Extended Infusions of Beta-lactams in Pediatric Patients · Extended Infusions of Beta-lactams in...

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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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Page 1: Extended Infusions of Beta-lactams in Pediatric Patients · Extended Infusions of Beta-lactams in Pediatric Patients: The long and the short of it . Holly Lien, Pharm.D. PGY1 Pharmacy

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 antibiotics2. Explain the pharmacokinetics and pharmacodynamics of time-dependent antibiotics3. Evaluate current literature to understand the potential of alternative infusion strategies of beta-

lactams in both adult and pediatric populations4. 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 pneumonia • 17 patients: continuous • 18 patients: intermittent

• Clinical efficacy, adverse events, and length of stay did not differ

• Costs were significantly lower with continuous group

VARIOUS β-LACTAMS Dulhunty JM, et al. (2013)

Severe sepsis (various β-lactams) • 30 patients: continuous • 30 patients: intermittent

• Plasma antibiotic concentrations and clinical cure were higher in the continuous group

• ICU-free days and survival to hospital discharge did not differ

Tamma PD, et al. (2011)

• Systematic review and meta-analysis • 14 randomized controlled trials with

patients on prolonged vs. intermittent infusions of β-lactams

• No clinical advantage was observed for prolonged infusions

• Most studies had notable methodological flaws

Dulhunty JM, et al. (2015)

Severe sepsis (various β-lactams) • Randomized controlled trial in 25

intensive care units • 219 patients: continuous • 224 patients: intermittent

• No difference between groups in ICU-free days, 90-day survival, or clinical cure

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V. CLINICAL QUESTION & LITERATURE REVIEW

A. Rationale in the Pediatric Population

1. Clinical Question a) What is the rationale and evidence for using alternative dosing strategies for

β-lactam antibiotics in pediatric patients? 2. Rationale

a) Evidence of clinical benefit from limited trials without evidence of toxicity b) Theoretical benefit of reduced emergence of drug resistance c) Pharmacodynamics principles d) Patients with altered pharmacokinetics

3. Review of pediatric literature16,19,21 a) Walker MC, et al. Continuous and Extended Infusions of β-lactam Antibiotics

in the Pediatric Population. Ann Pharmacother. 2012;46(11):1537-46. b) Nichols KR, et al. Population Pharmacokinetics and Pharmacodynamics of

Extended Piperacillin and Tazobactam in Critically Ill Children. Clin Ther. 2015;34(6):1459-65.

c) Shabaan AE, et al. Continuous Versus Prolonged Infusion of Meropenem in Neonates with Gram Negative Late Onset Sepsis: A Randomized Controlled Trial. Pediatr Infect Dis J. 2016.

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Table 5. Continuous and Extended Infusions of β-lactam Antibiotics in the Pediatric Population Walker MC, et al. Ann Pharmacother. 2012;46(11):1537-46.21

Study Objective To conduct a systematic review of available data on the use of extended or continuous infusion of β-lactams in pediatrics (<18 years old)

METHODS Study Design & Inclusion Criteria

• Systematic review performed using PubMed (1975 – 2012), International Pharmaceutical Abstracts (1970 – 2012), and Web of Science (1977 – 2012); Clinicaltrials.gov was searched for ongoing research

• Combinations of the following search terms were used: pediatric, children, infant, adolescent, neonate, β-lactam, cephalosporin, carbapenem, penicillin, continuous infusion, extended infusion, and prolonged infusion

• Names of drugs within each class of antibiotics were included in the search • Only English-language publications were included and references from

retrieved articles were manually searched for additional articles Included Publications

1 randomized controlled trial, 5 PK studies, 2 PD studies using Monte Carlo simulation, 1 case series, and 7 case reports

RESULTS Data Synthesis (See Appendix A, Table 1)

• PK studies conducted in the pediatric population demonstrate the feasibility and safety of alternative infusion times

• Cephalosporins have been studied the most, but overall, there is limited clinical evidence available to support the use of extended or continuous infusion of β-lactams in the pediatric population

• The single prospective clinical trial by Rappaz, et al. using continuous infusion of ceftazidime failed to demonstrate any clinical benefit over traditional dosing, however, there was equal efficacy

DISCUSSION Author Conclusions • As of this review, existing publications have been performed only in neonates,

2-year-old, 10-year-old, and 12-year-old patients (isolated age groups) • Optimal dose for continuous infusion β-lactam antibiotics has not been well

established in the pediatric population • Most studies used continuous infusions rather than extended (3- or 4-hour)

infusions currently being advocated for adults Strengths • Systematic review that provided an excellent summary of available literature in

the pediatric population regarding alternative dosing infusion times • Had an inclusive list of possible search terms including names of specific drugs

