Antimicrobials in the Pediatric ICU February 24, 2015 Ashley Casper, Pharm.D.

Antimicrobials in the Pediatric ICU

February 24, 2015Ashley Casper, Pharm.D.

Objectives• Evaluate general aspects of microbiology including

bacterial differentiation, microbial terminology, and classes of antibiotics.

• Explain the mechanism of action, spectrum of activity, and toxicities of the most commonly used antimicrobials in the PICU setting.

• Use patient, culture results, and location of infection to select appropriate antimicrobial coverage.

Bacterial Differentiation• Gram Positive Organisms– Purple on gram stain

– Shape• Cocci• Bacilli

Sanford Guide 44th Editionhttp://faculty.ccbcmd.edu/courses/bio141/lecguide/unit1/prostruct/gpstaph.html

Gram Positive Organisms

Sanford Guide 44th Edition

Gram Positive Organisms

• Staphylococcus aureus• Staphylococcus

epidermis• Streptococcus

pneumoniae• Enterococcus faecalis• Enterococcus faecium

• Bacillus• Corynebacterium• Clostridium• Actinobacteria• Listeria


Gram Negative Organisms• Gram Negative Organisms– Pink on gram stain

– Shape• Cocci• Bacilli• Coccobacilli


Gram Negative Organisms


Gram Negative Organisms

• Acinetobacter spp.• Enterobacter spp. • Escherichia coli• Haemophilus influenzae• Klebsiella pneumoniae• Moraxella catarrhalis• Pseudomonas

aeruginosa

• Proteus spp. • Serratia spp.• Salmonella spp.• Stenotrophomonas

maltophilia• Aeromonas spp.• Neisseria spp.


Miscellaneous Organisms

• Anaerobes– Peptostreptococcus

spp.– Bacteroides fragilis– Clostridium spp.

• Atypicals– Chlamydia

pneumoniae– Mycoplasma

pneumoniae– Legionella spp.


Fungi• Two groups– Yeast• Solitary rounded form – clusters

– Mold• Branching filaments - hyphae

http://www.doctorfungus.org/imageban/index.htm

Fungi

• Aspergillus spp• Blastomyces dermatitidis• Candida spp.• Coccidioides immitis• Cryptococcus spp.• Histoplasma spp.

• Paracoccidioides brasiliensis

• Sporothrix schenckii • Zygomycetes spp.


Viruses

• Adenovirus• Coronavirus• Coxsackievirus• Enterovirus• Hepatitis • Cytomegalovirus• Herpes virus

• Parainfluenza• Parvovirus• Respiratory syncytial

virus• Rhinovirus• Influenza• Rotavirus


Definitions• Bactericidal– an antibiotic that kills microorganisms

• Bacteriostatic – an antibiotic that inhibits the growth of

microorganisms

Tortora. Microbiology. 2014

Definitions• Minimum Inhibitory Concentration (MIC)– lowest concentration of an antibiotic that

completely inhibits the growth of a microorganism

• Minimum Bactericidal Concentration (MBC)– lowest concentration of an antibiotic that

completely kills the growth of a microorganism


Definitions• Cpmax

– Serum peak concentration after administration of an antimicrobial agent

• Area under the curve (AUC)– Measures the extent of exposure and time in which antimicrobital

levels remain above the target MIC during a dosing interval

• Post-Antibiotic Effect (PAE)– Continued inhibition of the organism for a period of time after the

concentration of the antimicrobial agent has dropped below the MIC


Predictors of Efficacy

http://www.rxkinetics.com/antibiotic_pk_pd.html

Antibiotic Activity• Concentration-Dependent

– Rate and extent of microorganism killing are a function of the antimicrobial concentration

– PD parameter: 24h-AUC/MIC; Peak/MIC

• Time-Dependent– Rate and extent of microorganism killing remain unchanged

regardless of antimicrobial concentration– Killing is dependent on time maintained above the MIC– PD parameter: Time > MIC

Int J Antimicrob Agents 1999;11:7Bradley, JS. Principles and Practice of Infectious Diseases. Ch 292 Antimicrobial Agents. 2015

Antibiotic Activity

Int J Antimicrob Agents 1999;11:7

Antibiotic Activity

Pattern of Activity Antibiotics Goal of Therapy PK/PD Parameter

Concentration-dependent killing

AminoglycosidesDaptomycin

FluoroquinolonesKetolides

Maximize concentrations 24h-AUC/MICPeak/MIC

Time-dependent killing

CarbapenemsCephalosporinsErythromycin

LinezolidPenicillins

Maximize duration of exposure T>MIC

Bradley, JS. Principles and Practice of Infectious Diseases. Ch 292 Antimicrobial Agents. 2015

Commonly Used Antimicrobials in PICU• Antivirals • Aminoglycosides• Antifungals • Carbapenems • Cephalosporins • Penicillins • Vancomycin• Linezolid

Antivirals• Acyclovir

– Mechanism of action: inhibition of DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase and being incorporated into viral DNA.

