Beta Lactam: To Extend or not to Extend: That is the Question!
1. β-Lactam
To Extend or not to
Extend: That is the
Question!
Hassan M. Al Tomy BSc Pharm, BCPS
Pharmaceutical Care Department
King Abdullah Medical City
2. Objective
To introduce the concept of extended infusion beta
lactam
To present the evidence of EI
Assess the “pillars” of evidence in support of extended
6. New systemic antibacterial agents approved by FDA
Boucher H W et al. Clin Infect Dis. 2013;56:1685-1694
Resistance
7. Systemic Antibacterial Drug Approvals Since
2000
Antibiotic Approval Date
Linezolid 2000
Cefditoren pivoxil 2001
Ertapenem 2001
Gemifloxacin 2003
Daptomycin 2003
Telithromycin 2004
Tigecycline 2005
Doripenem 2007
Telavancin 2009
Ceftaroline fosamil 2010
Boucher H W et al. Clin Infect Dis. 2013;56:1685-1694
8. What Can We Do?
Improve the antibiotic pipeline
Antimicrobial stewardship program
9. “Optimization of antimicrobial dosing based
on individual patient characteristics,
causative organism, site of infection, and
pharmacokinetic and pharmacodynamic
characteristics of the drug is an important
part of antimicrobial stewardship (A-II)”
“Examples of these principles in practice include
prolonged or continuous infusion of b-lactams”
Dellit, Owens et al. Clin Infect Dis 2007, 44(2), 159-177
11. Open, prospective, multicenter study in four ICUs
80 patient with severe sepsis or septic shock
The percent of patients who attained the target PK
profile was
Meropenem (75%)
Ceftazidime (28%)
Cefepime (16%)
Piperacillin-tazobactam (44%)
Taccone, F. S., et al. Crit Care 2010 14(4):R126.
12. Open label , prospective study
53 ICU patients treated with CRRT and receiving
either meropenem , piperacillin tazobactam, cefepime
or ceftazidime
Conclusions: In septic patients receiving CRRT
recommended doses of b-lactams for Pseudomonas
aeruginosa are adequate for Meropenem
for piperacillin-tazobactam, cefepime and ceftazidime;
for higher doses and/or extended infusions should be
used to optimise serum concentrations.
Seyler et al. Crit Care 2011, 15:R137
13. Prospective, multinational pharmacokinetic point-
prevalence study including 8 β-lactam antibiotics.
384 ICU patients across 68 hospitals in 10 countries
the median APACHE II score was 18
16% did not achieve 50% f T>MIC
Roberts, J.A., et al. Clin Infect Dis, 2014. 58(8): p. 1072-83
16. History
Eagle et al. 1950, 1953,
Schmidt and Walley 1951
Jawetz 1946;
Schmidt et al. 1949
More frequent dosing or continuous infusion
of penicillin resulted in a superior outcome
compared to once or twice daily dosing
18. β-Lactam Pharmacodynamics
For penicillins, fT>MIC must be:
>30% of dosing interval to produce bacteriostasis
≥50% of dosing interval for optimum (maximal)
bactericidal effect
Required %T>MIC for maximal bactericidal effect:
~60-70% for cephalosporins
~50% for penicillins
~40% for carbapenems
Clin Infect Dis 2007;44:357-363
28. Extended and continuous-infusions with same daily
doses had similar bactericidal exposure
Both dosing strategies improved PD profile over
intermittent-infusion regimens:
Probability of achieving 50% fT>MIC at 16 µg/mL:
67.8% for intermittent regimen 3.375 g q6hr (13.5 g/day)
100% for Extended & continuous-infusions (12 g/day)
Probability of achieving 50% fT>MIC at 32 µg/mL was:
45% for high intermittent dose 4.5 g q6hr (18 g/day)
90% for Extended & continuous infusions (16 g/day)
Kim et al. Pharmacotherapy 2007;27(11):1490–1497
29. How Can We Maximize T>MIC ?
Increasing the dosing frequency
Using a higher dose
Increasing the duration of infusion (extended
infusion)
Using a continuous infusion
Administration of a drug that interferes with
elimination (e.g. probenicid)
Replace with a therapeutically equivalent antibiotic
with a longer T1/2
van Zanten, A.R., Crit Care Med, 2009. 37(6): p. 2137-8.
