients, continuous infusion-treated patients showed significantly higher cure rates when infected with gram-negative bacteria with higher MICs (8-16 mg/L). Continuous-infusion P/T showed similar efficacy as intermittent-infusion P/T with regard to mortality rate, length of ICU stay, and duration of mechanical ventilation.

Lodise et al performed a retrospective cohort study of 194 patients who had cultures positive for Pseudomonas aeruginosa (~ 50% from respiratory tract).10 Outcome measures included 14-day mortality and hospital length of stay. Patients either received P/T 3.375 g infused every four hours or P/T 3.375 infused over four hours every eight hours. The study investigators conducted a classification- and regression-tree analysis and found that patients with APACHE II scores of 17 and higher showed significantly lower 14-day mortality rates, along with significantly shorter median length of stay with extended-infusion P/T compared with intermittent-infused P/T.

In a prospective, randomized, controlled trial of 40 septic patients presenting with systemic inflammatory response syndrome,11 the clinical efficacy of piperacillin-intermittent (not combined with tazobactam; 3 g every six hours) infusion and piperacillin-continuous infusion (8 g daily) was assessed. Clinical outcome measures included reduction in APACHE II score, time to defervescence, normalization of white blood cell count, and mortality rate. Continous infusion-treated patients trended toward a shorter time to defervescence compared with intermittent infusion-treated patients (p = 0.08). Patients receiving continuous-infusion piperacillin exhibited significantly greater reductions in APACHE II scores compared with intermittent-infusion-treated patients (p < 0.05) on days two through four of piperacillin therapy. Continuous infusion-treated patients did not demonstrate superior mortality rates or shorter times to normalize white blood cell count compared with intermittent infusion-treated patients.

Conclusion

Over the past decade, novel dosing strategies for P/T, such as prolonged and continuous infusion, have been considered over traditional intermittent infusion in an attempt to optimize efficacy against challenging pathogens. Pharmacokinetic/ pharmacodynamic studies have primarily utilized doses of continuous infusion P/T ranging from 12/1.5 g to 16/2 g in critically ill patients. Clinical studies assessing the efficacy of continuous-infusion regimens have used daily doses of piperacillin ranging from 8g/day up to 16 g/day. In contrast, studies of extended-infusion P/T have used lower daily doses of P/T (9/1.125 g), which could result in substantial cost savings, given the high acquisition cost of P/T.

At Santa Clara Valley Medical Center (San Jose, CA), the acquisition costs of P/T 4.5 g IV Piggyback and P/T 3.375 g vial are $19.70 and $14.40, respectively (per Pharmacy Purchasing, Feb. 9, 2010). Typical daily doses of P/T in critically ill patients range from 4.5 g infused every six hours to 4.5 g infused every eight hours. Reducing the daily dose of P/T from 12/1.5 g-16/2 g to 9/1.125 g (given as extended infusion) would result in a 27%-45% dose reduction for each patient. Since the estimated annual P/T expenditure (2009) approached $800,000, switching from intermittent infusion of P/T to extended infusion of P/T could potentially lower annual expenditures by $216,000 to $360,000.

Numerous pharmacodynamic studies have established the efficacy of continuous-infusion and extended-infusion P/T regimens in attaining 50% T > MIC. However, randomized clinical studies with larger patient populations are warranted to further substantiate the benefits of extended infusion of piperacillin-tazobactam.