Limitations Systematic review, no statistical analysis Clinical Significance • Further PK/PD studies need to be performed in different pediatric age groups

and also for additional disease states before alternative dosing strategies of β-lactams can be routinely recommended

• Prospective clinical trials are needed to determine whether there is clinical benefit to alternative dosing strategies beyond PK/PD advantages

• Situations with potentially the most benefit of using alternative infusion times include serious gram-negative infections and presence of high MIC pathogens

MIC = minimum inhibitory concentration; PD = pharmacodynamics; PK = pharmacokinetics

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Table 6. Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children

Nichols KR, et al. Clin Ther. 2012;34(6):1459-65.16

Study Objective To evaluate the population PK/PD of extended-infusion piperacillin-tazobactam (TZP) in children hospitalized in a pediatric intensive care unit

METHODS Inclusion Criteria • Patients 9 months to 11 years of age admitted to the pediatric ICU at Riley

Hospital for Children at Indiana University Health • Already receiving extended-infusion (4 hours) TZP for a suspected or proven

bacterial infection Exclusion Criteria • Estimated glomerular filtration rate of <60 mL/min/1.73 m2

• Receiving dialysis or renal replacement therapy Study Design • Population PK analyses and Monte Carlo simulations (see figure below) used to

estimate PK profiles for different dosing regimens

Treatment • Patients received 100 mg/kg of piperacillin (infused over 4 hours) q8h

• Maximum dose: 3000 mg of piperacillin and 375 mg of tazobactam RESULTS Baseline Characteristics (See Appendix A, Table 2)

• Average age of study population was approximately 5 years, with an even distribution of males and females

• Nine of twelve patients were on TZP empirically • Seven of twelve patients had an infectious indication of pneumonia

Probability of Target Attainment

Probability of target attainment (PTA) at a TMIC>50% for four intermittent-infusion and four prolonged-infusion regimens of TZP at specific MICs in critically ill children.

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Probability of Target Attainment (continued)

Probability of target attainment (PTA) at a TMIC>100% for four intermittent-infusion and four prolonged-infusion regimens of TZP at specific MICs in critically ill children. *Dashed, horizontal line represents a PTA of 90% TMIC, the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC for the organism(s) under steady-state PK conditions

DISCUSSION Author Conclusions • Based on the population PK model, piperacillin clearance was significantly

associated with weight; tazobactam clearance was significantly associated with weight and sex

• Differences in drug clearance can also be affected by various factors such as severity of illness and varying degrees of renal dysfunction

• Data from this study suggest equivalent exposures between traditional and extended-infusion regimens for pathogens with MICs < 8 mg/L

• Extended-infusion strategies shows potential but should be specifically utilized in certain situations, such as for pathogens with high MICs or for cost-saving reasons

Strengths • First study to evaluate PK/PD of extended-infusion TZP in pediatric patients in an intensive care unit

• Patients who received 4-hour infusions of TZP used for analysis • Well-designed PK/PD models and dose simulations

Limitations • Relatively small sample size (n = 12) • Study results may not be applicable to all age groups • Not a prospective study

Clinical Significance This is a well-designed PK/PD study that demonstrated the potential utilization of extended-infusion piperacillin-tazobactam if higher targets of time above the MIC are desired for less susceptible pathogens. Optimal empirical and directed regimens are ultimately impacted by the typical pathogens and MIC distributions encountered in a given institution.

MIC = minimum inhibitory concentration; PD = pharmacodynamics; PK = pharmacokinetics; TZP = piperacillin-tazobactam

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Table 7. Conventional Versus Prolonged Infusion of Meropenem in Neonates with Gram Negative Late Onset Sepsis: A Randomized Controlled Trial

Shabaan AE, et al. Pediatr Infect Dis J. 2016.19

Study Objective To compare the clinical and microbiologic efficacy and safety of prolonged infusions versus conventional dosing of meropenem in neonates GN-LOS

METHODS Inclusion Criteria • All neonates with GN-LOS sensitive to meropenem Exclusion Criteria • Neonates with GN-LOS after 72 hours of birth; low birth weight for GA

• Major congenital malformations; chromosomal anomalies • Inborn errors of metabolism • Renal failure (SCr >1.5 mg/dL, urine output <0.5 mL/kg/hr) • Clinical or laboratory evidence of a congenital infection

Study Design Prospective, single center, randomized, open label pilot clinical trial conducted in the neonatal ICU of Mansoura University Children’s Hospital (2013 – 2015)

