challenges in antibiotic selection for pediatric … peds selection...5/14/2012 1 challenges in...

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Challenges in Antibiotic Selection for Pediatric Patients: Issues and

AnswersAnswersWhat a Pediatrician Needs to

know in 2012!!

Disclosure I have no financial or other arrangements with the

companies who make the products presented.

Some of the dosing recommendations are based on common use (e.g., guidelines, review articles, studies, and current practice). As is common in pediatric pharmacotherapy, this may differ from the manufacturers’ package inserts.

Objectives Discuss the current issues related to antibiotic

resistance in pediatric patients

Suggested alternative methods and agents for select group of patients in both the outpatient and inpatient arena

Discuss ways to minimize drug toxicity and adverse events in pediatric patients on long term antibiotic therapy

Discuss recent “break point “ changes and implications on drug selection for pediatric infections

Update you on HIV treatment in pediatric patients

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Expected Outcome What is the desired change/result following this

educational intervention? Refine strategies to help select antibiotics for selected

infections in children

Apply the principles of antibiotic killing to practical ways toApply the principles of antibiotic killing to practical ways to manage infection

Have a current reference for pediatric HIV infections available for your patients

The Antibiotic Rules Once a day is best

Give IV antibiotics over 30-60 minutes except vancomycin

Resistance is a problem but not for my patients Resistance is a problem but not for my patients

Vitamin R is still golden

Clindamycin suspension taste great and is less filling

Cedinir taste great and treats almost everything

Azithromycin is good for everything from inflammation to infection

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Why we do what we do? 1. Volumetric Infusion devices

2. Free flow protection of IV infusion

3. Many portable, small IV infusion with smart phone technologytechnology

4. Many drug safe to give over very short periods of time .e.g. gentamicin 3-4mg/kg push over 5-10 minutes

5. Convenience

6. Better analytical capacity to measure drugs

7. Better understanding of Pharmacokinetics

Is this the right thing to do Peak to MIC ratio

AUC to MIC ratio

Time above MIC

Special Populations

Critically Ill

CF

Immunocompromised

Rule 1 Once a day is best

Great data on once a day medication for chronic therapy improves adherence

Limited data that once a day for short term therapy is Limited data that once a day for short term therapy is really much better than two times a day. Some studies suggest no real difference.

No new studies in this area in the last 10 years

Taste does make a huge difference in completing therapy

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Rule 1 revisited Pharmacokinetics/pharmacodynamics plays a huge

role in treating moderate to severe infections

More frequent dosing may be important than convenience in dosing.

We have now technology to minimize the complexity of drug delivery in inpatient and outpatient settings

Show me

Rule 2 Give IV antibiotics over 30-60 minutes except

vancomycin

Why do we do that?

It was hard to administer many of these drugs when we It was hard to administer many of these drugs when we tested them and wanted to make sure they were safe but not allow patients to be hooked up for too long

What we have now!

The Breakpoint “Breakpoint”: MIC (in mcg/ml) at or below which organism

considered susceptible Unique for drug-organism-(infection)

Examples: Ceftriaxone & Haemophilus influenzae: ≤2 mcg/ml

Ceftriaxone & Streptococcus pneumoniae: ≤1 mcg/ml (non CSF Ceftriaxone & Streptococcus pneumoniae: ≤1 mcg/ml (non-CSF isolates)

Ceftriaxone & Streptococcus pneumoniae: ≤0.5 mcg/ml (CSF isolates)

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Setting Breakpoints Set by CLSI, FDA, EUCAST

Factors considered MIC distributions of collections of isolates

Achievable drug concentrationsg

Response rates by MIC in clinical trials (rare)

Probability of achieving target PK/PD values

PK/PD Parameters

cen

trat

ion

Peak/MIC

AUC/MIC

AminoglycosidesFluoroquinolonesLipopeptides

Glycopeptides

Co

n

Time (hours)

MIC

0

Time > MIC

Beta-lactams

Bacteriostatic effectTime>MIC ~40%

Bactericidal effectTime>MIC ~60%Target Time>MIC

Static activity ≥40% Cidal activity ≥60%

Drusano GL. Clin Infect Dis 2007;45(S2):S89-S95. Used with permission

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Antibacterial Use in Pediatrics in Academic Hospitals 2002-2007

Pakyz AL, et al. Infect Control Hosp Epidemiol 2009;30:600-603. Used with permission.

TEM-1TEM-2

SHV-1

Extended-spectrum beta-lactamases1)Acquired2)Resistance to penicillins & 1st

Group 2b

Group 2be

point mutation

ESBLs

Narrow-spectrum beta-lactamases1)Acquired or chromosomal2)Resistance to penicillins (& sometimes 1st-gen cephs)3) Inhibited by clavulanate

2)Resistance to penicillins & 1st

- 4th-gen cephalosporins3) Inhibited by clavulanate

TEM≥3 SHV≥2

CTX-Mmobilization

CTX-M

OXAPER

AmpC

Other GroupsBroad-spectrum beta-lactamases not generally considered “ESBLs”

ESBL fever: the beginning Retrospective review 32 patients w/Klebsiella bacteremia

ESBL+ via confirmatory test

Treated with cephalosporin C ft idi f t i ft i f i Ceftazidime, cefotaxime, ceftriaxone, cefepime

