Pediatric Infections: Treatment of

Resistant Pathogens

Focus : MRSA and DRSP Infections,

Including Pneumonia

Blaise L. Congeni M.D.

Patient 1-LP

• 8 yo with 8 days of fever and 6 days of

cough.

• She had consistently demonstrated

fever of about 102.

• Because of worsening cough and

persistent fever the patient was given

ceftriaxone and then cefdinir.

• Because of failure to improve the pt.

was admitted.

Patient HPI

• 16 y/o male, with PMH of exercise-

induced asthma, ADHD, and Asperger

syndrome, presents with 4 day hx of

SOB. Associated with pressure-like

pain in chest and back, worsening with

inspiration. Denies fevers, sick

contacts, change in asthma sx. ROS

positive for nonproductive cough,

decreased appetite and possible 5# wt

loss over 2-3 weeks PTA

Exam and Labs

• Vitals: 36.2 P66 R18 BP117/40 100% 2L

• Exam: In NAD, Resp are easy and non-labored, No rales or rhonchi, no wheezes, S1S2 RRR, no murmurs noted, nailbeds are pink, no pain to palpation of chest

• Labs: WBC 5.2 with normal diff, ESR 22 CRP 2.74

• CXR: WNL

O2 was weaned, pt did well

Chest CT

5 days later…

• Pt is seen by PCP for new onset fever

with Tmax 102, left hip/thigh pain,

frontal “pressure” HA that is non-

radiating and not associated with N/V,

photophobia.

• Elevated liver enzymes on lab, so a CT

of abdomen and pelvis were ordered.

Case of Severe CAP

30 y/o female

presents to ER at

0400 with acute fever,

cough, dyspnea;

recent ‘viral syndrome’

Severely hypoxic

Requires immediate

intubation

Treated with 3rd Gen

Ceph +

Fluoroquinolone

Case of Severe CAP

Gram stain of ET aspirate reveals GPC in clusters

Vancomycin added

Patient has multi-organ dysfunction; expires at 1600

CO- MRSA isolated

– PVL +

Community Acquired Pneumonia

Akron Children’s Guidelines 2011

1. Early, appropriate antibiotic therapy/optimizes clinical outcomes

2. Customized, effective DX & RX strategies must be based on best available evidence

3. Minimizing diagnostic and therapeutic variability is an important goal of guidelines

4. The target population for theses guidelines are: a) Non neonates (>30 of age)

b) Immunocompetent

c) Immunizations up to date

5. Mycoplasma should be suspected in moderately ill school aged/adolescent patients

Draft: many thanks to committee, esp MF and JB

Toxic Appearing (DX) Recommended

O Optional

Θ Not Recommended

CXR Θ

CBC Θ

SpO2 O

APR* Θ

BCX* Θ

Rapid Viral O

No Yes=(Severe Sepsis)

F/U radiographs not routinely recommended

O

Especially if a. failed b. disease progression

Early influenza RX independent of negative rapid result

If rapid positive, consider limiting ABX use

Suspected mycoplasma (school aged or adolescent)

consider Macrolide

Suspected Bacterial

Pathogen

Toxic Appearing (TX)

No Yes

APR=Acute Phase Reactants

PCX=Blood Cx

PPE=Parapneumonic Effusion

1. Amoxicillin

consider Macrolide

1. Ceftriaxone 50-100 MG/KG/day

-Consider Azithromycin for school age/adolescent

-Consider Vancomycin if:

a. 3-6 months

b. pneumatocele

c. suspected influenza

d. sputum/Cx suspected staph

e. Parapneumonic effusion

2010 Antibiogram

ORGANISM ANTIBIOTIC Total

Streptococcus

Pneumoniae

Total= 99

Penicillin

Ceftriaxone

Erythromycin

Clindamycin

Tetracycline

Ofloxacin

Vancomycin

97

98

94

94

98

98

98

Sensitive

%

Intermediate

%

Resistant

%

54

79

45

56

61

91

98

55.7%

80.6%

47.9%

59.6%

62.2%

92.9%

100.0%

11

17

0

0

2

6

0

11.3%

17.3%

0.0%

0.0%

2.0%

6.1%

0.0%

32

2

49

38

35

1

0

33.0%

2.0%

52.1%

40.4%

35.7%

1.0%

0.0%

Therapy of S. pneumo

Focus: CAP and DRSP

• Use third generation ceph if local

epidemiology documents high-level

pen resistance, or life-threatening dis.

• For oral therapy, amox PK/PD,

tolerability more favorable than pen.

• To cover possibility of RRSP, (MIC-2),

use 90 mg/kg/d (3 doses).

• No oral ceph provides comparable

activity to HD amox.

Therapy of S. pneumo

Focus: CAP and DRSP

• Significant macrolide resistance is

seen in currently available macrolides.

• For patients with non-serious allergic

reactions to amoxicillin, treatment is

not well defined, and should be

individualized.

• For more serious allergies treatment

options include linezolid, a macrolide,

(up to 40% R), or clindamycin.

Therapy of S. pneumo

Focus: IV amp v ceftriaxone.

• Ceftriaxone and cefotaxime are

substantially more active in vitro than

Pne G. Ceftriaxone has been

documented to be effective in adults

with ceftriaxone R strains.

• Although no prospective studies exist,

iv amp appears as effective as IV

ceftriaxone for strains with MICs up to

2 µg/mL.

