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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
Nicolau DP, et al. Antimicrob Agents Chemother. 1996
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Continuous infusion Ceftazidime
Ceftazidime
MIC 8mcg/ml
Nicolau DP, et al. Antimicrob Agents Chemother. 1996
PK/PD Advantages of CI vs. Intermittent
1. Ability to maintain levels above the MIC
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
PK/PD Advantages of CI vs. Intermittent
1. Ability to maintain levels above the MIC
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)
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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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
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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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
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.
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%
Case 7 y/o male admitted for CAP
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
Over the last 48hr, pt had new cough, fever to 103.1
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
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.
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
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.
MSSA/OSSA: PO Preferred Cephalexin 75-100 mg/kg/day ÷ Q6-8H
Alternative Clindamycin* 30-40 mg/kg/day ÷ Q8Hy g g y
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.
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
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.
Mycoplasma or Chlamydia: PO Preferred Azithromycin 10 mg/kg then 5 mg/kg/day x 4 days
Alternative: Clarithromyciny
Erythromycin
Doxycycline
Levofloxacin or moxifloxacin
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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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
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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Empiric Inpatient Atypical Therapy for Immunized Patient with Low Local PCN Resistance
Preferred Azithromycin
+/- Beta-lactam
Alternatives Clarithromycin
Erythromycin
Doxycycline (> 7 y/o)
Levofloxacin*
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 Unimmunized Patient OR Significant Local Pneumococcal
Resistance
Preferred Ceftriaxone or cefotaxime
+/- Vancomycin or clindamycin
AlternativesAlternatives Levofloxacin
+/- Vancomycin or clindamycin
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 Atypical Therapy for Unimmunized Patient OR Significant Local Pneumococcal Resistance
Preferred Azithromycin
+/- Beta-lactam
Alternatives Clarithromycin
Erythromycin
Doxycycline (> 7 y/o)
Levofloxacin*
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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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)
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.
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
10 mg/kg/day ÷ Q12H
Cefuroxime axetil
Extremely bitter taste
20 mg/kg/day ÷ Q12H
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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Case 7 y/o male admitted for CAP
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
Over the last 48hr, pt had new cough, fever to 103.1
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
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.
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
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.
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
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.
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Care of a HIV‐Exposed Neonate
• 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
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.
Care of a HIV‐Exposed Neonate
• 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
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.
Care of a HIV‐Exposed Neonate
• 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
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.
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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
DHHS. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 2011;1-268.
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
DHHS. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 2011;1-268.
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
DHHS. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 2011;1-268.
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!!