32. Dissociation Between Preclinical Data and
Clinical Reports
Comparative clinical studies had previously failed to
demonstrate significant differences in pts outcome
Two meta-analyses of these clinical trials found
similar outcomes between CI and IB
This dissociation prevented global practice shift
toward CI of β-Lactam antibiotics
Kasiakou SK. Lancet Infect Dis 2005, 5:581
Roberts JA. Crit Care Med 2009, 37:2071
34. 14 studies 1229 patient
8 studies were retrospective, 3 prospective , and 3
RCTs
6 studies (302 patients) reported on carbapenems, 7
(806 patients) on piperacillin/tazobactam, and 1 on
both classes of antibiotics
6 studies evaluated patients with pneumonia,
whereas the remaining studied patients with several
types of infections. In 8 of 14 studies the causative
pathogens were gram-negative bacteria only
Falagas ME et al. Clin Infect Dis 2013 56: 272-282.
35. Falagas M E et al. Clin Infect Dis. 2013;56:272-282
Mortality
36. Falagas M E et al. Clin Infect Dis. 2013;56:272-282
Mortality
37. Falagas M E et al. Clin Infect Dis. 2013;56:272-282
Clinical Cure
39. Effects of pharmacodynamic-based antibiotic dosing on ICU and
hospital mortality grouped by RCT versus cohort studies
Chantet al. Crit Care 2013,17:R279
40. Effects on clinical failure, grouped by RCT versus cohort
studies
Chantet al. Crit Care 2013,17:R279
41. Effects on ICU length of stay
Chantet al. Crit Care 2013,17:R279
42. Effects on mortality separated by class of antibiotic
Chantet al. Crit Care 2013,17:R279
49. Cost
After implementation of EI approach total daily dose of
Tazocin was reduced by 25%–50% which reduce a total annual
cost of Tazocin from $275,000 to $135,475 - $206,250∼
Costs associated with continuous infusion ceftazidime, $627 ±
388, were significantly lower (p≤0.001) than with intermittent
infusion, $1007 ± 430.
EI cefepime save $23,183 per patient compared with
intermittent infusion
Use of EI meropenem significant reduce antibiotic cost,
whichwas $1038.83±51.08 in the intermittent dosing group
and$684.06±36.25 in EI group
Lodise, T. P., Jr., et al. Clin Infect Dis,2007. 44(3): 357-363
McNabb, J.J., et al., Pharmacotherapy, 2001. 21(5): p. 549-55.
Bauer, K.A., et al.,. Antimicrob Agents Chemother, 2013. 57(7): p. 2907-1
Wang, D., Int J Antimicrob Agents, 2009. 33(3): p. 290-291.
50. Adverse Reaction
No significant difference in rate of ADR between EI
and Intermittent infusion
In meta-analysis of 14 studies no significant
differences between the 2 treatment groups
Chytra et al. Critical Care 2012, 16:R113
Falagas M E et al. Clin Infect Dis. 2013;56:272-282
51. Advantages Disadvantages
More predictable antibiotic PK profiles Relatively new antibiotic administration
method thus requiring intensive
educational effort to update clinical staff
on the administration method prior to
implementation
Lower antibiotic daily dose may be
appropriate with continuous infusion
Requires special infusion pumps and
infusion bags that are costly
Reduced drug acquisition costs when
lower antibiotic doses are used
Stability
May be more effective in special
populations
Abdul-Aziz, M.H., et al., Ann Intensive Care, 2012. 2(1): p. 37.
53. Conclusion
Overall, available evidence from PK-PD, clinical
outcomes, and pharmacoeconomic studies consistently
suggest that EI administration of PIP-TAZ is a safe,
efficacious, cost-effective, and potentially superior
strategy compared with traditional 30-minute infusions
Extended infusion of β-lactams is unlikely to be
advantageous for all hospitalized pts
It may be very beneficial for specific groups, such as
critically ill pts and pts with higher MIC pathogens such
as MDR Pseudomonas, Acinetobacter , Carbapenem
resistant Enterobacteriacae
A large a prospective multicentered, randomized trial is
needed
Notes de l'éditeur
New systemic antibacterial agents approved by the US Food and Drug Administration per 5-year period, through 2012. Modified from Spellberg 2004 [23].
Forest plot depicting the risk ratios of clinical cure of patients receiving extended or continuous versus short-term infusion of carbapenems and piperacillin/tazobactam, stratified by continuous and extended infusion. Vertical line, “no difference” point between the 2 regimens; squares, risk ratios; diamonds, pooled risk ratios; horizontal lines, 95% confidence interval. Abbreviation: CI, confidence interval.