E test: Utilization of antibiotic concentration gradient

MICs of Vancomycin for S. aureus

0 20 40 60 80 100

<0.25

0.5

1.0

2.0

4.0

8.0

1/1/11-6/21/11 6/2010-12/31/10 6/2009-6/2010*

MIC

=

% % % % % %

*Vancomycin MIC reported from automated instrument only; no E-test confirmation

Mechanisms of Resistance

MRSA

Penicillin Binding Proteins

Catalyze synthesis of cell wall

Site of lactam action – inhibit cell wall

PBP-2

mecA gene synthesizes an altered PBP-2a

Lower binding of lactam

mecA Gene

Part of mobile genetic element

A genetic element that has the ability to

move from one site on a chromosome to

another.

Staphylococcal cassette chromosome

(SCCmec)

May harbor other virulence genes

or other antibiotic resistance genes

CA-MRSA

Empiric Treatment

Assess disease severity and host

Consider resistance issues

Obtain cultures

TMP/SMX

Few studies (Ann Intern Med 1992;117:390-

8)

Side effects

Hypersensitivity rxns

Bone marrow suppression

No GABHS coverage

Resistance potential, but remains low

Tetracycline

Doxycycline or minocycline

Age restriction

Resistance in 3% of isolates

Some data on use in skin and soft tissue

infections

No indication for serious disease

Clindamycin Resistance S. aureus

Clindamycin resistance varies by region

5-25%

Macrolide and lincosamide resistance closely

related

23S rRNA

Risk of induced clinda resistance in Erythro

resistant strains

MLSB Resistance via erm gene

No MLS resistance (no erm)

ERYTH – S; CLINDA - S

Constitutive MLS resistance (erm present)

ERYTH – R; CLINDA - R

Possible Inducible resistance

ERYTH – R; CLINDA – S (erm-repressed)

ERYTH – R; CLINDA – S (mef)

“D” Test

CA-MRSA

Empiric Treatment

Life threatening (e.g. endocarditis,

septicemia, toxic shock)

lactam antibiotic (e.g. Nafcillin)

and

Non lactam reliably active against CA-

MRSA (Vancomycin)

May require additional agents for broader

spectrum

CA-MRSA

Empiric Treatment

Moderate localized infections (e.g.

osteomyelitis, cellulitis +/- abscess)

Incision and drainage when appropriate

Consider:

Clindamycin

Vancomycin

Doxycycline ( 8 yrs)

TMP/SMX

CA-MRSA

Empiric Treatment

Mild (e.g. simple skin infection)

Topical therapy - mupirocin

Clindamycin

TMP/SMX

lactam – await culture and clinical

response

Vancomycin Dosing and Monitoring

Adults

• IV Vanco, 15-20 mg/kg/dose Q 8-12 hrs. (abw) – Not to exceed 2 grams/dose

• In seriously ill patients with suspected MRSA, consider a loading dose of 25-30 mg/kg. – Consider prolonged infusion, 2°; antihistamine

use

• Trough levels after the 3rd dose most accurate way to guide dosing.

• For most pts with SSTI-1 gram Q 12 hrs.

• Trough levels rec. for morbidly obese, fluctuating volume of distribution, renal dysfunction.

CID 2011:52. pg. 1-38.

Vancomycin Dosing and Monitoring

Pediatrics

• IV Vancomycin 15 mg/kg/dose Q 6 hrs. is recommended in children with serious or invasive disease.

– Consider other issues (NSAIDs, dehydration, use of concomitant antivirals or antimicrobics), and consider modifying dose and additional levels and monitoring renal status. Double Consider Rule also called Law of Unintended Consequences)

• The efficacy of targeting trough concentrations of 15-20 µg/ml requires additional study, but should be considered.

CID 2011:52 pg 1-38.

Linezolid vs Vancomycin in the

Management of Nosocomial Pneumonia

*

Kunkle M et al. Abstract LB-49. Annual meeting Infectious Diseases Society America. Vancouver Oct 24, 2010.

Linezolid Vancomycin

Clinical response

(per protocol)

95/165 (57.5%) 81/174 (46.5%)

p=0.042

Adverse events 5.2% (anemia) 7.2% anemia

•Phase IV double-blind, RCT

•1225 patients enrolled; 448 with MRSA

•Linezolid 600 mg Q12 vs Vancomcin 15mg/kg Q12

(adjusted for renal function and levels); 7-14 days

•No difference in mortality

Outcomes in MSSA Bacteremia

Nafcillin vs Vancomycin

0

5

10

15

20

25

Persistent >3 but ≤7 Days

Persistent >7 Days

Relapse Bacteriologic Failure

Nafcillin (n=18)

Vancomycin (n=70)

6

21

0

11

0

7

0

19

Chang et al. Medicine (Baltimore). 2003;82:333-339.

Prospective Observational Study With 6 Months Follow-up

Influence of Vancomycin MIC on

Outcome in S aureus Infection

Moise-Broder et al. Clin Infect Dis. 2004;38:1700-1705.

Perc

en

t

0

10

20

30

40

50

60

70

80

90

100

0.5 1 2

Failure

Success

MIC

Susceptibility Testing

Vancomycin MIC ≤ 2 µg/mL indicates

susceptibility

Vancomycin MIC >2 µg/mL “an alternative to

vanc should be used,” ”confirm and further

characterize.”

4-8=VISA; ≥16=VRSA.

Best parameter to predict efficacy of vanc is

AUC/MIC (area under curve/minimum inhibitory concentration),

determined by measuring trough

concentrations