MICs to treating cephalosporin S- or I- Breakpoint ≤8 mcg/ml

Paterson DL. J Clin Micro 2001;39:2206-2212

Susceptibility Clinical Failure

Intermediate 4/4(100%)

Susceptible 15/28 (54%)

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Approved CLSI Changes for Enterobactericeae

Lower breakpoints regardless of ESBL +/-

ESBL testing not needed except for epidemiology/infection control purposes

Drug Old breakpoints New breakpoints

S I R S I R

Cefazolin ≤8 16 ≥32 ≤2 4 ≥4

Cefotaxime ≤8 16-32

≥64 ≤1 2 ≥4

Ceftriaxone ≤8 16-32

≥64 ≤1 2 ≥4

Ceftazidime ≤8 16-32

≥64 ≤4 8 ≥16

Aztreonam ≤8 16 ≥32 ≤4 8 ≥16

Cefepime ≤8 16 ≥32 ≤8 16 ≥32Clinical Laboratory Standards Institute M-100 S-20 2010

Drusano GL, et al. Antimicrob Agents Chemother 2011;56:231-242 Used with permission.

Tobramycin MIC Target attainment for resistance suppression tobramycin 7mg/kg/day

0.25 100%

0.5 100%

1.0 70%

2.0 <1%

4.0 (breakpoint) 0%

Ceftazidime Ceftazidime + tobramycin

Imipenem Imipenem + netilmicin

Cefoperazone/ceftazidime Cefoperazone/ceftazidime + gentamicin

Mezlocillin Ampicillin + gentamicin

Ceftazidime Cefazolin/ticarcillin + tobramycin

Imipenem Cefotaxime + gentamicin

Emergence of resistance to therapy

y

Ceftazidime Ticarcillin + tobramycin

Piperacillin Carbenicillin/ticarcillin +gentamicin/tobramycin

Bliziotis IA, et al. Clin Infect Dis 2005;41:149-158. Used with permission.

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Pseudomonas: Hard to KillAntibiotic

E. coli Pseudomonas

MIC50 MIC90 % S MIC50 MIC90 %S

Ceftazidime 0.25 0.5 96.3 2 16 86.0

Cefepime ≤0.03 0.12 97.2 2 16 88.0

Ciprofloxacin 0.015 64 75.0 0.5 32 69.1

Imipenem 0 25 0 25 99 8 2 16 81 0Imipenem 0.25 0.25 99.8 2 16 81.0

Meropenem ≤0.015 0.03 99.8 0.5 8 89.8

• Even when susceptible, Pseudomonas less susceptible than most E. coli

Lodise TP. Clin Infect Dis 2007;44:357-363. Used with permission.

• Probability of pip/tazo target attainment by dosing regimen & MIC for Pseudomonas

• What seems like a reasonable breakpoint?

Tam VH. Clin Infect Dis 2008;46:862-867. Used with permission.

Drug Old breakpoints New breakpoints

S I R S I R

Ceftazidime ≤8 16 ≥32 ≤8 16 ≥32

Cefepime ≤8 16-32

≥64 ≤8 16 ≥32

Pip/tazo ≤64 32 ≥64 ≤16 32 ≥64

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Pseudomonas – Resistance MechanismsMutated DNA topoisomerase

FluoroquinolonesAminoglycoside modifying enzymes

Gentamicin, Tobramycin>AmikacinMultidrug

Efflux PumpPenicllins

CephalosporinsMonobactams

FluoroquinolonesAminoglycosides

Meropenem

AmpC β-lactamasePenicillins

CephalosporinsMonobactams

ImpermeabilityAll antimicrobialsLoss of porin channels

Imipenem>Meropenem

Roberts JA, et al. J Antimicrob Chemother 2011;66:227-231 Used with permission

Continuous Infusion

Mouton et al., Antimicrob Agents Chemother. 1994.Wysocki et al., Antimicrob Agents Chemother. 2007.Adembri et al., Int J Antimicrob Agents. 2008.

CI Vancomycin

CI Linezolid

CI Ceftazidime

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PK/PD Advantages of CI vs. Intermittent

1. Ability to maintain levels above the MIC

Intermittent vs CI Ceftazidime in CF

N=12 Healthy volunteers

Open label, randomized, crossover

Intermittent vs Continuous Infusion 1 IV 8h 1gm IV q8hr

1gm IV q12hr

3gm CIV q24hr

2gm CIV q24hr

Nicolau DP, et al. Antimicrob Agents Chemother. 1996

Intermittent infusion Ceftazidime

Ceftazidime

MIC 8mcg/ml


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Continuous infusion Ceftazidime

Ceftazidime

MIC 8mcg/ml




2. Predictable attainment of target concentrations (i.e. 4-6 x’s MIC)

Intermittent Ceftazidime Dosing

Mouton JW, et al., Antimicrob Agents Chemother. 1994.

MIC 8 mcg/mL

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Continuous Infusion Ceftazidime

MIC 8

Mouton JW, et al., Antimicrob Agents Chemother. 1994.

MIC 8 mcg/mL



2. Predictable attainment of target concentrations (i.e. 4-6 x’s MIC)

3 Ability to attain higher PK/PD MIC breakpoints (i e kill 3. Ability to attain higher PK/PD MIC breakpoints (i.e kill resistant “bugs”)

p

Bulitta JB, et al., Antimicrob Agents Chemother. 2010.

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PK/PD breakpoints in Critically-ill

Lodise TP, et al., CID. 2007.

