Extended Infusions of Beta-lactams in Pediatric Patients: The long and the short of it

Holly Lien, Pharm.D. PGY1 Pharmacy Resident

The Children’s Hospital of San Antonio, San Antonio, Texas Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center University of Texas Health Science Center at San Antonio

March 10, 2017

Learning Objectives:

1. Understand basic concepts of beta-lactam antibiotics 2. Explain the pharmacokinetics and pharmacodynamics of time-dependent antibiotics 3. Evaluate current literature to understand the potential of alternative infusion strategies of beta-

lactams in both adult and pediatric populations 4. Understand practical concerns and considerations and formulate evidence-based

recommendations for the use of these strategies

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I. CLINICAL RELEVANCE

A. Guideline-based Recommendations for Antimicrobial Stewardship6,9 1. 2007 IDSA guidelines for developing an institutional program to enhance

antimicrobial stewardship a) “Dose optimization of antibiotics that accounts for individual patient

characteristics, causative organism and site of infection, and pharmacokinetic/pharmacodynamics characteristics of the drug (e.g. time or concentration dependent) is an important part of antimicrobial stewardship” [A-II]

2. 2016 IDSA guidelines for implementing an antibiotic stewardship program a) “In hospitalized patients, antibiotic stewardship programs should advocate for

the use of alternative dosing strategies versus standard dosing for broad- spectrum β-lactams to decrease costs” [weak recommendation, low-quality evidence]

II. BETA-LACTAM ANTIBIOTICS

A. Overview 1. β-lactams are antibiotics that inhibit bacterial cell wall synthesis 2. Time-dependent and bactericidal activity 3. Different levels of antimicrobial coverage against gram positive, gram negative, and

anaerobic organisms

Figure 1. Classification of antibiotics http://file.scirp.org/Html/19-8202738x/deded38f-5620-48d3-bda4-56e4bcccb0c1.jpg

β-lactams

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Table 1. Examples of β-lactam antibiotics

B. Structure

1. β-lactam ring present 2. Carboxylic acid entity with the exception of aztreonam 3. Differ by side chains adjacent to carbonyl group on β-lactam ring and side rings

a) Penicillins: acylamino (RCONH) b) Cephalosporins: acylamino (RCONH) c) Carbapenems: hydroxyethyl (CHOHCH3) d) Monobactams: acylamino (RCONH)

Figure 2. Chemical structures of β-lactam antibiotics

Antibiotic Class Examples Coverage Natural penicillins penicillin G/V Mostly gram positive

Synthetically modified penicillins

nafcillin, oxacillin, amoxicillin, piperacillin

gram positive, few gram negative

Beta-lactamase inhibitors piperacillin/tazobactam, ampicillin/sulbactam

gram positive, greater activity against gram negative, anaerobes

Cephalosporins cefazolin, cefuroxime, ceftriaxone, cefepime,

ceftaroline

gram positive/negative

Carbapenems meropenem, doripenem, imipenem, ertapenem

gram positive/negative, anaerobes

Monobactam aztreonam only gram negative

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C. Mechanism of Action 1. Peptidoglycan is a polymer consisting of linear chains of two alternating amino

sugars (N-acetyl muramic acid [NAM] and N-acetyl glucosamine [NAG]) which are cross-linked by transpeptidase (TP), a penicillin-binding protein (PBP), to form peptide bridges, creating a strong, solid mesh-like layer outside the plasma membrane of most bacteria

2. β-lactam antibiotics inhibit bacterial cell wall synthesis by binding to TP, which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls

3. Interference with peptidoglycan synthesis leads to fewer cross-links, weaker bacterial cell walls, and eventual cell lysis and death

Figure 3. Mechanism of action of β-lactam antibiotics http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit2/control/penres_fl.html

III. ALTERNATIVE DOSING STRATEGIES FOR BETA-LACTAMS

A. Pharmacokinetics (PK) and Pharmacodynamics (PD) of β-lactam Antibiotics1,3,8 1. For time-dependent antibiotics, microbiological and clinical outcomes are

associated with the cumulative percentage of the dosing interval that the drug concentration exceeds the minimum inhibitory concentration (MIC) for the organism(s)

2. Pharmacokinetic parameters for β-lactams vary among the pediatric age groups which may result in increased drug clearance in pediatric patients compared to adults