Treatment

• Duration of meropenem therapy varied based on the type of infection • Positive blood, cerebrospinal fluid, urine, and/or synovial fluid culture

obtained before initiation of antibiotics was required for confirmation of sepsis

• Routine repeat blood culture was taken at 7 days of antibiotic therapy to assess microbiologic response

Primary Endpoints • Clinical success, defined as complete resolution of clinical signs and symptoms of sepsis at the end of therapy

• Microbiological success, defined as eradication of organism previously sensitive to meropenem at 7 days of meropenem therapy

Secondary Endpoints

• Neonatal mortality • Meropenem-related duration of mechanical ventilation, length of stay,

adverse events, duration of inotropes • Total length of neonatal ICU stay • Duration of respiratory support/mechanical ventilation • CRP concentrations at 7 days

STATISTICS • Kolmogorov-Smirnov test

• Student t-test and Mann-Whitney U test • Chi-square test and Fisher’s exact test

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RESULTS Screening & Randomization

Baseline Characteristics (See Appendix A, Tables 3-4)

• Mean GA was 34 weeks for both groups; majority were preterm infants • Majority of patients had bloodstream infections, with Klebsiella species and

Escherichia coli as the most frequently isolated organisms • No statistically significant differences between groups

Primary Endpoints Clinical success • 61% (prolonged infusion group) vs. 33% (conventional group); p=0.009 Microbiological success • 82% (prolonged infusion group) vs. 56.8% (conventional group); p=0.009

Secondary Endpoints (See Appendix A, Tables 5-6)

• Prolonged infusion group had a significantly lower rate of mortality, shorter duration of respiratory support, and acute kidney injury

• No statistically significant differences between groups in regards to the other secondary outcomes

DISCUSSION Author Conclusions • Results from this study suggest higher bactericidal activity and rates of clinical

improvement as well as lower mortality with prolonged meropenem infusions • Improved microbiologic success with prolonged infusions may be explained by

mal-distribution of blood flow in critically ill patients • No significant differences between groups in terms of length of stay and

duration of mechanical ventilation Strengths • First study to evaluate clinical and microbiologic efficacy as well as safety of

prolonged meropenem infusion in neonates with GN-LOS • Prospective randomized trial with equally matched sites of infection in both

groups; homogeneity of dosing regimens Limitations • Single center; lack of generalizability

• Neonatal discharge criteria not predefined; no sample size calculation • MICs were not determined for individual isolates; no baseline SCr reported • “Improved” respiratory support duration in prolonged infusion group

Clinical Significance Although there were various methodological flaws in this study, prolonged infusions of meropenem and time-dependent antibiotics in general have the potential for improved efficacy and safety of eradicating infections and improving clinical outcomes.

CRP = C-reactive protein; GA = gestational age; GN-LOS = gram-negative late onset sepsis; ICU = intensive care unit; MIC = minimum inhibitory concentration; SCr = serum creatinine

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VI. CONCLUDING REMARKS

A. Alternative Infusion Times of β-lactam Antibiotics 1. Concerns

a) Intravenous concerns b) Concerns regarding lack of safety and efficacy data, drug stability, and

inappropriate dosing including dose adjustments in acute kidney injury c) Prescriber confusion

2. Considerations

a) Elevated MICs and resistance to β-lactams are becoming more common b) Hospitals that frequently encounter drug resistant organisms may be more

inclined to adopt alternative dosing strategies as an antimicrobial stewardship initiative (institution specific)

c) Alternative strategies may potentially reduce drug acquisition costs and the total amount of drugs patients receive

d) Reduced lengths of stay in the ICU or hospital have been observed

3. Potential Indications a) Patients with a high severity of illness or infection b) Patients with structural lung disease (including cystic fibrosis) c) Infections due to pathogens with high intrinsic resistance and tendency for

developing acquired resistance during therapy (e.g. Pseudomonas aeruginosa)

4. Potential Exceptions a) Patients in the emergency department, ambulatory clinics, or patients

receiving peri-operative doses of antibiotics b) Medication scheduling and/or drug compatibility conflicts that cannot be

resolved without placing additional lines c) Patients with other medical interventions (e.g. physical therapy) that cannot

be performed adequately during intravenous infusion, and administration times cannot be modified to accommodate the intervention

d) Patients on a prolonged course of antibiotics and are clinically improving

B. Recommendations 1. There is a potential pharmacologic advantage to extending the infusion time of β-

lactams that can lead to potential clinical benefits 2. Current literature is not compelling enough to support the preference of always

using extended infusions of β-lactams over traditional infusion times in all pediatric patients