References

  1. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare associated pneumonia. Am J Respir Crit Care Med. 2005; 171: 388-416.
  2. Solomkin JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010; 50:133-164.
  3. Nelson L, et al. Clinical role of beta-lactam/beta-lactamase inhibitor combinations. Drugs. 2003;63:1511-1524.
  4. Xamplas RC, et al. Implementation of an extended-infusion piperacillin-tazobactam program at an urban teaching hospital. Am J Health-Syst Pharm. 2010;67:622-628.
  5. Roberts JA, et al. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents. 2010;35:156-163.
  6. Patel N, et al. Identification of optimal renal dosage adjustments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients. Antimicrob Agents Chemother. 2010;54:460-465.
  7. Roberts JA, et al. Piperacillin penetration into tissue of critically ill patients with sepsis: bolus versus continuous administration? Crit Care Med. 2009;37:926-933.
  8. Boselli E, et al. Alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to patients with ventilator-associated pneumonia. Crit Care Med. 2008;36:1500-1506.
  9. Lorente L, et al. Clinical cure of ventilator-associated pneumonia treated with piperacillin/tazobactam administered by continuous or intermittent infusion. Int J Antmicrob Agents. 2009;33:464-468.
  10. Lodise TP, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: Clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44:357-363.
  11. Rafati MR, et al. Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients. Int J Antimicrob Agents. 2006;28:122-127.
  12. Burgess DS. Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance. Chest. 1999;115:19S-23S.
  13. Klepser ME, et al. Comparison of the bactericidal activities of piperacillin-tazobactam, ticarcillin-clavulanate, and ampicillin-sulbactam against clinical isolates of Bacteroides fragilis, Enterococcus faecalis, Escherischia coli, and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 1997;41:435-443.

Table 1: Pharmacokinetics/Pharmacodynamics of Continuous Infusion/Extended Infusion Piperacillin/Tazobactam in Critically Ill Patients

Study Outcomes

Inclusion Criteria

Dosing Regimens

Patient Population

Results

Comments

Roberts (2010)

1. Probability of target attainment (PTA) of 50% time for which the free concentration of piperacillin/tazobactam (P/T) is maintained above minimum inhibitory concentration (MIC) during a dosing interval

2. Clearance (Cl), volume of distribution (Vd), maximum concentration (Cmax), and minimum concentration (Cmin)

Known or suspected sepsis; normal renal function (plasma creatinine < 120 μmol/L).

Intermittent bolus (IB): 4.5 g IV Q 6-8 h; continuous infusion (CI): day 1, 4.5 g loading dose followed by 8/1g P/T (in 500 mL normal saline); day 2 CI: 12/1.5 g P/T in 500 mL normal saline (given over 24 h)

Other Regimens Evaluated for PTA

P/T 3.375 g IV Q4h; P/T 3.375 g IV Q6h; P/T extended infusion 4.5 g IV Q6-8 h; P/T CI 16/2 g/d.

Sixteen critically ill patients (half assigned to each group); median ages, 41 y IB, 20 y CI; day 1 APACHE IIa scores 24 IB, 20, CI; all patients ventilated.

PTA: cumulative fraction of response (CFR) for P/T 3.375 g IV Q6g, 74%; P/T 3.375 g IV Q4h, 49%; P/T 4.5g IV Q8h, 40%; P/T 4.5g IV Q6h, 53%: P/T extended infusion (EI, over 3h for Q6 h and 4h for Q8h) 4.5g IV Q8h, 69%; P/T EI 4.5g IV Q6h, 81%; P/T CI 8/1g/d, 89%; P/T CI 12/1.5g/d, 92%; P/T CI, 16/2g/d, 93%

Pharmacokinetics: Cl 17.1 L/h (95% CI, 14.4-20.6); Vd: 25.0 L (95% CI, 19.2-34.4) ; Cmax 266.6 mg/L (208.2-292.3) for IB and 144 mg/L (118-224) for CI; day 1 Cmin 7.2 mg/L (3.2-12.5) for IB and 7.1 mg/L (3.8-26.4) for CI; day 2 Cmin 6.2 (2.7-10.7) mg/L for IB and 21.2 mg/L (15.9-30.6) for CI.

1. Cl of P/T in critically ill patients 52%-112% higher vs. healthy volunteers; 25% higher in critically ill vs. patients with intra-abdominal infections.

2. Vd of P/T in critically ill patients 2.5-3.4-fold higher vs. healthy volunteers and 12% higher vs. intra-abdominal infection patients.

3. Likelihood of attaining 50% fT > MICb improved with EI and CI P/T regimens.

Patel (2010)

To determine PTA of 50% fT > MIC for patients with varying degrees of renal impairment who received traditional (IB) vs. extended infusion (EI) P/T.

Provision of plasma samples from hospitalized patients receiving P/T.

