AMC Company Logo AMC Asan Medical Center Company

A. baumannii § For susceptible isolates § carbapenem + AG § IRAB § Ampicillin/sulbactam

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AMC Company Logo 소아의 약동학 특성과 사례 김승란 AMC Asan Medical Center

Company Logo Pharmacokinetics/Pharmacodynamics Other routes Depot IV Bioavailability Circulation Distribution PO (free; protein binding) Pharmacologically active and Inactive metabolites Other routes GI Renal Pharmacokinetics Dose Concentration Metabolism Excretion Pharmacodynamics Effect

Company Logo 유효혈중 농도

Company Logo 분포용적 혈중농도 Dose 7. 5 mg/kg 분포용적 0. 6 L/kg 25 12. 5 0. 6 L/kg 0. 3 L/kg 7. 5 mg/kg 15 mg/kg

Company Logo 분포용적의 변화 § amikacin 연령 투여량 TBW 신생아 12 mg/kg/dose q 12 hr 70 -80% 소아 7. 5 mg/kg/dose q 8 hr 60%

Organ dysfunction Company Logo

Company Logo 투여량의 감량 DOSE 1/2 DOSE

Company Logo Suggested Alterations in Dose or Dosing Interval Measured Serum Concentrations Compared to Desired Values Suggested Change in Dosage Regimens Trough Peak Dose Dosing Interval desired no change higher decrease or no change increase higher lower increase or no change decrease lower higher decrease desired higher decrease no change desired lower increase no change higher desired no change or increase lower desired no change or decrease no change increase decrease

Company Logo Limitation In Scr § It is secreted in small amounts at the tubules § As plasma concentrations increase, tubular secretion of Scr increase § Overestimation of GFR in patients with moderate to severe decrease in GFR (<50 ml/min) § Muscle mass. § Age and gender § Less sensitive to detect minimal declines in GFR § Non-linear relationship between plasma concentration and GFR

Company Logo Cystatine C § 122 -amino acid, 13 -Kda endogenous protein § cysteine proteinase inhibitor § It is the Product of a houskeeping gene § Expressed in all nucleated cells at a constant rate. § Freely filltered by the glomerulus § Almost completely reabsorbed by tubular epithelial cells and subsequently catabolized § It does not return to the blood flow.

Company Logo Pediatrics and cystatin C § >1 year of age § Constant and similar to that of adults § Reference interval § 0. 51 -0. 95 mg/L : 125 healthy children (1 -14 yrs) § Immediately after birth § Twice those of older children and adults § a mean value of 0. 95 mg/L : 1 -2 months of age § Premature infants § Increased during the first few months of life.

AMC Company Logo 신생아 및 미숙아 Asan Medical Center

Company Logo 신생아의 생물학적 기능이 약물성질에 미치는 영향 § 대사 § Hepatic enzyme activity 감소 § Biliary excretion 감소 § Alternative hepatic biotrancsformation pathways 활성화 § 약물 대사 감소 § 약물의 반감기 연장

AMC Company Logo case Tobramycin & once daily dosing Vancomycin & initial dosing Vancomycin & ECMO Vancomycin & NEC Theophylline & viral infection 미숙아 & vancomycin, amikacin Digoxin & 나이 Asan Medical Center

Company Logo PK Parameter of aminoglycosides Neonates 분포용적 (L/kg) 0. 45 ± 0. 1 반감기 (hr) 6± 2 Infants 0. 40 ± 0. 1 4± 1 Children 0. 35 ± 0. 15 1. 5 ± 1 Adults 0. 3 ± 0. 1 2± 1

Company Logo Tobramycin 과 once daily dosing § 12개월의 남아, 체중 9 kg, 키 77 cm, § Brief hx § 입원 1주전부터 mild cough, 4일전 fever, irritability & respiratory difficult & cyanosis 소견 보여 입원, ARDS로 인공호흡기치료 치료 중 § meropenem #20일, amikacin #3일 치료하고 있 는 중 CRP 증가하고, 산소포화도 감소, follow up culture상 endotracheal tube sputum에서 Acineto. baumannii 보고.