PK/PD breakpoints in Pediatrics

Courter JD, et al. Pediatr Blood Cancer. 2009.

Community-Acquired Pneumonia: Evidence

for Changes in Practice

Robert J. Kuhn, Pharm.D.Bill Maish, Pharm.D.

Pediatric Clinical Specialist: Pediatric Internal MedicineArnold Palmer Medical Center

Orlando, FL

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Case 7 y/o male admitted for CAP

H/O URI starting 10 days ago, saw PMD 8 days ago. No prior respiratory illness other than URTIs in the past.

Got better with Azithromycin 300 mg po, then 150 mg po daily x 4 days

Over the last 48hr, pt had new cough, fever to 103.1

Wt 25 kg, Temp 102.5, RR 40, Sats 90% on RA, CXR positive for RLL infiltrate, WBC 17.5 (46% segs, 18% bands, 25% lymphs)

UTD, NKDA

Ceftriaxone 1gm IV x1, Maint IVF, Acetaminophen

Comparative Trials Placebo-controlled-unethical since 1940’s

Causative organisms are rarely isolated (so heterogeneous populations studied)

Clinical course is short and potentially self Clinical course is short and potentially self-resolving

Dose-ranging could be done…but which outcome to measure? What if low dose increases risk?

Pediatric patients are “vulnerable”Bradley JS, Clin Infect Dis 2008;47:S241-4

Pharmacotherapy Hospitalization (if meet criteria)

IV antibiotics for bacteria Empiric

Streamlined

Oxygen

IV Fluids

+/- Bronchodilators

Antipyretics

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Pneumonia Etiology Viruses 45-80%

S. pneumoniae 4-44%

Viral + bacterial coinfection: 2-50%

Atypicals 2-33% C. pneumoniae

M. pneumoniae

Bradley JS, et al. Clinical Infectious Bradley JS, et al. Clinical Infectious Diseases Advance Access Published Diseases Advance Access Published August 30, 2011.August 30, 2011.

3 m/o to 5 y/o: Therapy Viral infection-no antibiotics

Coinfection known or suspected-use antibiotics If immunized & healthy: amoxicillin

Bradley JS, et al. Clinical Infectious Diseases Advance Bradley JS, et al. Clinical Infectious Diseases Advance Access Published August 30, 2011.Access Published August 30, 2011.

Respiratory Syncytial Virus (RSV) Ineffective acute therapy for bronchiolitis Systemic corticosteroids Albuterol or racemic epinephrine Palivizumab (Synagis)

Supportive Care: nasal flush IV fluids Supportive Care: nasal flush, IV fluids

May be associated with coinfection

Prophylaxis Palivizumab (Synagis) 15 mg/kg IM monthly Season “October to February” High risk patients Cost: $1000-2,000/dose Outpatient requires prior approval

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Etiology: 5y/o - Adolescence Viral Infection Possible

Bacteria Streptococcus pneumoniae

Group A Streptococcusp p

Staphylococcus aureus

Chlamydia pneumoniae

Mycoplasma pneumoniae

S. pneumoniae PCN Susceptibility

IV Penicillin May increase dose and treat if MIC <= 2 mcg/mL

PO Penicillin Susceptible: <= 0.06 mcg/mLp g

Intermediate: 0.12-1 mcg/mL

Resistant: >= 2 mcg/mL

Weinstein MP, et al. Clin Infect Dis; 2009;48:1596-1600

Cross-susceptibility and cross-resistance analysis of MIC breakpoints of penicillin, compared with MIC breakpoints of ceftriaxone, involving 23,669 isolates of

Streptococcus pneumoniae.

Weinstein M P et al. Clin Infect Dis. 2009;48:1596-1600

© 2009 by the Infectious Diseases Society of America

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S. Pneumoniae and Susceptibility

50

60

70

80

90

100 PCN

Amoxicillin45mg/kg/day

Amoxicillin90mg/kg/day

Amox/Clav <= 2/1

0

10

20

30

40

% Susceptible

Ceftriaxone <=1

Clindamycin

Azithromycin

Trimethoprim/Sulfamethoxazole

Adapted from Harrison, CJ, et al. J Antimicrob Chemo 2009:63:511-9.

Pneumococcal Susceptibility Penicillin susceptibility down to 89% &

ceftriaxone to 88% in many areas

Intermediate resistance Typically due to altered penicillin binding proteins Typically due to altered penicillin-binding proteins

Overcome by increasing beta-lactam dose

Non-beta Lactam Alternatives Vancomycin (IV)

Clindamycin (IV or PO)

And others

S. pneumoniae w PCN MIC<=2

Preferred IV Ampicillin 150-200 mg/kg/day ÷ Q6H

Penicillin 200,000-250,000 Units/kg/day ÷ Q4-6H

Alternate Parenteral Ceftriaxone 50-100 mg/kg/day ÷ Q12-24Hg g y Q

Cefotaxime 150 mg/kg/day ÷ Q8H

Clindamycin 40 mg/kg/day ÷ Q6-8H

Vancomycin 40-60 mg/kg/day ÷ Q6-8H (60-80mg/kg/day)


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S. pneumoniae w PCN MIC<=2

(Step-Down or Mild Infection) Preferred

Amoxicillin 90 mg/kg/day ÷ Q12H

Amoxicillin 45 mg/kg/day ÷ Q8H

Oral AlternativesOral Alternatives

Cefpodoxime/cefuroxime/cefprozil

Levofloxacin 0.5-5 y/o: 16-20 mg/kg ÷ Q12H

>5 y/o: 10 mg/kg ÷ Q24H

Linezolid < 12 y/o: 30 mg/kg/day ÷ Q8H

>=12 y/o: 20 mg/kg ÷ Q12HBradley JS, et al. Clinical Infectious Diseases Advance Bradley JS, et al. Clinical Infectious Diseases Advance Access Published August 30, 2011.Access Published August 30, 2011.