IB P/T: If CrClc > 40 mL/min, 4.5 g IV Q6 h; if CrCl 20-40 mL/min, 3.375 g IV Q6h; infusion, 0.5h

EI P/T:If CrCl > 40 mL/min, 3.375 g IV Q8h (infused 4h); if CrCl 20-40 mL/min, 3.375 g IV Q12h (infused 4 h)

93 hospitalized patients received IB P/T, and 12 hospitalized patients received EI P/T; mean age 53.2 y, 63% male, mean weight 71.3kg, mean CrCl, 91.6 mL/min (only 3 patients had CrCl < 40 mL/min)

Probabilities of achieving 50% fT>MIC with IB P/T:

4.5 g IV Q6 h (CrCl 100 mL/min): 0.93 for MIC (mg/L) 1; 0.88 for MIC 2; 0.81 for MIC 4; 0.67 for MIC 8; 0.46 for MIC 16; 3.375g IV Q6h (CrCl 40 mL/min): 0.99 for MIC 1; 0.98 for MIC 2; 0.95 for MIC 4; 0.90 for MIC 8; 0.77 for MIC 16; 3.375g IV Q6h (CrCl 20 mL/min): 0.99 for MIC 1; 0.99 for MIC 2; 0.98 for MIC 4; 0.95 for MIC 8; 0.88 for MIC 16

Probabilities of achieving 50% fT>MIC with EI P/T:

3.375 g IV (4h) Q8 h (CrCl 100 mL/min): 0.99 for MIC (mg/L) 1; 0.99 for MIC 2; 0.99 for MIC 4; 0.97 for MIC 8; 0.73 for MIC 16; 3.375g IV Q12h (CrCl 40 mL/min): 0.98 for MIC 1; 0.96 for MIC 2; 0.90 for MIC 4; 0.79 for MIC 8; 0.52 for MIC 16; 3.375g IV Q12h (CrCl 20 mL/min): 0.99 for MIC 1; 0.98 for MIC 2; 0.96 for MIC 4; 0.90 for MIC 8; 0.74 for MIC 16

1. This analysis included a small number of patients with CrCl < 40 mL/min

2. Consider using P/T 3.375 g IV Q6h for patients with CrCl ≤ 20 mL/min and extended infusion P/T 3.375 g IV Q12h for patients with CrCl ≤ 20 mL/min

3. Avoid using P/T (both bolus and extended infusion) if MIC ≥ 32mg/L

Roberts (2010)

To determine plasma and tissue concentrations achieved with IB P/T and CI P/T in ventilator-associated pneumonia (VAP) patients

Critically ill patients with known or suspected sepsis with plasma creatinine < 120 μmol/L

Traditional (IB) P/T: 4.5 g IV Q6-8 h

CI P/T : day 1, 4.5g P/T loading dose, then 8/1g P/T over 24h (p = 333 mg/h) ; day 2, 12/1.5 g P/T over 24h (p = 500 mg/h).

13 VAP patients; seven randomized to IB and six to CI group. Patients in CI group significantly younger (p = 0.04); day 1 APACHE II scores of 24.0 for IB and 17.5 for CI group (p = 0.17).

Tissue Concentrations:day 1, 2.4 mg/L in CI and 2.2 mg/L in IB (p = 0.48); day 2, 5.2 mg/L in CI and 0.8 mg/L in IB (p = 0.45).

Plasma Concentrations: day 1, 8.9 mg/L in IB and 4.9 mg/L in CI (p = 0.078); day 2, 16.6 mg/L in CI and 4.9 mg/L in IB (p = 0.007).

1. Small number of patients.

2. Patients with impaired renal function excluded.

3. Comparable degree of tissue penetration seen with 25% lower dose used in CI vs. bolus dosing.

Boselli (2008)

To determine epithelial lining fluid (ELF) concentrations of lower and higher dose CI P/T in VAP patients with normal or impaired renal function

Critically ill patients on mechanical ventilation with suspected VAP (developing five or more days after start of mechanical ventilation)

CI P/T Regimens

P/T 4/0.5 g loading dose followed by 12/1.5 g or 16/2 g over 24 h (diluted in 48 mL sterile water, infused at rate of 2 mL/h).