3. Alternative dosing strategies of β-lactams is institution-specific and should be utilized on a case-by-case basis, taking various benefits and logistical barriers into consideration (see Appendix B, Tables 1 and 2, for pediatric institutional implementation studies and external responses from children’s hospitals, respectively)

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APPENDIX A: Supplementary Tables for Pediatric Literature

Table 1. Summary of Evidence for β-lactam Continuous Dosing in Pediatric Patients21

Drug Class Study Design, Disease

CI Antibiotic Concomitant Antibiotic

# patients (age)

Comments & Outcomes

CEPHALOSPORINS David (1989) PK, cystic fibrosis Ceftazidime

100 mg/kg LD, then 300 mg/kg/day

None 9 (NR) Successful treatment of Pseudomonas

aeruginosa infection with CI ceftazidime

Dalle (2002) PK, febrile neutropenia

Ceftazidime 65 mg/kg LD,

then 200 mg/kg/day

Amikacin, vancomycin

20 (1 – 15 years)

Confirmed the feasibility and safety

of CI ceftazidime

Rappaz (2007) Randomized, crossover; cystic

fibrosis

Ceftazidime 200

mg/kg/day divided into 3 doses/day

or 100 mg/kg/day

Amikacin 14 (5 – 16.8 years)

Significant improvement in

prealbumin status (0.11 vs. 0.08; CI vs.

II; p=0.015)

Moriyama (2010)

Case report, bacteremia,

primary immunodeficiency

Ceftazidime 2 g LD, then 163 – 240 mg/kg/day

Tobramycin 1 (18 years)

Negative repeat blood cultures;

patient died from failure of response to chemotherapy

CARBAPENEMS Falagas (2006) Case report,

postappendectomy Klebsiella

pneumoniae septicemia

Meropenem 100

mg/kg/day

Gentamicin, colistin

1 (15 years)

Clinical cure of blood cultures,

resolution of fever

PENICILLINS Dickinson (1981)

Retrospective cohort, meningitis

Piperacillin, initial LD

(NR), then 400

mg/kg/day

None 1 (16 years)

Resolution of infection; CSF

cultures positive until day 4 of

treatment Monckhof (2005)

Retrospective cohort, vascular

infection

Ticarcillin 12.4 g/day

None 1 (14 years)

Resolution of infection; 41-day

course of therapy; no adverse effects

noted

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Knoderer (2010)

Case report, sternal

osteomyelitis

Nafcillin 185 mg/kg/day

NR 1 (42 days) Resolution of infection, 35-day

course of therapy; no adverse effects

noted Colding (1982)

Case series, neonatal

postsurgical complications

Ampicillin 138 – 290 mg/kg/day

(mean)

Gentamicin 7 (GA 28 – 42 weeks)

Determined feasibility of CI ampicillin and gentamicin in

neonates receiving parenteral nutrition

Colding (1982)

Prospective; proven or suspected infection

Ampicillin, mean (SD) 162 (45)

mg/kg/day

Gentamicin 88 (GA 27 – 42 weeks; median 34

weeks)

Development of an individualized dosing

schedule for CI ampicillin to target a

steady state concentration of 40

μg/mL Colding (1986)

PK, proven or suspected septicemia

Ampicillin, mean (SD) 160 (24)

mg/kg/day

Gentamicin 36 (GA 24 – 42 weeks; median 32

weeks)

Validation of dosing schedule in infants

additional to previous study

MONOBACTAM Moriyama (2010)

Case report, wound infection

Aztreonam 127 – 171 mg/kg/day

Nebulized colistin (13

days)

1 (17 years)

Successful treatment with a

long course (8 months) of CI

therapy for complicated

Pseudomonas aeruginosa infection

Hayes (2008) Case report, cystic fibrosis

Aztreonam 200

mg/kg/day

Tobramycin 1 (3 months)

Successful eradication of Pseudomonas

aeruginosa before chronic colonization; pt initially received

CI cefepime 200 mg/kg/day for 3

days CI = continuous infusion; CSF = cerebrospinal fluid; GA = gestational age; II = intermittent infusion; LD = loading dose; NR = not reported; PK = pharmacokinetics; SD = standard deviation

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APPENDIX A: Supplementary Tables for Pediatric Literature (continued)

Table 2. Individual Baseline Characteristics of Study Patients16

Pt no.

