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piperacillin/tazobactam. There were 102 patients who received the prolonged infusion of
piperacillin/tazobactam dosed 3.375g every 8 hours. There were 92 patients who received the
conventional infusion of piperacillin/tazobactam dosed 3.375g every 4 hours (4 patients) or 6
hours (88 patients). There was no difference in baseline characteristics between the two groups.
The 14-day mortality rate was 8.8% in the prolonged infusion group versus 15.2% in the
conventional infusion group (p=0.17). The median length of stay after sample collection was 18
days in the prolonged infusion group versus 22.5 days in the conventional infusion group
(p=0.09). However, in the subgroup of patients with an Acute Physiological and Chronic Health
Evaluation-II (APACHE-II) score ≥17, the prolonged infusion group (n=41) had a significantly
lower 14 day mortality (12.2% vs. 31.6% [p=0.04]) and decreased median length of stay (21 days
vs. 38 days [p=0.02]) verses the conventional infusion group (n=38). However, there was not a
significant improvement in mortality (p=0.5) or median length of stay (p=0.5) in patients with an
APACHE-II score<17. The authors suggested the differences found with respect to APACHE-II
score may have been because more critically ill patients with P. aeruginosa infection are most
dependent on drug exposure for good clinical outcome. The Trauma Life Center uses APACHEIV scoring for patient stratification and there is no direct correlation between APACHE-II and
APACHE-IV. It is estimated that most patients in TLC who receive systemic antibiotics would
have an APACHE-II score > 17.
A retrospective study was conducted in TLC after implementing prolonged infusions of
piperacillin-tazobactam and meropenem. The study showed statistically significant
decreased ventilator days (16.8 days to 9.6 days, 95% CI: -12.4 to -2.4), ICU length of
stay (15.3 days to 10.7 days, 95% CI: -8.3 to -1.4), and hospital length of stay (30.9 days
to 22.4 days, 95% CI: -18.7 to -1.2) between the intermittent infusion and the prolonged
infusion group. There was also a decrease in mortality in the prolonged infusion group
(20.7% to 12.4%, OR 0.54 (95% CI 0.18-1.66)) that didn’t reach statistical significance.
The use of the prolonged infusion was also associated with an estimated $10,000 cost
savings for the 54 patients included in the prolonged infusion group.
Mattoes et al. reviewed the pharmacodynamic data of several alternative dosing regimens for
meropenem including continuous infusions, prolonged infusions, increased frequency of
administration, and higher doses.3 The authors reported that for severe infections caused by
meropenem susceptible pathogens with higher MICs, equivalent bactericidal activity was
achieved with 500mg every 8 hours over 3 hours, 1000mg every 8 hours over 30 minutes, and
500mg every 6 hours over 30 minutes. For treatment of mild to moderate infections caused by
pathogens with low MICs (such as E coli and K pneumoniae), prolonged infusions would only
have a slight benefit over conventional 30 minute infusions. For clinical situations with a higher
risk of antibiotic resistant, gram-negative pathogens, treatment with meropenem 1g every 8 hours
as a 3-hour infusion, or 2g every 8 hours as either a 30-minute or 3-hour infusion would optimize
pharmacodynamic parameters. One study reported that for an MIC of 4mg/L, the %T>MIC
achieved with a 30-minute infusion of 500mg and 2000mg every 8 hours was 30% and 58%,
respectively. Increasing the infusion time to 3 hours every 8 hours achieved a %T>MIC of 43%
and 73% for the 500mg and 2000mg doses, respectively. Currently, there are no clinical trials
comparing prolonged versus intermittent dosing for meropenem.
An internal audit of organisms recovered during calendar year 2008 revealed that 85% of
common gram-negative species had MIC values less than or equal to 2 mcg/ml to meropenem.
There were 15 isolates (a single Acinetobacter, and 14 Pseudomonas) that had MIC values
greater than 2 mcg/ml. Pharmacokinetic and pharmacodynamic data suggest that equal
outcomes would be achieved with 500mg every 8 hours infused over 3 hours for organisms with
MIC less than 2 mcg/ml. A yearly audit will continue to be conducted.