– Spectrum of activity: HSV 1, HSV 2, and Varicella Zoster Virus (VZV)

Lexi-Comp.http://depts.washington.edu/hivaids/derm/case2/discussion.html#ref

Antivirals• Acyclovir– Dosing: • HSV encephalitis: 10-15 mg/kg/dose Q8H x 14-21 days• VZV treatment: 10 mg/kg IV Q8H x 7-10 days (continue for

> 48h after last lesion has appeared)– Adverse effects/toxicities:• GI: nausea/vomiting• Renal: acute renal failure (increased creatinine or BUN)

Lexi-Comp.Micromedex

Aminoglycosides• Gentamicin/Tobramycin– Mechanism of action: interferes with bacterial protein

synthesis by binding to 30S and 50S ribosomal subunits resulting in a defective bacterial cell membrane

– Spectrum of activity: susceptible gram negative bacilli (Pseudomonas, E. coli, Proteus, Serratia, and syngergy for gram-positive Staphylococcus)


Aminoglycosides• Gentamicin/Tobramycin

– Dosing (several dosing schemes): • KCH – extended interval dosing

– Infants and children: 7.5 mg/kg/dose IV Q24H• Synergy – 3 mg/kg/dose IV Q24H or 1 mg/kg/dose IV Q8H

– Monitoring: 4 and 8 hour levels (calculate PK parameters)– Adverse effects/toxicities:

• Neurologic: Neuromuscular blockade finding• Otic: Ototoxicity• Renal: Nephrotoxicity


Antifungals• Fluconazole – Mechanism of action: interferes with fungal cytochrome P450 activity,

decreasing ergosterol synthesis therefore inhibiting cell membrane formation

– Spectrum of activity: Candida, Blastomycoses, Histoplasma (more active against C. albicans than other candidal strains like C. parapsilosis, C. glabrata, and C. tropicalis)


Antifungals• Fluconazole

– Dosing: • Treatment: 6-12 mg/kg x 1, followed by 3-12 mg/kg Q24h

– Adverse effects/toxicities:• GI: nausea, vomiting• Neurologic: headache

– Resistance is becoming an issue


Antifungals• Voriconazole (second generation triazole)– Mechanism of action: interferes with fungal cytochrome P450

activity (selectively inhibits 14-alpha-lanosterol demethylation), decreasing ergosterol synthesis (principal sterol in fungal cell membrane) and inhibiting fungal cell membrane formation

– Spectrum of activity: Candida, Aspergillus (drug of choice!)


Antifungals• Voriconazole (second generation triazole)

– Dosing: 9 mg/kg/dose IV or PO Q12H – Monitoring:

• Trough levels after 3-5 days of therapy or change in formulation (PO versus IV)

• Renal function (contraindicated if CrCl < 50)– Adverse effects/toxicities

• CNS: hallucinations• Visual: abnormal vision, color vision change, photophobia• Hepatic: hepatitis, jaundice, cholestasis


Antifungals• Caspofungin (echinocandin)

– Mechanism of action: inhibits β(1,3)-D-glucan to block fungal cell wall synthesis

– Spectrum of activity: Candida, Aspergillus, Blastomycoses, Histoplasmosis


Antifungals• Caspofungin (echinocandin)

– Dosing: • 70 mg/m2 x 1, followed by 50 mg/m2/dose IV Q24h

– Adverse effects/toxicities:• CV: hypotension• Dermatologic: rash• GI: diarrhea• Hepatic: increased AST/ALT• Other: fever, shivering


Carbapenems• Meropenem– Mechanism of action: inhibits bacterial cell wall synthesis by

binding to penicillin-binding proteins which inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls

– Spectrum of activity: multi-drug resistant infections caused by gram-negative and gram-positive aerobic and anaerobic pathogens


Carbapenems• Meropenem

– Dosing:• 20 mg/kg Q8H - non-CNS infections• 40 mg/kg Q8H – meningitis/concern for multi-drug resistant

organisms (CF population, chronic patients)– Adverse effects/toxicities:

• Dermatologic: rash• GI: diarrhea, nausea, vomiting• Hematologic: anemia• Increased risk for seizures?!


Cephalosporins• Cefazolin (1st generation)– Mechanism of action: inhibits bacterial cell wall synthesis by

binding to penicillin-binding proteins which inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell wall

– Spectrum of activity: treatment of Streptococcus sp, MSSA, E. coli, H. influenzae


Cephalosporins• Cefazolin (1st generation)– Dosing: • 25 mg/kg/dose IV Q6-8H (Max: 1-2 g)

– Adverse effects/toxicities:• Dermatologic: pruritus• GI: diarrhea


Cephalosporins• Ceftriaxone (3rd generation)

– Mechanism of action: inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins which inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls.