Age; sex; weight (kg)

TZP dose (mg)a; type of

therapy

eGFRb Underlying disease

process(es)

Infectious indication; site of isolated organism(s)

1 8 yr; M; 20 2,250; directed

106 CP, small bowel

resection

Sepsis due to CLABSI • Blood: Candida parapsilosis,

CoNS, Enterococcus faecalis • BAL: P. aeruginosa, S.

marcescens 2 5 yr; F; 18.8 2,100;

directed 98 CCHD,

tracheostomy VAP

• BAL: P. aeruginosa and S. marcescens

3 12 mo; F; 11.9 1,465, empirical

93 Previously healthy, ARDS

Pneumonia; none

4 5 yr; M; 19.7 2,200; empirical

107 s/p MVA with TBI

Pneumonia • BAL: MSSA

5 2 yr; F; 9.5 1,070; empirical

86 CCHD Suspected sepsis; none

6 13 mo; M; 10 1,125; empirical

102 Laryngo-malacia

Pneumonia; adenovirus

7 5 yr; M; 14.5 1,630; empirical

98 Epilepsy, microcephaly

Pneumonia; influenza A virus

8 8 yr; F; 16.8 1,860; empirical

189 CCHD, CLD Open sternum; none

9 6 yr; F; 23 2,600; empirical

105 Heart transplant, B

cell lymphoma

Pneumonia; none

10 9 yr; F; 30.1 3,375; empirical

90 Optic glioma Neutropenic fever, typhlitis • Blood: Bacteriodes ovatus

11 13 mo; M; 9.6 1,078; directed

129 Previously healthy, HHV encephalitis

VAP • BAL: E. cloacae, H.

influenzae 12 6 yr; M; 20 2,081.25;

empirical 122 Cornelia de

Lange syndrome,

epilepsy

Pneumonia • BAL: MRSA

aAll doses were administered q8h. beGFR values are reported in mL/min/1.73 m2 and were rounded to the nearest whole number. Abbreviations: ARDS = acute respiratory distress syndrome; BAL = bronchoalveolar lavage; CCHD = complex congenital heart disease; CLABSI = central line-associated bloodstream infection; CLD = chroniC liver disease; CoNS = coagulase negative Staphylococcus; CP = cerebral palsy; eGFR = estimated glomerular filtration rate (determined by Schwartz equation); F = female; HHV = human herpesvirus; M = male; MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-susceptible Staphylococcus aureus; MVA = motor vehicle accident; s/p = status post; TBI = traumatic brain injury; VAP = ventilator-associated pneumonia.

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APPENDIX A: Supplementary Tables for Pediatric Literature (continued)

Table 3. Demographic and Baseline Characteristics of Randomized Neonates19

Characteristic Conventional Group (n=51) Infusion Group (n=51) P value Gestational age (weeks) 33.5 + 3.8 34.3 + 3.5 0.25 Preterm infants (<37 weeks) 37 (72%) 32 (63%) 0.39 Birth weight (g) 1893 + 629 2153 + 797 0.07 Male sex 30 (59%) 25 (49%) 0.32 Singleton 42 (82%) 40 (78.5%) 0.80 Inborn 15 (29%) 18 (35%) 0.67 Mode of delivery Vaginal delivery Cesarean section

11 (21.5%) 40 (78.5%)

8 (16%)

43 (84%)

0.44

Maternal chorioamnionitis 8 (16%) 13 (25%) 0.22 Age at randomization (days)*

6 (5 – 15) 8 (6 – 13) 0.16

Central line devices 18 (35%) 19 (37%) 1.0 Need for respiratory support 46 (90%) 39 (76%) 0.06 Need for mechanical ventilation

18 (35%) 19 (37%) 0.9

CRP before intervention (mg/dL)

84 (25 – 96) 48 (12 – 136) 0.80

Inotropic therapy 21 (41%) 21 (41%) 1.0 Data expressed as mean + SD, median (interquartile range)*, or number (percentage)

Table 4. Site of Infection and Bacterial Isolates in the Study Population19

Characteristic Conventional Group (n=51) Infusion Group (n=51) P value SITE OF INFECTION Primary bloodstream infection

26 (51%) 23 (45%) 0.68

Central line bloodstream infection

14 (27%) 16 (31%) 0.82

Pneumonia 4 (8%) 5 (10%) 1.0 Meningitis 3 (6%) 3 (6%) 1.0 Urinary tract infection 3 (6%) 3 (6%) 1.0 Septic arthritis 1 (2%) 1 (2%) 1.0 TYPE OF ORGANISM Klebsiella spp. 23 (45%) 18 (35%) 0.42 Escherichia coli 11 (21.5%) 12 (23.5%) 1.0 Pseudomonas spp. 5 (10%) 6 (12%) 1.0 Serratia spp. 4 (8%) 5 (10%) 1.0 Acinetobacter spp. 3 (6%) 2 (4%) 1.0 Enterobacter spp. 3 (6%) 3 (6%) 1.0 Proteus spp. 2 (4%) 5 (10%) 0.43 Data expressed as mean + SD, median (interquartile range)*, or number (percentage)