S. pneumoniae w PCN MIC>=4 Preferred IV

Ceftriaxone 100 mg/kg/day ÷ Q12-24H

Alternate IV

Ampicillin 300-400 mg/kg/day ÷ Q6H

Levofloxacin

0.5-5 y/o: 16-20 mg/kg ÷ Q12H

>5 y/o: 10 mg/kg ÷ Q24H

Linezolid

< 12 y/o: 30 mg/kg/day ÷ Q8H

>=12 y/o: 20 mg/kg ÷ Q12H

Clindamycin 40 mg/kg/day ÷ Q6-8H

Vancomycin 40-60 mg/kg/day ÷ Q6-8H


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S. pneumoniae w PCN MIC>=4 (Step-

Down or Mild Infection) Preferred

Levofloxacin 0.5-5 y/o: 16-20 mg/kg ÷ Q12H

>5 y/o: 10 mg/kg ÷ Q24H

Li lid Linezolid < 12 y/o: 30 mg/kg/day ÷ Q8H

>=12 y/o: 20 mg/kg ÷ Q12H

Oral Alternative

Clindamycin 40 mg/kg/day ÷ Q8H


Cefdinir and Future Changes? N=37

Older infants and children

Desired % time>MIC > 40% for resistant S. pneumoniae strains (MIC

CefdinirDose

% Time >MIC 1

14mg/kg q12h 21 +/- 8 7%pneumoniae strains (MIC 1)

Diarrhea to 35% in < 2y/o on higher dose

Larger trial for safety efficacy of greater dosing regimens will help determine place in therapy Adapted from Bowlware KL, et al. Pediatric Infect

Dis J 2006;25:208-210.

14mg/kg q12h 21 +/- 8.7%

25mg/kg q24h 31 +/- 21%

25mg/kg q12h 44 +/- 18%


H/O URI starting 10 days ago, saw PMD 8 days ago. No prior lower RTIs before

Got better with azithromycin 300mg po, then 150mg po daily x 4 daysp y y


Wt 25kg, Temp 102.5, RR 40, Sats 90% on RA, CXR positive for RLL infiltrate, WBC 17.5 (46% segs, 18% bands, 25% lymphs)

UTD, NKDA

Ceftriaxone 1gm IV x1, maint IVF, acetaminophen

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Preferred empiric therapy for an immunized 7 y/o admitted for lobar pneumonia would be:

A C ft i IVA. Ceftriaxone IV

B. Ceftriaxone IV + azithromycin PO

C. Ampicillin and cefotaxime IV

D. Ampicillin IV

Group A Streptococcus: IV Preferred Penicillin 100,000-250,000 units/kg/day ÷ Q6H

Ampicillin 200 mg/kg/day ÷ Q6H

Alternatives Ceftriaxone 50-100 mg/kg/day ÷ Q12-24H

Cefotaxime 150 mg/kg/day ÷ Q8H

Clindamycin* 40 mg/kg/day ÷ Q6-8H

Vancomycin* 40-60 mg/kg/day ÷ Q6-8H


Group A Streptococcus: PO Preferred Amoxicillin 50-75 mg/kg/day÷ Q12H

Penicillin V 50-75 mg/kg/day÷ Q6-8H

Alternatives Clindamycin 40 mg/kg/day ÷ Q8H Clindamycin 40 mg/kg/day ÷ Q8H

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Group A Streptococcus: Azithromycin Risk

Therapy to eradicate colonization

12mg/kg/day po x 5 days

N=152

Eradication 95%

NP pneumococcal colonization decreased from 46 to 12% by Day 17 and 20% by Day 32

Erythromycin-resistant pneumococcal isolates increased from 2% to 4% to 8% by Day 32

Morita JY, et al. Pediatr Infect Dis J 2000;19:41-6.

Empiric Outpatient CAP Therapy< 5 y/o

Bacterial

Preferred: Amoxicillin 90 mg/kg/day ÷ Q12H*

Alternative: Amoxicillin/Clavulanate 90 mg amox/kg/day ÷ Q12H*

Atypical Atypical

Preferred: Azithromycin 10 mg/kg then 5 mg/kg/day Alternatives Clarithromycin 15 mg/kg ÷ Q12H

Erythromycin 40 mg/kg ÷ Q6H

Bradley JS, et al. Clinical Infectious Diseases Bradley JS, et al. Clinical Infectious Diseases Advance Access Published August 30, 2011.Advance Access Published August 30, 2011.

