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Antimicrobials in the Pediatric ICU

Antimicrobials in the Pediatric ICU. February 24, 2015 Ashley Casper, Pharm.D. Objectives. Evaluate general aspects of microbiology including bacterial differentiation, microbial terminology, and classes of antibiotics.

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Antimicrobials in the Pediatric ICU

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

  2. 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.

  3. Bacterial Differentiation • Gram Positive Organisms • Purple on gram stain • Shape • Cocci • Bacilli Sanford Guide 44th Edition http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit1/prostruct/gpstaph.html

  4. Gram Positive Organisms Sanford Guide 44th Edition

  5. Gram Positive Organisms • Staphylococcus aureus • Staphylococcus epidermis • Streptococcus pneumoniae • Enterococcus faecalis • Enterococcus faecium • Bacillus • Corynebacterium • Clostridium • Actinobacteria • Listeria Sanford Guide 44th Edition

  6. Gram Negative Organisms • Gram Negative Organisms • Pink on gram stain • Shape • Cocci • Bacilli • Coccobacilli Sanford Guide 44th Edition

  7. Gram Negative Organisms Sanford Guide 44th Edition

  8. 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. Sanford Guide 44th Edition

  9. Miscellaneous Organisms • Anaerobes • Peptostreptococcus spp. • Bacteroides fragilis • Clostridium spp. • Atypicals • Chlamydia pneumoniae • Mycoplasma pneumoniae • Legionella spp. Sanford Guide 44th Edition

  10. Fungi • Two groups • Yeast • Solitary rounded form – clusters • Mold • Branching filaments - hyphae http://www.doctorfungus.org/imageban/index.htm

  11. Fungi • Aspergillus spp • Blastomyces dermatitidis • Candida spp. • Coccidioides immitis • Cryptococcus spp. • Histoplasma spp. • Paracoccidioides brasiliensis • Sporothrix schenckii • Zygomycetes spp. Sanford Guide 44th Edition

  12. Viruses • Adenovirus • Coronavirus • Coxsackievirus • Enterovirus • Hepatitis • Cytomegalovirus • Herpes virus • Parainfluenza • Parvovirus • Respiratory syncytial virus • Rhinovirus • Influenza • Rotavirus Sanford Guide 44th Edition

  13. Definitions • Bactericidal • an antibiotic that kills microorganisms • Bacteriostatic • an antibiotic that inhibits the growth of microorganisms Tortora. Microbiology. 2014

  14. 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 Tortora. Microbiology. 2014

  15. 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 Tortora. Microbiology. 2014

  16. Predictors of Efficacy http://www.rxkinetics.com/antibiotic_pk_pd.html

  17. 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;11:7 Bradley, JS. Principles and Practice of InfectiousDiseases. Ch 292 Antimicrobial Agents. 2015

  18. Antibiotic Activity Int J Antimicrob Agents 1999;11:7

  19. Antibiotic Activity Bradley, JS. Principles and Practice of InfectiousDiseases. Ch 292 Antimicrobial Agents. 2015

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

  21. 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

  22. 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

  23. 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) Lexi-Comp. Micromedex

  24. 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 Lexi-Comp. Micromedex

  25. 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) Lexi-Comp. Micromedex

  26. 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 Lexi-Comp. Micromedex

  27. 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!) Lexi-Comp. Micromedex

  28. 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 Lexi-Comp. Micromedex

  29. 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 Lexi-Comp. Micromedex

  30. 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 Lexi-Comp. Micromedex

  31. 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 Lexi-Comp. Micromedex

  32. 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?! Lexi-Comp. Micromedex

  33. 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 Lexi-Comp. Micromedex

  34. Cephalosporins • Cefazolin (1st generation) • Dosing: • 25 mg/kg/dose IV Q6-8H (Max: 1-2 g) • Adverse effects/toxicities: • Dermatologic: pruritus • GI: diarrhea Lexi-Comp. Micromedex

  35. 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 Lexi-Comp. Micromedex

  36. 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 Lexi-Comp. Micromedex

  37. 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 Lexi-Comp. Micromedex

  38. 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 Lexi-Comp. Micromedex

  39. 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 Lexi-Comp. Micromedex

  40. 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 Lexi-Comp. Micromedex

  41. 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! Lexi-Comp. Micromedex

  42. 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 Lexi-Comp. Micromedex

  43. 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, Enterococcusfaecalis *including multi-drug resistant S. pneumo, methicillin- resistant S. aureus, and vancomycin-resistant Enterococcus Lexi-Comp. Micromedex http://www.antibiotics-info.org/linezolid.html

  44. 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? Lexi-Comp. Micromedex

  45. Antimicrobial Summary Mechanism of Action (Linezolid)

  46. 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. aureusinfections with MIC of > 2: goal vancomycin trough 15-20 mcg/mL; consider transition to linezolid Lexi-Comp. Micromedex Herbert, ME et al. West J Med. 2000 Liu, C et al. Clinical Infectious Diseases. 2011

  47. 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 Lexi-Comp. Micromedex

  48. KCH Antibiogram

  49. Patient Case 5 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 cefotaxime b. ampicillin and ceftriaxone c. ampicillin and gentamicin d. vancomycin and ceftriaxone

  50. Patient Case 7 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? • voriconazole • fluconazole • amphotericin B d. flucytosine

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