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APPENDIX A: Supplementary Tables for Pediatric Literature (continued)

Table 5. Impact of Meropenem on Clinical Outcomes19

Conventional Group (n=51)

Infusion Group (n=51) P value

Neonatal mortality 16 (31%) 7 (14%) 0.03 Necrotizing enterocolitis

7 (14%) 6 (12%) 1.0

Length of hospital stay (LOS)*

23 (14 – 33) 27 (13 – 43) 0.31

Meropenem-related LOS (days)*

25 (15 – 36) 27 (15 – 39) 0.2

Duration of respiratory support (days)*

12.5 (5.7 – 17.2) 4 (0 – 18) 0.03

Duration of mechanical ventilation (days)*

3 (0 – 8) 1 (0 – 10) 0.6

Meropenem-related duration of mechanical ventilation (days)*

2 (0 – 5) 0 (0 – 7) 0.8

Meropenem-related duration of inotropes (days)*

0 (0 – 3.5) 0 (0 – 4) 0.8

CRP after intervention (mg/L)*

72 (6 – 100) 12 (6 – 96) 0.01

Data expressed as median (interquartile range)* or number (percentage)

Table 6. Adverse Effects of Meropenem Therapy19

Adverse Effect Conventional Group (n=51)

Infusion Group (n=51) P value

Acute kidney injury after meropenem therapy

12 (23.5%) 3 (6%) 0.02

Elevated hepatic transaminases

4 (8%) 3 (6%) 1.0

Others (diarrhea, rash, vomiting, seizures)

13 (25.5%) 6 (12%) 0.12

Data expressed as mean + SD or number (percentage)

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APPENDIX B: PEDIATRIC INSTITUTIONAL IMPLEMENTATION

Table 1. Institutional implementation of alternative infusion strategies in pediatric populations14,17,18

Nichols KR, et al. (2012)18 Knoderer CA, et al. (2014)14 Nichols KR, et al. (2015)17

Objective To determine the feasibility of using an extended 4-hour infusion piperacillin-tazobactam (TZP) dosing strategy as the standard of care in a children’s hospital

To describe the use of extended and continuous infusions of antibiotics in pediatric hospitals in the U.S.

To determine the feasibility of implementing extended 4-hour infusion cefepime as the standard dosing strategy in a pediatric population

Methods Prospective observational study of patients aged >30 days who received TZP after admission to a freestanding, tertiary care children’s hospital • Patients prospectively

assessed for presence of and reasons for changes in dosing regimen

National survey of children’s hospital with practice-based survey questions • Primary outcome:

percentage utilization of extended and continuous dosing strategies

• Secondary outcomes: reasons for not using these dosing strategies

Descriptive study of children 1 months to 17 years of age who received cefepime at a children’s hospital • Primary outcome:

feasibility of extended-infusion cefepime

• Secondary outcomes: infection resolution and safety

Results • A total of 332 patients received TZP

• Extended-infusion was used for the duration of therapy in 92% of patients

• Most common reasons for not using extended infusions was co-administration of vancomycin (61%) and lack of compatibility data with TZP

• 36% of 215 identified practitioners from various children’s hospitals participated in the survey

• Extended infusions and continuous infusions of β-lactams were used in 24% and 13%, respectively, of responding hospitals

• Most common reasons for not using alternative dosing strategies for β-lactams included concern due to lack of pediatric efficacy data, need for more intravenous access, and compatibility issues

• 143 patients received extended-infusion cefepime and 7% of those were changed to a 30-minute infusion during treatment

• Most common reasons for infusion time change were intravenous incompatibility and access concerns

• Dosing errors and reported incidents during therapy were sparse (8%) and were most commonly related to renal dosing errors and/or initial dosing error

Conclusion Extended-infusion TZP dosing was feasible with 92% of patients receiving the dosing strategy of a 4-hour infusion time

There is still some lag in adopting alternative infusion times of β-lactams for pediatrics; additional studies may provide much-needed evidence for implementation

Implementation of extended-infusion cefepime as the standard dosing strategy was feasible in 93% of patients

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Table 2. External Responses from Children’s Hospitals Institution Q1: Does your institution use

extended/continuous infusion times (e.g. 4-hour vs.

traditional 30-min infusion time) for β-lactam antibiotics

for pediatric patients? Y/N

Q2: If answered "Yes" to the first question: • Which specific β-lactam antibiotics? • Used for empiric or targeted therapy? • How was this implemented at your institution? • Are there specific indications for using extended

infusion times?