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MSSA/OSSA: IV Preferred Cefazolin 150 mg/kg/day ÷ Q8H

Alternative Clindamycin* 40 mg/kg/day ÷ Q6-8Hy g g y

Vancomycin 40-60 mg/kg/day ÷ Q6-8H


MSSA/OSSA: PO Preferred Cephalexin 75-100 mg/kg/day ÷ Q6-8H

Alternative Clindamycin* 30-40 mg/kg/day ÷ Q8Hy g g y


MRSA/ORSA: IV then PO Preferred Vancomycin 40-60 mg/kg/day ÷ Q6-8H

(or dose to AUC/MIC ratio > 400)

Clindamycin* 40 mg/kg/day ÷ Q6-8H

Alternative Linezolid < 12 y/o: 30 mg/kg/day ÷ Q8H

> 12 y/o: 20 mg/kg/day ÷ Q12H

Bradley JS, et al. Clinical Infectious Diseases Advance Access Bradley JS, et al. Clinical Infectious Diseases Advance Access

Published August 30, 2011Published August 30, 2011..

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Mycoplasma or Chlamydia: IV Preferred Azithromycin 10 mg/kg/day ÷ Q24H x 2 days then change

to PO

Alternatives Erythromycin lactobionate

Levofloxacin


Mycoplasma or Chlamydia: PO Preferred Azithromycin 10 mg/kg then 5 mg/kg/day x 4 days

Alternative: Clarithromyciny

Erythromycin

Doxycycline

Levofloxacin or moxifloxacin


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Suitable agents for atypical CAP include all but:

A. Azithromycin PO

B. Ampicillin/amoxicillin

C. Levofloxacin PO

D. Doxycycline PO in older patients

Empiric Outpatient CAP Therapy >= 5 y/o

Bacterial Preferred: Amoxicillin 90 mg/kg/day ÷ Q12H* (up to 4 gm/day)

+/- Azithromycin

Alternative: Amoxicillin/Clavulanate 90 mg amox/ kg/day ÷Q12H* (up to 4 gm amox/day) Q ( p g y)

Atypical Preferred: Azithromycin 10 mg/kg (up to 500mg) then 5

mg/kg/day (up to 250mg)

Alternatives Clarithromycin 15 mg/kg ÷ Q12H

Erythromycin 40 mg/kg ÷ Q6H

Doxycycline Bradley JS, et al. Clinical Infectious Diseases Bradley JS, et al. Clinical Infectious Diseases Advance Access Published August 30, 2011.Advance Access Published August 30, 2011.

Empiric Inpatient Bacterial Therapy for Immunized Patient with Low Local PCN Resistance

Preferred Ampicillin

Pen G

Alternatives C ft i f t i Ceftriaxone or cefotaxime

If CA-MRSA Suspected Vancomycin

Clindamycin


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Empiric Inpatient Atypical Therapy for Immunized Patient with Low Local PCN Resistance

Preferred Azithromycin

+/- Beta-lactam

Alternatives Clarithromycin

Erythromycin

Doxycycline (> 7 y/o)

Levofloxacin*


Empiric Inpatient Bacterial Therapy for Unimmunized Patient OR Significant Local Pneumococcal

Resistance

Preferred Ceftriaxone or cefotaxime

+/- Vancomycin or clindamycin

AlternativesAlternatives Levofloxacin

+/- Vancomycin or clindamycin


Empiric Inpatient Atypical Therapy for Unimmunized Patient OR Significant Local Pneumococcal Resistance

Preferred Azithromycin

+/- Beta-lactam

Alternatives Clarithromycin

Erythromycin

Doxycycline (> 7 y/o)

Levofloxacin*


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Amoxicillin Allergy? Possible non-serious reaction: Not well-defined,

individualize therapy Amoxicillin trial

Prepen and penicillin test (not in Guidelines)

Cephalosporin trial p p

Cefpodoxime—in future at higher doses?

Cefprozil

Cefuroxime

Levofloxacin

Linezolid

Clindamycin

Macrolide

Presumed Influenza Pneumonia

< 5 y/o Oseltamivir PO

Amantadine/Rimantadine PO (if susceptible)

>= 5 y/oy Oseltamivir PO

Zanamivir IH (if >= 7 y/o)

Alternatives

Peramivir

Oseltamivir and zanamivir

Amantadine /Rimantadine PO (if susceptible)

IV zanamivir (compassionate use study)


IV Agents: Ampicillin Narrow spectrum

Time-dependent killing

Q6H dosing for most patients

Oral alternative available (amoxicillin 45-90 mg/kg/day ÷ Q8-12H)

Relatively inexpensive*

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IV Agents: Cefotaxime & Ceftriaxone Covers many GNB and some gram positive

Time-dependent killing

Interval Cefotaxime typically Q6HCefotaxime typically Q6H Ceftriaxone Q12 or Q24H

Disposition Cefotaxime: renal by GFR Ceftriaxone: hepatobiliary Highest risk of sludging if < 1m/o or on IV Ca+2

Max 2gm/dose and 4gm/day

Oral alternative available-Generics available

Oral Cephalosporin Alternatives Cefotaxime/Ceftriaxone 2nd/3rd Generation Cephalosporins

Cefdinir

Not in Guidelines due to MICs (t>MIC <40-50%)

Cefprozil

Good taste

30 mg/kg/day ÷ Q12H

Cefpodoxime proxetil

Extremely bitter taste


Cefuroxime axetil

Extremely bitter taste


What would be comparable oral therapy for a 3 y/o patient who has received IV ceftriaxone?