Forty patients (20 normal renal function, 20 renally impaired): age, 56-59 years for no/mild renal failure and 65-68 for moderate/advanced renal failure; SAPS II scoresd: 33-41 for no/mild renal failure and 60-63 for moderate/advanced renal failure; CrCl of 34 ml/min in moderate/ advanced renal failure.

Steady State ELF Concentration

No/Mild Renal Failure Patients with Identified Pathogens (20): 60% had ELF levels of piperacillin < 16 mg/L with P/T 12/1.5 g and 40% had ELF levels of piperacillin < 16 mg/L with P/T 16/2 g; median ELF/serum ratios were 0.43-0.46 for piperacillin.

Moderate/Advanced Renal Failure Patients with Identified Pathogens

None of the 20 patients receiving P/T 12/1.5g or 16/2 g had ELF levels of piperacillin < 16mg/L; median ELF/serum ratios were 0.39-0.49 for piperacillin.

1. Authors suggested target serum concentration of piperacillin of 35-40 mg/L to provide alveolar concentrations of P/T necessary to eradicate Enterobacteriaceae and non-fermentative gram-negative bacteria in VAP patients.

2. P/T CI 12/1.5 g too low for VAP patients with normal renal function?

aAPACHE, Acute Physiology and Chronic Health Evaluation
bfT>MIC: time for which the free (unbound) concentration is maintained above the minimum inhibitory concentration (MIC) during adosing interval
cCrCl = creatinine clearance
dSAPS II, Simplified Acute Physiology Score

Table 2: Clinical Efficacy of Continuous/Extended Infusion Piperacillin/Tazobactam in Critically Ill Patients

Study Design/ Primary
Outcomes

Inclusion Criteria

Exclusion Criteria

Patient Population

Dosing Regimens

Results

Lorente (2009)

Historical cohort study

Outcomes

1. Clinical Cure: complete resolution of all clinical signs and symptoms of pneumonia.

2. Mortality rate

3. Length of ICU stay

4. Duration of mechanical ventilation

Patients with VAPa due to gram-negative bacteria who were administered P/T (Piperacillin/ Tazobactam) from June 2002 to December 2007.

Age < 18 y; pregnancy or lactation; allergy to ß-lactam antibiotics; VAP due to gram (-) bacteria resistant to P/T; acquired immune deficiency syndrome (AIDS); neutropenia (< 1000 cells/mm3); solid or hematological tumor; CrCl < 60mL/min

Continuous Infusion (CI) P/T (n = 37): mean age 63.2 y; APACHE IIb score on ICU admission, 16.1; common causative organisms for VAP: P. aeruginosa (29.7%), E. coli (13.5%); Enterobacter spp (10.8%); Serratia marcescens(10.8%); H. influenzae (10.8%)

Intermittent Infusion (II) P/T (n = 37): mean age 61.8 y; APACHE II score on ICU admission, 16.2; common causative organisms for VAP: P. aeruginosa (28.3%), E. coli (17.4%); Enterobacter spp (10.9%); Serratia marcescens (10.9%); H. influenzae (8.7%)

II P/T: 4.5 g IV Q6h (infused over 30 minutes)

CI P/T: P/T loading dose of 4/0.5 g infused over 30 minutes, followed by 4/0.5 g infused over 6 hours IV Q 6h (each P/T dose diluted in 100 mL normal saline).

Clinical Cure for CI P/T vs. II P/T: MIC (mg/L) 4, 18/20 (90%) vs. 19/25 (76%), p = 0.20; MIC 8, 8/9 (88.9%) vs. 6/15 (40%), p = 0.02; MIC 16, 7/8 (87.5%) vs. 1/6 (16.7%), p = 0.02.

Other Outcomes:no difference between two different dosing regimens with regard to mortality rate, length of ICU stay, and duration of mechanical ventilation.

