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
Gram + cocci in clusters – S. aureus
Sanford Guide 44th Edition

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
Pink on gram stain
Shape
Cocci
Bacilli
Coccobacilli
Can you think of any examples?
Gram negative bacilli
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 Mold Solitary rounded form – clusters
Branching filaments - hyphae

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
MIC: lowest concentration of an antibiotic that completely inhibits the growth of a microorganism in vitro. So in simple terms, if you fall below the MIC, bacterial growth is not inhibited
MIC = primary measure of abx activity
Tortora. Microbiology. 2014

15. Definitions Cpmax Area under the curve (AUC)
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
AUC: after a dose of antibiotic measures how high (concentration) and how long (time) the antibiotic levels remain above the target MIC during any one dosing interval. In essence, the AUC indirectly measures the two major factors for bacterial eradication and quantifies the amount of exposure of the organism to the antibiotic during any one dosing interval.
Tortora. Microbiology. 2014

16. Predictors of Efficacy
PK parameters quantify the serum level time course of an antibiotic. The three pharmacokinetic parameters that are most important for evaluating antibiotic efficacy are the peak serum level (Cmax), the trough level (Cmin), and the Area Under the serum concentration time Curve (AUC). While these parameters quantify the serum level time course, they do not describe the killing activity of an antibiotic.

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
Rate and extent of microorganism killing are a function of the antimicrobial concentration (killing increases as the concentration increases)
Int J Antimicrob Agents 1999;11:7
Bradley, JS. Principles and Practice of Infectious Diseases. Ch 292 Antimicrobial Agents. 2015

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

19. Antibiotic Activity Pattern of Activity Antibiotics Goal of Therapy
PK/PD Parameter
Concentration-dependent killing
Aminoglycosides Daptomycin Fluoroquinolones Ketolides
Maximize concentrations
24h-AUC/MIC Peak/MIC
Time-dependent killing
Carbapenems Cephalosporins Erythromycin Linezolid Penicillins
Maximize duration of exposure
T>MIC
Bradley, JS. Principles and Practice of Infectious Diseases. 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)
In this HSV-infected human cell, the acyclovir molecules enter the cell and are converted to acyclovir monophosphate by the HSV enzyme thymidine kinase (TK). Enzymes in the human cell add two more phosphates to eventually form the active drug acyclovir triphosphate. The acyclovir triphosphate competes with 2-deoxyguanosine triphosphate (dGTP) as a substrate for viral DNA polymerase, as well as acting as a chain terminator. In actual infection, the HSV releases its naked capsid that delivers DNA to the human nucleus; the active drug acyclovir triphosphate exerts its action on the viral DNA located in the nucleus.
Lexi-Comp.

22. Antivirals Acyclovir Dosing:
HSV encephalitis: mg/kg/dose Q8H x 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)
CNS and disseminated infections: 21 day treatment duration; skin and mucous membrane infections: 14 day treatment duration
Renal side effects are not commonly seen with PO dosing just IV
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
Nephrotoxicity may occur from gentamicin with persistent peak serum concentrations of more than 12 mcg/mL or trough concentrations more than 2 mcg/mL. Goal extrapolated peak mcg/mL (MIC testing to 4, you want to be 8-10 times your MIC for max killing). Goal extrapolated trough < 0.6 mcg/mL
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)
Spectrum of activity: Treatment of candidiasis (vaginal, oropharyngeal, esophageal, urinary tract infections, peritonitis, pneumonia, and systemic infections); cryptococcal meningitis; antifungal prophylaxis in allogeneic bone marrow transplant recipients (All indications: FDA approved in all ages); strains of Candida with decreased in vitro susceptibility to fluconazole are being isolated with increasing frequency; fluconazole is 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
Duration and dosage depends on severity of infection
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!)
2nd generation triazole, synthetic derivative of fluconazole
Fungicidal against aspergillus (superior to Ampho B), fungistatic against Candida
Monitor trough concentrations at steady sate and with change in formulation. IV:PO conversion is technically 1:1 but clinical experiences suggests varying levels with IV and PO. Goal: 1.5 – 6 mcg/mL. Could consider every 8 hour dosing in patients whose levels are not therapeutic. 1 mg/kg dose increase is ~0.5 mcg/mL trough increase for peds patients.
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
2nd generation triazole, synthetic derivative of fluconazole
Fungicidal against aspergillus (superior to Ampho B), fungistatic against Candida
Monitor trough concentrations at steady sate and with change in formulation. IV:PO conversion is technically 1:1 but clinical experiences suggests varying levels with IV and PO. Goal: 1.5 – 6 mcg/mL. Could consider every 8 hour dosing in patients whose levels are not therapeutic. 1 mg/kg dose increase is ~0.5 mcg/mL trough increase for peds patients.
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
Caspofungin specifically inhibits beta 1,3-d-glucan synthesis, essential to the cell-wall integretiy of mang fungi –compromises the integrity of the cell wall which allows the cell wall to become permeable and then cell lysis
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
Only available IV
FDA approval for 3 months and greater (but neonatal dosing does exist, small population)
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
Mechanism of action: inhibits bacterial cell wall synthesis by binding to several of the penicillin-binding proteins, which in turn inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis; bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested
Spectrum: Really for meropenem what you need to remember is what it doesn’t cover because its spectrum of activity is SO BROAD (doesn’t cover MRSA, Steno, Legionella, Chlamydophilia/M. pneumoniae). It DOES cover S. aureus, S. pyogenes, S. agalactiae, S. pneumoniae, H. influenzae, N. meningitidis, M. catarrhalis, E. coli, Klebsiella, Enterobacter, Serratia, P. aeruginosa, B. cepacia, and B. fragilis
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
With cephalosporins, generally you see increasing gram negative coverage as you moved towards the higher generation cephalosporins. Another thing to note about cephalosporins is that they LACK coverage for Enterococcus sepcies!!!
Mechanism of action: inhibits bacterial cell wall synthesis by binding to several of the penicillin-binding proteins, which in turn inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis; bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested
Commonly used as post-op prophylaxis in our NES patients x 3 doses/EVD prophy
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
With cephalosporins, generally you see increasing gram negative coverage as you moved towards the higher generation cephalosporins.
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
Max dose: 2 g
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
With cephalosporins, generally you see increasing gram negative coverage as you moved towards the higher generation cephalosporins.
Mechanism of action: inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested. Cefotaxime has activity in the presence of some beta-lactamases, both penicillinases and cephaolsporinases, of gram-negative and gram-positive bacteria
Lexi-Comp.
Micromedex