A. Augmentin ES 80-90 mg/kg PO ÷ Q12H

B. Amoxicillin 80 mg/kg PO ÷ Q12H

C. Cefdinir 14 mg/kg PO Q24H

D. Cefprozil 30 mg/kg PO ÷ Q12H

E. Clindamycin 13 mg/kg/dose Q8H

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Doxycycline >= 8 y/o

2-4 mg/kg/day (max 200mg/day)

BID or once daily dosing

Levofloxacin Trial CAP in children 0.5-16 y/o, n 539

Open-label, multicenter, multinational non-inferiority trial

10 days therapy 10 days therapy

0.5-5 y/o levofloxacin 10mg/kg q12h PO or IV vs. amoxicillin/clavulante or ceftriaxone

> 5 y/o levofloxacin 10mg/kg q24h PO or IV vs clarithromycin or clarithromycin or erythromycin + ceftriaxone

Bradley JS, et al. Pediatr Infect Dis J 2007;26:868-78.

Levofloxacin Trial Clinical Cure

60

70

80

90

100

0

10

20

30

40

50

60

Clinical Cure

Levofloxacin

Comparator

Bradley JS, et al. Pediatr Infect Dis J 2007;26:868-78.

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Clindamycin Dose is typically 40 mg/kg/day

Availability IV

PO: 75mg/5mL, 150mg, 300mg

Major taste issues Coat tongue with chocolate syrup

Dilute with cherry syrup

Other flavors

Teach child (>=4 y/o) to swallow capsules

D-test if S. aureus “R” to erythromycin and “S” to clindamycin

IV Agents: Vancomycin Time and AUC Dependent Killing

Interval: Q6H or Q8H

Disposition Renally eliminated T1/2 2-4hr Vd approx 0.7-0.9L/kg Target level “trough 10-20” mg/L

AUC/MIC ratio > 400

Three-compartment, so accumulation will occur

Ineffective Orally for Systemic Infections

Low Acquisition Cost Liu C, et al. Clin Infect Dis 2011;52(3):285Liu C, et al. Clin Infect Dis 2011;52(3):285--292.292.Bradley JS, et al. Clinical Infectious Diseases Advance Access Published August Bradley JS, et al. Clinical Infectious Diseases Advance Access Published August 30, 2011.30, 2011.

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Azithromycin Covers atypicals and some gram positive organisms

Unique dosing 10mg/kg then 5mg/kg daily for 4 days 10mg/kg daily x3 (not in Guidelines) 30-60mg/kg (max 2,000 mg) x1 (not in Guidelines)

Disposition Intracellular Oral = IV

Caution: slow IV infusion (QT Syndrome possible)

Preferred over erythromycin (hypertrophic pyloric stenosis in neonates and infants)

More palatable than clarithromycin

Duration of Therapy Patients 2 m/o to 5 y/o with non-severe CAP

4 trials

3 vs. 5 days y

No difference in clinical cure (RR 0.99, 95% confidence interval 0.97-1.01)

No difference in treatment failure (RR 1.07, 95% confidence interval 0.92-1.25)

Haider BA, et al. Cochrane Database of Systematic Reviews 2008; Issue 2. Art. No. CD005976, DOI:10.1002/14651858. CD005976.pub2.

Typical Therapy Duration “10 days” for most patients

Varies based on Disease severity > if empyema or abscess

> if CA-MRSA

Disease response

Medication

Liu C, et al. Clin Infect Dis 2011;52(3):285Liu C, et al. Clin Infect Dis 2011;52(3):285--292.292.Bradley JS, et al. Clinical Infectious Diseases Advance Bradley JS, et al. Clinical Infectious Diseases Advance Access Published August 30, 2011.Access Published August 30, 2011.

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H/O URI starting 10 days ago, saw PMD 8 days ago. No prior lower RTIs before

Got better with Azithromycin 300mg po, then 150mg po daily x 4 daysp y y


Wt 25kg, Temp 102.5, RR 40, Sats 90% on RA, CXR positive for RLL infiltrate, WBC 17.5 (46% segs, 18% bands, 25% lymphs)

UTD, NKDA

Ceftriaxone 1gm IV x1, Maint IVF, Acetaminophen

What is true about your patient’s antibiotic therapy?

A. Typically duration is 10 days

B. May change to comparable PO therapy if responds well in 2 days

C. All of the above

But what if your hospitalized patient is really ill?

Requiring increased oxygen requirement

Necrosis

Abscess

Multilobar effusion

WBC increase to 50K with continued left shift

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Complications Associated With CAP

Pulmonary Pleural effusion or

empyema

Pneumothorax

Lung abscess

Metastatic Meningitis Central nervous system

abscess Pericarditis

E d ditig

Bronchopleural fistula

Necrotizing pneumonia

Acute respiratory failure

Endocarditis Osteomyelitis Septic arthritis

Systemic SIRS or sepsis Hemolytic uremic

syndrome


Necrotizing Pneumonia Liquification and necrosis of lung tissue

Virulent organisms with toxins

Obtain blood cx

Tap and get cultures

Total antibiotic therapy 2-4 weeks

Lung Abscess Often follow aspiration or related to seizure or

neuromuscular disease

Mouth microbes Streptococcus species St h l Staphylococcus aureus GNR Anaerobes

Tuberculosis

Rare

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Purulent Effusions: Empyema Imaging needed to determine if free-flowing or

loculated

Thoracentesis (chest tubes) Lower mortality, LOS, antibiotic duration

Medical management targeting pneumococcus and S. aureus

Therapy duration depends on Drainage adequacy

Clinical response

Often 2-4 weeks is adequate

What is the bacteria most likely to cause empyema in a pediatric patient?