Q3: If answered “No” to Q1, what are reasons for not?

Carolinas Healthcare System Charlotte, NC

In general, no Yes, on a case-by-case basis for CF, MDROs/intermediate to high MICs or persistent line associated bacteremia.

Due to lack of clinical data in the pediatric setting (outside of in vitro and feasibility data).

Children’s Health Dallas, TX

Yes We have a prolonged infusion policy. Empirically we start all febrile neutropenia patients on extended infusion Zosyn for those who receive that agent rather than cefepime for febrile neutropenia.

N/A

Children’s Healthcare of Atlanta Atlanta, GA

Yes Occasionally extended or continuous, based on specific cases. Standard is 30-minute infusion. We have utilized this with Zosyn and meropenem in the past for targeted therapy with a high MIC pathogen that warrants extended infusion. No official guideline/policy yet but working on it.

Typically the argument against is line access issues and no apparent problem with the standard 30-minute administration. However we are investigating creating some new guidance on situations when extended/continuous strategies will be recommended.

Children’s Hospital at Summerlin Hospital Medical Center Las Vegas, NV

No N/A We currently have an 11-year-old male going home on Zosyn for appendicitis and the home infusion company had recommended a continuous infusion (24 hr). I know there is plenty of data to support this in adults, but I can’t find a lot of data to support this in pediatric patients. Conceptually, I think it sounds great but I wondered if anyone else has ever used Zosyn in this fashion before. The physicians are notably concerned.

Connecticut Children’s Medical Center Hartford, CT

Yes We use them for specific types of patients. We do Zosyn, ceftazidime, cefepime, and meropenem. We have it as a general option and recommend it on some patients. Common for cystic fibrosis.

N/A

Johns Hopkins All Children’s Hospital St. Petersburg, FL

Yes Prolonged infusion times used for Zosyn, Cefepime, Ceftazidime, meropenem. Standard of care for all patients with cystic fibrosis. ASP will use in non-CF patients on a case-by-case basis. A few years ago we (ID) met with pulmonology and developed guidelines. Since it is practice-specific and not house-wide, did not feel approval was needed from committees.

N/A

Nicklaus Children’s Hospital Coral Terrace, FL

Yes Currently only done in cystic fibrosis patients that have extensively resistant gram-negative organisms. Only used for targeted therapy. Our ID physician directed extended infusion use but has not been formally approved at any committee. We did not institute it throughout the whole hospital, because from a cost-savings perspective, most of our Zosyn dosing is q8h and would not save us an extra dose.

N/A

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Norton Children’s Hospital Louisville, KY

Yes We have use meropenem over 4 hours for pathogens with high MICs, and have also discussed it for difficult to treat infections requiring meropenem. In the next month we will go live with Verigene for rapid blood culture identification. Our “treatment pathway” includes meropenem over 4 hours + colistin for any CRE infections.

N/A

NYU Langone Medical Center New York, NY

Yes We have a protocol of extended-infusion Zosyn in place for all of our pediatric patients for empiric therapy. The protocol includes dose adjustments after cultures and susceptibilities return, which are mainly based on MIC.

N/A

Seattle Children’s Seattle, WA

No N/A We do not have susceptibility profiles that warrant longer infusions, which potentially complicate medication compatibilities or line time. We do not see clinical failures of beta-lactam therapies that warrant modifying our practice from traditional infusion times.

St. Jude Children’s Research Hospital Memphis, TN

Yes Only used for meropenem as targeted therapy for CRE organisms. Initiated by our antimicrobial stewardship program and approved by P&T. Overall reserved for patients with high MICs or suspected treatment failure.

N/A

St. Louis Children’s Hospital St. Louis, MO

Yes We use prolonged infusions for Zosyn and meropenem for targeted patient case scenario on a case-by-case basis, so no standardized implementation currently. Typically used for patients with high MICs or patients not responding appropriately to standard infusion time.