3. Alternative infusion strategies of β-lactams can potentially improve the likelihood of obtaining bactericidal targets from a PK/PD standpoint

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Table 2. Comparison of time-dependent versus concentration-dependent antibiotics

T

B. Dosing Optimization Strategies for Time-Dependent β-lactam Antibiotics3,4,5,7

1. Traditional infusion time a) Small doses are administered over 15-30 minute infusions two to four times

daily, depending on the serum half-life of the antibiotic and kidney function Table 3. Comparison of susceptibility breakpoints for standard 30-minute infusions of β-lactams

Clinical Laboratory Standards Institute (CLSI) susceptibility breakpoints for several β- lactam antibiotics against Pseudomonas aeruginosa vs. pharmacodynamics derived breakpoints. Derived from DeRyke and colleagues.

2. Extended or prolonged infusion time a) Doses are administered over 3-4 hour infusions b) Changes in dose or dosing interval in comparison to that of traditional dosing

strategies are not necessary, although higher doses may be used to treat pathogens with higher MICs

3. Continuous infusion time a) Doses are administered over 24 hours b) Higher doses may be used to treat pathogens with higher MICs

Time-Dependent Concentration-Dependent Rate and extent of

bacterial killing Unchanged regardless of

concentration Function of drug

concentration

Parameters that optimize bacterial killing

T>MIC • Penicillins: ~50% • Cephalosporins: 50-70% • Carbapenems: 30-40% • Monobactams: 50-60%

Cmax/MIC or AUC/MIC

Post antibiotic effect Minimal Prolonged Example Beta-lactam antibiotics Aminoglycosides

T>MIC = time above minimum inhibitory concentration; Cmax/MIC = ratio of maximum serum concentration to minimum inhibitory concentration; AUC/MIC = ratio of area under curve to minimum inhibitory concentration

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Figure 4. Concentration of β-lactam antibiotics over time http://cmr.asm.org/content/29/4/759/F4.large.jpg

C. Practical Considerations of Alternative Infusion Strategies

1. Rationale a) Pharmacodynamics principles b) Evidence of clinical benefit from limited trials without evidence of toxicity c) Theoretical benefit of reduced emergence of drug resistance d) Patients with altered pharmacokinetics (e.g. kidney dysfunction, pediatric

populations) e) Potential cost benefit f) Ease of administration in outpatient setting with home health (continuous

infusions) 2. Drawbacks

a) Logistical barriers (1) Need for intravenous access for prolonged periods of time (2) Infusion interruptions (3) Nursing and provider education

b) Compatibility issues between antibiotics and other intravenous agents c) Compounded admixture stability issues for certain antibiotics

(1) Example: meropenem prepared for infusion at concentrations up to 20 mg/mL is stable for up to 4 hours at room temperature and up to 24 hours refrigerated

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IV. SUMMARY OF CLINICAL DATA IN ADULT POPULATIONS10-13,15,20,22

A. Data suggests that prolonged (extended or continuous) infusions of β-lactams are at least equally effective, and in some cases, more effective than traditional infusion times

B. Greatest benefit found in critically ill patients or those infected with higher MIC pathogens C. Data overall are limited by small sample sizes, heterogeneity of dosing strategies, and other

methodological flaws

Table 4. Literature summary of alternative dosing strategies of β-lactams in adult populations Study Population & Antibiotic(s) Results & Conclusion

PIPERACILLIN-TAZOBACTAM Grant EM, et al. (2002)

• 47 patients: continuous • 51 patients: intermittent

• Equivalent clinical and microbiologic outcomes

• Continuous infusion significantly shortened time to fever normalization and reduced overall costs

Yost RJ, et al. (2011)

• 186 patients: 4-hour extended infusion • 173 patients: non-extended infusions

of β-lactams

• In-hospital mortality was significantly decreased in the extended infusion group (9.7% vs. 17.9%, p=0.02)

Falagas ME, et al. (2013)

• Systematic review and meta-analysis • 14 studies with patients on

piperacillin-tazobactam or carbapenems

• Extended or continuous infusions were associated with lower mortality (e.g. piperacillin-tazobactam: risk ratio 0.59; statistically significant)

CEFTAZIDIME McNabb JJ, et al. (2001)

Nocosomial