A. Mycoplasma pneumoniae

B. Streptococcus pneumoniae

C. Chlamydia pneumoniae

D. Hemophilus influenza

Which is/are FALSE about vancomycin monitoring for patients with pneumonia?

A. Target concentrations are often 15-20mg/L due to poor penetration

B. Target concentrations are often 15-20mg/L due to i tresistance

C. Target is AUC/MIC > 400

D. Peak levels reflect efficacy

E. Accumulation will occur with therapy > 1-2 weeks

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Future Research Rate pneumonia and standardize validate

therapy with outcomes*

Determine therapy based on regional antimicrobial resistance patterns*p

Resistance patterns once the CAP guidelines are uniformly used

Collect and publish expected CAP response by pathogen*

Match vancomycin dosing with desired troughs and AUC/MIC targets

Future Research Refine hospital discharge criteria*

Define time acceptable for IV to PO switch

Determine role for higher doses of other gpalatable cephalosporins.

Refine role of atypical antibacterial therapy for children < 5 y/o*

Validate short course azithromycin

Determine role of combination therapy for severe pneumonia*

Questions?

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http://www.sif.it/SIF/resources/public/images/highlights/fig1.png041

CCR5 InhibitorMaraviroc

Fusion InhibitorEnfuvirtide

NNRTIsNevirapine

NRTIsZidovudineLamivudineEmtricabineDidanosineStavudineAbacavirTenofovir

EfavirenzEtravirineRilpivirine PIs

LopinavirRitonavirAtazanavirDarunavirFosamprenavirIndinavirSaquinavirNefinavirTipranavirIntegrase Inhibitor

Raltegravir

HIV Epidemiology

• Global – 33.3 million persons

– Women: 15.7 million

– Children < 15 years: 2.5 million

Mother to child transmission (2009): 370 000– Mother‐to‐child transmission (2009): 370,000

UNAIDS report on the global AIDS epidemic. 2010.

HIV Epidemiology

• US (2008, 2009 data)

– Persons living with HIV (≥ 13 years): 1.2 million

– Women: ~290,000

Children < 13 years of age: ~3 000– Children < 13 years of age: ~3,000

• 2009 Perinatal infections: 131

• Pediatric Deaths from HIV in 2009‐28

CDC. MMWR. 2011;60:689-693.CDC. HIV Surveillance Report 2009. http://www.cdc.gov/hiv/topics/surveillance/resources/reports/. Updated 2011.

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Mother‐to‐Child Transmission (MTCT)

• Accounts for ~90% of all pediatric HIV cases in the US between 1985‐2005

– Intrauterine 25‐40% cases

Intra partum 60 75% cases– Intra‐partum 60‐75% cases

– Postpartum related to breast feeding

MMWR. 2006;55:592-7.

MTCT of HIV Infection

• Mother‐to‐child transmission rate ~25% without antiretroviral treatment

– ACTG076: pregnant women treated with zidovudine during antepartum period decreasedzidovudine during antepartum period decreased transmission to 8%

• In HAART era, transmission rate is < 2%

– Perinatal HIV infection in US is considered a “sentinel event”

DHHS. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. 2011;1-207.

Perinatal HIV Infection: Risk Factors

Maternal Factors

• High serum viral load

• Breastfeeding

• Sexually transmitted co‐

Obstetrical factors

• Preterm delivery

• Low birth weight

• Prolonged rupture of yinfections

• Advanced maternal HIV disease

• Maternal age > 30 years

• Drug abuse

• No HAART

g pmembranes

• Vaginal delivery

• Chorioamnionitis

• Breastfeeding

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Prevention of MTCT

• Early identification and treatment of HIV infection is key to prevention of perinatal HIV infection

– If HAART is not indicated, treatment can be postponed until the 2nd trimester

• Zidovudine + lamivudine + lopinavir/ritonavir is the preferred antiretroviral (ARV) combination in pregnant women naïve to HAART

– Nevirapine can used if CD4 count < 250 cells/mm3


Intrapartum Care

• Consider cesarean section if VL > 1,000 copies/mcL

• Continue PO HAART (if on ARVs)( )

• IV zidovudine should be initiated in all women at the start of labor, regardless of resistance or absence of zidovudine in current HAART regimen– 2 mg/kg IV over 1 hour then 1 mg/kg IV per hour

Care of a HIV‐Exposed Neonate

• Neonates born to an HIV‐infected mother on HAART should be initiated on zidovudine and continued for 6 weeks

Gestational Age Standard Regimen

Term Zidovudine 4 mg/kg PO q12h

30‐34 weeks Zidovudine 2 mg/kg PO q12h, then q8h after 2 weeks

< 30 weeks Zidovudine 2 mg/kg PO q12h, then q8h after 4 weeks


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• Neonates born to an HIV‐infected mother who was not taking HAART should receive zidovudine and 3 doses of nevirapine

– Dose:– Dose:

• 1.5 – 2 kg: 8 mg/kg/dose

• > 2 kg: 12 mg/kg/dose

– Timing:

• Birth, 48 hours, and 96 hours after the 2nd dose



• HIV‐infected infants at risk for developing Pneumocystis jiroveci Pneumonia (PCP)

– Highest incidence in 1st year of life

In addition to respiratory/pneumonia symptoms:– In addition to respiratory/pneumonia symptoms:

• Age < 6 months, RR > 59 breath/min, PaO2 < 92%, absence of vomiting, high HIV RNA level



