Are extended infusions of Beta lactam antibiotics more effective over standard infusions?

Beta lactams are a broad class of antibiotics commonly used to treat a wide spectrum of bacterial
infections in particular gram negatives in hospitalized and critically ill patients. Clinicians for a long time
have debated whether extended infusions of beta lactam antibiotics is more effective than standard
intermittent infusions. There have been many Pharmacokinetic and Pharmacodynamic (PK/PD) studies
that have shown that extended IV infusion of β-lactams enhances antimicrobial exposure and the
activity of these time-dependent agents. The results provided by these studies suggested that prolonged
infusion of beta lactams resulted in a significant reduction of all-cause mortality but the clinical benefit
has been challenging to demonstrate.

Beta-lactams antibiotics exhibit time-dependent bactericidal activity. In order to achieve optimal

efficacy with these agents, the free drug concentrations must remain above the minimum inhibitory
concentration (MIC) of the pathogen for an extended duration of the recommended dosing interval.
PK/PD models have consistently shown that prolonging the infusion of beta-lactam antibiotics to 3- 4
hours increases the achievement of PD goal. For instance, maximal bactericidal effect for penicillins,
cephalosporins, carbapenems, occurs when the fT>MIC is approximately 50 to 60%, 60 to 70%, 40%
respectively. Therefore, the optimal antibacterial effect is dependent on PK/PD parameters and the
organism’s MIC.

In a RCT study conducted by Vardakas et al, 22 clinical trials involving 1,876 patients
prescribed intravenous anti-pseudomonal beta-lactam antibiotics and who were
randomized to receive them either as a brief (> 60 minutes) or prolonged (3-4 hours)
infusion. Almost all enrolled patients were receiving intensive care and were severely ill
as indicated by a mean or median APACHE II score ≥ 20. The total daily antibiotic dose
were different, but in 13 of the 22 trials, patients assigned to prolonged administration
received 50-67% of the total daily dose received by those in the comparator arm.
(Vardakas, 2018. Clinical benefit in terms of patient improvement (reported in 18 of the
trials) did not significantly differ between the groups. However, a statistically significant
all-cause mortality difference was observed in the 17 studies reporting this endpoint,
with the results favoring prolonged infusion (relative risk [RR] 0.70; 95% confidence
interval [CI], 0.56-0.87). (Vardakas, 2018)
However, the clinical benefit of prolonged infusion has been difficult to demonstrate, and the
reported results have been mixed. Among other obstacles, this is likely to depend to a
significant degree on the actual MIC of the infecting pathogen. Thus, the duration of infusion
probably has little potential effect when the MIC is at the extremes. If it is extraordinarily low,
PTA is likely to be achieved readily regardless of the duration of beta-lactam infusion. If it is
extraordinarily high, the duration of infusion is likely to be irrelevant — the antibiotic has little
chance of efficacy. Thus, the greatest clinical benefit resides in the treatment of infections due
to pathogens with MICs clustering around the breakpoint, both just below and just above it, and
this limits the ability to detect treatment outcome differences when the overall study population
is undifferentiated with regard to actual MIC.

For instance, maximal bactericidal effect for penicillins, cephalosporins, carbapenems, occurs when
the fT>MIC is approximately 50 to 60%, 60 to 70%, 40% respectively. Therefore, the optimal
antibacterial effect is dependent on PK/PD parameters and the organism’s MIC.

furthermore, prolonged infusion may attain target

pharmacokinetic/pharmacodynamic exposures with similar or lower cumulative
daily doses than those used for intermittent infusion
Prolonged (3-4 hours) or continuous infusion of IV beta-lactams has a
higher probability of achieving pharmacodynamic goals compared with
standard 30-minute intermittent infusions.

When PK/PD targets are achieved, β-lactams have their maximal antibiotic effect,
and hence patient outcomes are optimized

Vardakas and colleagues examined 22 clinical trials involving 1,876 patients prescribed
intravenous anti-pseudomonal β-lactam antibiotics and who were randomized to receive
them either as a brief (over ≤ 60 minutes) or prolonged (≥ 3 hours, including continuous)
infusion. Almost all enrolled patients were receiving intensive care and were severely ill
as indicated by a mean or median APACHE II score ≥ 20. The total daily antibiotic dose
varied, but in 13 of the 22 trials, patients assigned to prolonged administration received
50-67% of the total daily dose received by those in the comparator arm.

Clinical cure or improvement (reported in 18 of the trials) did not significantly differ
between the groups. However, a statistically significant all-cause mortality difference
was observed in the 17 studies reporting this endpoint, with the results favoring
prolonged infusion (relative risk [RR] 0.70; 95% confidence interval [CI], 0.56-0.87)

In 2013, Bauer and colleagues performed a retrospective, quasi-

experimental study of patients with bacteremia or pneumonia caused by
susceptible P aeruginosa treated with cefepime 2 g every 8 hours.17 The
hospital changed its standard administration to 4-hour prolonged
infusion, and outcomes were compared in patients who had received
standard infusion prior to the change and patients who received
prolonged infusion. Mortality (20% vs. 3%, P = .03) and ICU length of
stay (18.5 vs. 8 days, P = .04) were significantly lower after
implementation of the prolonged-infusion protocol

Based on a meta-analysis in the Lancet, Prolonged infusion of antipseudomonal β-

lactams for the treatment of patients with sepsis was associated with significantly
lower mortality than short-term infusion

The BLING I10, BLING II,11 and BLISS13 trials collectively represent the least
heterogeneous and highest-quality evidence available to date. A meta-analysis of
pooled patient-level data from these trials showed that patients who received
continuous infusion had lower 30-day hospital mortality (20% versus 26%; relative
risk 0.74, 95% confidence interval 0.56–1.00; p = 0.045)

t rewards the population that is most at need,

 critically ill patients with the greatest risk of multidrug-resistant organisms and fluctuations in
PK

Prolonged infusion has the highest probability of improving clinical

outcomes in patients infected with organisms with elevated MICs or
virulent pathogens, such as P aeruginosa, and in critically ill patients.

Prolonged infusion has been demonstrated to have at least similar—and,

in many studies, better—clinical outcomes compared with standard
dosing strategies. Hospital systems are encouraged to explore this
dosing modality, particularly as rates of bacterial resistance continue to
rise.

References

Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged versus short-
term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a
systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2017.
Drusano GL. 2004. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev
Microbiol 2:289–300. doi:10.1038/nrmicro862.
Mordechai G. 2016. Continuous and Prolonged Intravenous β-Lactam. Dosing: Implications for the
Clinical Laboratory. Clinical Microbiology Reviews:759-772.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201667

https://www.sciencedirect.com/science/article/pii/S1473309917306151?via%3Dihub

1. Felton TW , Hope WW , Lomaestro BM , Butterfield JM , Kwa AL , Drusano GL , Lodise TP

. 2012. Population pharmacokinetics of extended-infusion piperacillin-tazobactam in hospitalized patients with
nosocomial infections. Antimicrob Agents Chemother 56:4087–4094. doi:10.1128/AAC.00521-12