N/A

The Johns Hopkins Hospital Baltimore, MD

Yes Done on a case-by-case basis for multi-drug resistant organisms with elevated beta lactam MICs. We do this for meropenem, Zosyn, cefepime, and ceftazidime for targeted therapy

N/A

University of North Carolina Hospitals Chapel Hill, NC

No N/A Competing priorities. We’re newly established and working on a lot of different things. In addition, our lab exclusively uses disk diffusion for susceptibilities and does not report MICs, just S/I/R. So since we’re not seeing those borderline MICs (i.e., Pseudomonas - Zosyn 16), it doesn’t come up.

ASP = antimicrobial stewardship program; CRE = carbapenem-resistant Enterobacteriaceae; ID = infectious diseases; MDRO = multidrug resistant organisms; MIC = minimum inhibitor concentration; P&T = Pharmacy & Therapeutics

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REFERENCES

1. Antibiotics Simplified, 3rd Edition by J.C. Gallagher & C. MacDougall. 2. Available at: http://www.asp.mednet.ucla.edu/files/view/guidebook/AntimicrobialFundamentalConcepts.

Accessed January 29, 2017. 3. Available at:

http://med.stanford.edu/content/dam/sm/bugsanddrugs/documents/dosingprotocols/SHC%20Extended%20Infusion%20Piperacillin-tazobactam.pdf. Accessed February 1, 2017.

4. Available at: http://www.nebraskamed.com/App_Files/pdf/careers/education/asp/pip-tazoEI-protocol-detail.pdf. Accessed February 15, 2017.

5. Available at: http://www.umt.edu/sell/cps/bigskypulmonary/BSP%20presentations/Richardson.PPpresentation.pdf. Accessed February 5, 2017.

6. Barlam TF, Cosgrove SE, Abbo LM, et al. Executive summary: implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):1197-202.

7. Connors KP, Kuti JL, Nicolau DP. Optimizing antibiotic pharmacodynamics for clinical practice. Pharmaceutica Analytica Acta. 2013;4(3):214.

8. Deryke CA, Kuti JL, Nicolau DP. Reevaluation of current susceptibility breakpoints for gram-negative rods based on pharmacodynamic assessment. Diagn Microbiol Infect Dis. 2007;58(3):337-44.

9. Dellit TH, Owens RC, Mcgowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-77.

10. Dulhunty JM, Roberts JA, Davis JS, et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis. 2013;56(2):236-44.

11. Dulhunty JM, Roberts JA, Davis JS, et al. A multicenter randomized trial of continuous versus intermittent β-Lactam infusion in severe sepsis. Am J Respir Crit Care Med. 2015;192(11):1298-305.

12. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis. 2013;56(2):272-82.

13. Grant EM, Kuti JL, Nicolau DP, et al. Clinical efficacy and pharmacoeconomics of a continuous-infusion piperacillin-tazobactam program in a large community teaching hospital. Pharmacotherapy. 2002;22(4):471-83.

14. Knoderer CA, Nichols KR, Cox EG. Optimized antimicrobial dosing strategies: a survey of pediatric hospitals. Paediatr Drugs. 2014;16(6):523-9.

15. Mcnabb JJ, Nightingale CH, Quintiliani R, Nicolau DP. Cost-effectiveness of ceftazidime by continuous infusion versus intermittent infusion for nosocomial pneumonia. Pharmacotherapy. 2001;21(5):549-55.

16. Nichols K, Chung EK, Knoderer CA, et al. Population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin and tazobactam in critically ill children. Antimicrob Agents Chemother. 2015;60(1):522-31.

17. Nichols KR, Karmire LC, Cox EG, et al. Implementing extended-infusion cefepime as standard of care in a children's hospital: a prospective descriptive study. Ann Pharmacother. 2015;49(4):419-26.

18. Nichols KR, Knoderer CA, Cox EG, Kays MB. System-wide implementation of the use of an extended-infusion piperacillin/tazobactam dosing strategy: feasibility of utilization from a children's hospital perspective. Clin Ther. 2012;34(6):1459-65.

19. Shabaan AE, Nour I, Eldegla HE, et al. Conventional versus prolonged infusion of meropenem in neonates with gram negative late onset sepsis: a randomized controlled trial. Pediatr Infect Dis J. 2016.

20. Tamma PD, Putcha N, Suh YD, et al. Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials. BMC Infect Dis. 2011;11:181.

21. Walker MC, Lam WM, Manasco KB. Continuous and extended infusions of β-lactam antibiotics in the pediatric population. Ann Pharmacother. 2012;46(11):1537-46.

22. Yost RJ, Cappelletty DM. The retrospective cohort of extended-infusion piperacillin-tazobactam (RECEIPT) study: a multicenter study. Pharmacotherapy. 2011;31(8):767-75.