• Prophylaxis with TMP/SMX following completion of zidovudine recommended until definitive HIV infection exclusion

– Do not need to start PCP prophylaxis if– Do not need to start PCP prophylaxis if “presumptively” HIV‐negative

• “Low risk” pregnancy and delivery

• Infant not being breastfed

• 2 negative virological tests at 2 weeks and ≥ 4 weeks

• 1 negative virological test at ≥ 8 weeks


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MTCT Prevention: Summary

Patient On HAART Not On HAART

Mother

Antepartum Continue or Initiate HAART

N/A

Intrapartum AZT IV + HAARTCesarean delivery if HIV VL > 1000 copies/mL

AZT IVCesarean delivery if HIV VL > 1000 copies/mL

Postpartum Continue therapy if needed

Evaluate need for HAART

Neonate AZT for 6 weeks AZT for 6 weeks + 3 doses of NVP

Case 2: Pediatric HIV Infection

The infant born to the HIV‐infected mother presents for follow‐up in li iclinic.

What kind of methods can be used to diagnose HIV infection in this infant?

Diagnostic Tests for HIV Infection

Useful in infants• HIV DNA PCR

Not As Useful• Enzyme immunoassay

(ELISA)

• Western blot

• Rapid antibody test

• HIV RNA PCR

• Viral culture

• HIV p24 Antigen

DHHS. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 2011;1-268.

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Diagnosis of Perinatal HIV

• Qualitative HIV DNA PCR preferred– Test at 2 weeks, 4‐6 weeks, and 2‐4 months of age

– 2 positive virological tests confirms diagnosis

• Antibody testing – > 6 months: 2 negative tests definitively excludes infection

– > 18 months: antibody testing can be used to diagnose infection


Who Should Start HAART?

Age Criteria Recommendation

< 12 months

Regardless of clinical symptoms,immune status, or VL

Treat

1 – 5 years • AIDS or significant HIV‐related Treatsymptoms

• CD4 < 25%• Asymptomatic/mild, CD4 > 25%, VL > 100K

≥ 5 years • AIDS or significant HIV‐related symptoms

• CD4 < 500 cells/mm3

• Asymptomatic, CD4 > 500 cells/mm3, VL > 100K

Treat


When Should HAART be Started?

• HAART should be started as soon as possible– FIRST, need to assess adherence factors, resistance panel, and treatment history

• i.e. Patient/family understanding, nutrition,i.e. Patient/family understanding, nutrition, medications

• Rarely, does HAART need to be initiated emergently– Recommended for OIs where HAART is the primary treatment

• i.e. Cryptosporidosis, progressive multifocal leukoencephalopathy (PML)

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 2011;1–166.

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http://www.sif.it/SIF/resources/public/images/highlights/fig1.png041

NRTIsZidovudineLamivudineEmtricabineDidanosineStavudineAbacavirTenofovir

NNRTIsNevirapineEfavirenz PIs

LopinavirRitonavirAtazanavirDarunavir

Integrase InhibitorRaltegravir

Preferred Regimens: Children

Age Regimen

> 14 days and < 3 years

2 NTRIs + Lopinavir/Ritonavir

≥ 3 years 2 NRTIs + Efavirenzy2 NRTIs + Lopinavir/Ritonavir

≥ 6 years 2 NTRIs + Atazanavir + Ritonavir2 NRTIs + Efavirenz2 NRTIs + Lopinavir/Ritonavir

Adolescents Treat as adults


Preferred Regimens: Adolescents

• NNRTI‐based

– EFV/TdF/FTC (Atripla)

• PI‐based

d / C ( d ) LUS– TdF/FTC (Truvada) PLUS

– ATV (Reyataz) + RIT (Norvir) OR

– DRV (Prezista) + RIT (Norvir)

• InSTI‐based

– Raltegravir (Isentress) + TdF/FTC (Truvada)

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services.

2011 1 166

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ARV Combinations to Avoid

• Zidovudine + Stavudine– Virologic antagonism

• Lamivudine + EmtricitabineV i il l f i i– Very similar; selects for same resistance mutation

• Stavudine + Didanosine– Increased toxicity (especially pregnant women)

• Not enough information to use in children:– ABC + ddI, ABC + TdF, ddI + TdF

Monitoring Parameters

Parameter Initial Visit1st 1‐2 months

Q3‐4 months

Q6‐12 Months

ARV Switch

Physical Exam X X X X

CD4 Count/% X X X

HIV RNA X X X X

CBC/diff X X XCBC/diff X X X

Electrolytes X X X

Glucose X X X

AST/ALT/Bili X X X X

BUN/Scr X X X

Alb./Prot. X X X

Lipid Panel X X

Urinalysis X X

Resistance Test X X

Adherence Evaluation X X X

Case 4: Non‐Occupational PEP (nPEP)

• An 12 year‐old male is abducted on his way home and is found 36 hours later. He reports being attacked by 2‐3 men and was raped several timesseveral times.

• Would you give him non‐occupational post‐exposure prophylaxis (nPEP)?

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Summary

• New ways to use old antibiotics

• New breakpoints‐ a changing fence with the source in mind

di i h• Pediatric HIV‐ what a success story

• CAP‐ guidelines are not commandments

• We must be willing to adapt as the microbes do!!

challenges in antibiotic selection for pediatric … peds selection...5/14/2012 1 challenges in...

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