Lodise (2007)

Retrospective, cohort study

Outcomes

1. 14-day mortality after P. aeruginosa culture collection

2. Hospital length of stay (LOS) after collection of P. aeruginosa positive culture sample up to discharge or death

Patients with cultures positive for P. aeruginosa: age ≥ 18 y; absolute neutrophil count ≥ 1000 cells/mm; P/T given within 1st 72 h of onset of P. aeruginosa infection; receipt of P/T ≥ 48 h; culture results meeting the Centers for Disease Control and Prevention's criteria for infection

Receipt of > 1d II of P/T prior to converting to extended infusion (EI); receipt of concomitant ß-lactam antibiotic with activity against P. aeruginosa ≤ 5 d of starting P/T; P. aeruginosa isolate with intermediate activity against P/T or resistant; requiring dialysis; solid-organ or bone marrow transplant; cystic fibrosis

EI P/T (n = 102): age 62.8 y; use of mechanical ventilator at culture sample collection, 54.9%; mean APACHE II score at onset of infection, 15.3; concomitant use of aminoglycoside, 22.8%; primary source of culture sample: respiratory tract (53.9%); urinary tract (20.6%); skin or soft tissue (10.8%)

II P/T (n = 92): age 63.9 y; use of mechanical ventilator at culture sample collection, 56.5%; mean APACHE II score at onset of infection, 16.2; concomitant use of aminoglycoside, 25.5%; primary source of culture sample: respiratory tract (52.2%); urinary tract (13%; skin or soft tissue (25%, p = 0.009 vs. EI P/T

II P/T 3.375 g IV (infused over 30 minutes) Q4 h

EI P/T 3.375 g (infused over 4 hours) IV Q8 h

Overall 14-day mortality

EI P/T vs. II P/T: 8.8% and 15.2% (p = 0.17)

Overall median LOS

18 d for EI P/T vs. 22.5 d for II P/T (p = 0.09)

Classification and Regression Tree Analysis

Patients with APACHE II score ≥ 17 showed lower 14-day mortality rates when receiving EI P/T vs. II P/T (p = 0.04) and shorter median LOS (p = 0.02).

Rafati (2006)

Prospective, randomized, controlled trial

Outcomes

1. APACHE II score

2. Defervescence

3. WBC normalization

4. Mortality

5. %T > MIC

All septic patients presenting with systemic inflammatory response syndrome (SIRS)c due to suspected or documented infection.

Age < 18 years; allergy or hypersensitivity to ß-lactam antibiotics; dialysis or CrCl < 40 mL/min.

CI Piperacillin (n = 20): mean age 50.1 y; mean baseline APACHE II score, 16.4; common infection sites: respiratory tract (45%), intra-abdominal (20%), urinary tract (20%)

II Piperacillin (n=20): mean age 48 y; mean baseline APACHE II score, 14.2; common infection sites: respiratory tract (45%), intra-abdominal (20%), urinary tract (15%)

Piperacillin (not combined with tazobactam) given as 2 g IV loading dose, followed by daily CI of 8g over 24 h

Piperacillin 3g IV Q 6 h (infused 0.5 h)

APACHE II Score

Days 2-4: significantly greater reductions in APACHE II score seen in CI vs. II groups (p < 0.05)

Defervescence

Times to normalize temperature: 1.7 ± 0.7 d for CI vs. 2.4 ± 1.5d for II (p = 0.08).

Other Clinical Outcomes

No difference between CI vs. II in normalizing WBC or improving mortality rates.

%T > MIC

1. Ten pathogens from eight CI patients and six pathogens from four II patients

2. MIC of 16: %T> MIC of 100% with CI and 62% with II

3. MIC of 32: %T>MIC of 65% with CI and 39% with II

qVAP = ventilator-associated pneumonia as defined by the following: chest radiography showing new or progressive infiltrate; new onset of purulent sputum or alteration in sputum character; body temperature < 35.5°C or > 38°C; white blood cell count > 10,000 cells/mm3 or < 4000 cells/mm3; tracheal aspirate > 106 colony-forming units/mL or isolation of the same microorganism in respiratory secretions and blood.
bAPACHE, Acute Physiology and Chronic Health Evaluation
cSIRS definition: presentation of two or more of the following criteria: temperature > 38°C or < 36°C; heart rate exceeding 90 beats/minute; respiratory rate > 20 reaths/minute or PCO2 < 32 mmHg; WBC (white blood cell) count < 4000 cells/mm3 or > 12,000 cells/mm3; or band (immature) cells > 10%