38. Cephalosporins Dosing:
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 mcg/mL: bacteremia, skin-soft tissue infection/cellulitis
Goal 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
Goal 10-20: Q8H
Goal 15-20: Q6H
A retrospective analysis demonstrated a positive relationship between the incidence of nephrotoxicity and initial vancomycin trough levels and suggested that trough levels greater than or equal to 15 mg/L may be an independent risk factor for 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, Enterococcus faecalis
*including multi-drug resistant S. pneumo, methicillin- resistant S. aureus, and vancomycin-resistant Enterococcus
Bacteriostatic against enterococci and staphylococci
Bactericidal against most strains of streptococci
Lexi-Comp.
Micromedex

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?
100% PO equivalent (PO is just as good as the IV)
Baseline CBC would be recommended as long-term use of linezolid may cause myelosuppression (reversible)
Serotonin syndrome is a warning that you may see when prescribing to patients on SSRI’s (because linezolid is a WEAK MAO-I). While using linezolid with SSRI’s is not CI, it should be noted that with the increase in a patient’s serotonin, the possibility exists for serotonin syndrome. Recommend a thoughtful risk-benefit analysis weighing the possible drawbacks of discontinuing the use of the antidepressant against the potential value of the MAOI antimicrobial is required. S/S: cognitive dysfunction, hyperpyrexia, hyperreflexia, incoordination
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 (
Vancomycin and MIC
For S. aureus infections with MIC of > 2: goal vancomycin trough 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
Rifampin (CYP3A4 inducer) and Midazolam is a CYP3A4 substrate – inducer will increase the metabolism! With regards to rifampin and fentanyl – rifampin may decrease the serum concentration of fentanyl and produce reduced analgesia and/or emergence of withdrawal sz
Meropenem and VPA: several case reports and case series describe significant decreases in serum valproate concentrations (usually to subtherapeutic values) following the initiation of therapy with a carbapenem antibiotic. In these cases, serum valproate concentrations decreased rapidly (often within days) and substantially (up to 90%) following carbapenem initiation. Valproate concentrations generally returned to normal in a similarly rapid fashion, though one case study reports persistent (up to two weeks) reduction of valproate concentrations after discontinuation of meropenem. Seizures accompanied some of the pharmacokinetic changes
Sulfonamides and ceftriaxone: Displaces bili and can result in neonatal encephalopathy/kernicterus
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
A or D are correct as it adequately covers the bugs we are considering (S. pneumo, Neisseria, GBS, H. flu, E.coli. IDSA recommends vancomycin plus a third generation cephalosporin

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
Answer A is incorrect
Answer B is correct; 3 mg/kg daily would be recommended dose per IDSA guidelines (max 200 mg)
Answer C is not completely incorrect but it is an alternative to fluconazole. Dose is mg/kg for 5-7 days. Consider using in patients with fluconazole-resistant organisms. Can use bladder irrigation in patinet with refractory fluconazole-resistant organisms (C. krusei, and C. glabrata)
Answer D is not completely incorrect but it is an alternative to fluconazole. Dose is 25 mg/kg q6h x 7-10 days

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