– Spectrum of activity: cefazolin activity + additional gram negative coverage including Enterobacter, Serratia, N. meningitidis, Citrobacter


Cephalosporins• Ceftriaxone

– Dosing: • Meningitis: 50 mg/kg/dose IV Q12H• Acute otitis media: 50 mg/kg/dose IM/IV Q24H x 3 doses• All other infections: 75 mg/kg/dose IV Q24H

– Adverse effects/toxicities:• Dermatologic: pruritus• GI: diarrhea


Cephalosporins• Cefepime (4th generation)– Mechanism of action: inhibits bacterial cell wall synthesis by

binding to penicillin-binding proteins which inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls. Activity in the presence of some beta-lactamases

– Spectrum of activity: ceftriaxone activity + Pseudomonas coverage


Cephalosporins• Cefepime (4th generation)

– Dosing:• Mild to moderate infections (UTI, SSSI): 50 mg/kg/dose IV Q12H• Severe infections (meningitis, febrile neutropenia, CF exacerbation):

50 mg/kg/dose IV Q8H

– Adverse effects/toxicities:• Dermatologic: pruritis/rash• GI: diarrhea


Penicillins• Ampicillin

– Mechanism of action: inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins which inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls

– Spectrum of activity: streptococci, pneumococci, enterococci, nonpenicillinase-producing staphylococci, Listeria, meningococci; some H. flu, P. mirabilis, Salmonella, Shigella, E. coli, Enterobacter, Klebsiella


Penicillins• Ampicillin– Dosing (utilize higher dosing at KCH due to resistance in area)• 100 mg/kg IV Q6H

– Adverse effects/toxicities:• Dermatologic: rash• GI: diarrhea


Vancomycin• Vancomycin

– Mechanism of action: inhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through binding tightly to D-alanyl-D-alanine portion of cell wall precursor

– Spectrum of activity: streptococci, staphylococci (including methicillin-resistant S. aureus, or beta-lactam resistant coagulase negative Staphylococcus.

NO GRAM NEGATIVE ORGANISMS!


Vancomycin• Vancomycin

– Dosing: 20 mg/kg/dose IV Q6-8H (frequency depends on target trough levels)– Monitoring: serum vancomycin trough levels

• Goal 10-20 mcg/mL: bacteremia, skin-soft tissue infection/cellulitis• Goal 15-20 mcg/mL: pneumonia, osteomyelitis, meningitis, MRSA MIC >2

– Adverse effects/toxicities:• CNS: chills, drug fever• Dermatologic: erythematous rash on face and upper body (red man

syndrome)• Renal: nephrotoxicity


Linezolid• Linezolid

– Mechanism of action: inhibits bacterial protein synthesis by binding to bacterial 23S ribosomal RNA of the 50S subunit preventing the formation of a functional 70S complex required for bacterial translation process

– Spectrum of activity: Streptococcus pneumonia, Staphylococcus aureus, Coagulase negative Staph, Enterococcus faecium, Enterococcus faecalis*including multi-drug resistant S. pneumo, methicillin- resistant S. aureus, and vancomycin-resistant Enterococcus

Lexi-Comp.Micromedexhttp://www.antibiotics-info.org/linezolid.html

Linezolid• Linezolid

– Dosing:• <12 years of age: 10 mg/kg/dose IV or PO Q8H• > 12 years: 10 mg/kg/dose IV or PO Q12H

– Adverse effects/toxicities:• GI: diarrhea, nausea, vomiting• Neurologic: headache• Hematologic (less common): myelosuppression,

thrombocytopenia– Serotonin syndrome?


Antimicrobial Summary Mechanism of Action

(Linezolid)

Antimicrobial Clinical Pearls• Antimicrobial stewardship

– Broad spectrum antibiotics…• PCN allergy

– Current data suggest true rate of penicillin-cephalosporin cross-reactivity is less than 1%• Renal dysfunction or hepatic dysfunction

– Lexi-Comp– Renal dosing handbook (https://kdpnet.kdp.louisville.edu/)

• Vancomycin and MIC– For S. aureus infections with MIC of > 2: goal vancomycin trough 15-20 mcg/mL;

consider transition to linezolid

Lexi-Comp.MicromedexHerbert, ME et al. West J Med. 2000Liu, C et al. Clinical Infectious Diseases. 2011

Antimicrobial Clinical Pearls• Other medication pearls to consider:

– Rifampin: increased sedation requirements– Cefdinir: reddish-colored stools– Ciprofloxacin: suspension clogs g-tube– Meropenem and valproic acid: concurrent use is NOT

recommended; consider alternative antibiotic OR add additional anti-seizure medication

– Avoid use of ceftriaxone/sulfonamides in neonates– Fluoroquinolones/TCN are not contraindicated if indication is

correct


KCH Antibiogram

Patient Case5 week old male (term) presenting with fever and poor feeding noted at home. What drug combination is proper for empiric coverage for meningitis evaluation?

a. vancomycin and cefotaximeb. ampicillin and ceftriaxonec. ampicillin and gentamicind. vancomycin and ceftriaxone

Patient Case7 year old chronically ill female presents after referral from ED due to urine culture which resulted positive for budding yeast (3 days after discharged home on cefdinir). The patient continues to have fever and pain during urination. What is the appropriate empiric regimen for treatment?

a. voriconazoleb. fluconazolec. amphotericin Bd. flucytosine

Antimicrobials in the Pediatric ICU

February 24, 2015Ashley Casper, Pharm.D.

Antimicrobials in the Pediatric ICU February 24, 2015 Ashley Casper, Pharm.D.

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