Company Logo Tobramycin 과 once daily dosing § Sputum gram stain § § § § WBC/LPF epithelial/LPF G(+) cocci G(-) rod G(+) rod yeast cell many rare moderate none

Company Logo Tobramycin 과 once daily dosing ET sputum culture # Acinetoba. Baumannii § § § § Amikacin 16 S Amp/sulbactam >16/8 R Aztreonam > 16 R Cefepime > 16 R Cefotaxime > 32 R Ceftazidime > 16 R Ceftriaxone > 32 R Ciprofloxacin > 2 R § § § § many Gentamicin 8 I Imipenem >8 R Piperacillin >64 R Ticar/K Clav’ate > 64 R Tobramycin 2 S Trimeth/Sulfa > 2/38 R Levofloxacin >4 R Meropenem >8 R

Company Logo A. baumannii Antibiotic name No. %감수 성 Imipenem 114 49. 1 Trimethoprim/Sulfamethoxazole 114 41. 2 Ciprofloxacin 114 29. 8 Tobramycin 114 29. 8 Ampicillin/Sulbactam 114 29. 8 Ceftazidime 114 28. 9 Piperacillin 114 28. 9 Ceftriaxone 114 27. 2 Amikacin 114 25. 4 Cefotaxime 114 25. 4 Ticarcillin/Clavulanic acid 108 25 Gentamicin 114 24. 6 IRAB 50. 1%

A. baumannii § For susceptible isolates § carbapenem + AG § IRAB § Ampicillin/sulbactam § Colistin § Drug synergism test § Tobramycin과 Unasyn 투여하기로 결정 Company Logo

Company Logo § Tobramycin § 초기 regimen 25 mg q 8 h § TDM : Peak 9 mcg/ml, trough 0. 4 mcg/ml § Pk parameter § 분포용적 0. 25 L/kg § 반감기 1. 7 시간 § 목표 혈중농도 § Peak : 5 -12 mcg/ml, or Cmax: MIC > 8: 1 § Trough : 0. 5 -1 mcg/ml § 환아의 감염상태 악화소견 § Fever 지속, CRP 상승, 산소포화도 감소

Company Logo Tobramycin 과 once daily dosing § 소아에서 ODD 는 많은 병원에서 alternative 이지만, standard practice는 아니다. § Daily dose in pediatrics (미확정) § 4. 5 -15 mg/kg/day § 신장배설속도가 성인보다 크다. § 혈중농도가 일정시간 동안 undetectable 하다. § PAE ; animal : 1 -8 hr, human : 2 hr § bacterial re-growth risk

Company Logo Tobramycin 과 once daily dosing § Tobramycin PK : Vd; 0. 25 L/kg, T 12; 1. 7 hr § IRAB : TM MIC : 2 mcg/ml § TM ; 25 mg q 8 h 70 mg q 12 h 140 mg q 24 h peak 9 24. 7 49 post 6 hr 70 mg q 12 h 2. 3 140 mg q 24 h 4. 7 (mcg/ml) trough 0. 4 0. 2 0 8 hr 10 hr 12 hr 1 0. 4 2 0. 8 0. 4 * Recommendation : 70 mg

Company Logo PK Parameter of vancomycin Neonates 분포용적 (L/kg) 0. 69 - 0. 79 반감기 (hr) 6. 7 Infants 0. 69 ± 0. 17 4. 1 Children (12세) Adults 0. 63 ± 0. 16 5. 6 ± 2. 1 0. 62 ± 0. 15 7. 0 ± 1. 5

Company Logo Vancomycin in renal impairment § § § Cl. Cr > > > 90 ml/min 70 -89 ml/min 46 -69 ml/min 30 -45 ml/min 15 -29 ml/min : normal dose q 6 hr : normal dose q 8 hr : normal dose q 12 hr : normal dose q 18 hr : normal dose q 24 hr

Medication & ECMO Company Logo § Pharmacokinetic alterations § Incresed volume of distribution, prolonged elimination half-lives § vancomycin, gentamicin, ranitidine, aminophylline Ref) Clin Pharmcokinet. 2003. 42(5); 403 -417

Company Logo Vancomycin & ECMO § Vancomycin § 초기 regimen (8. 18) § 70 mg q 8 h § TDM(8. 22) 70 mg q 24 h § Peak : 81. 6(mcg/ml) § trough : 31. 6(mcg/ml) § TDM(8. 28) 50 mg q 12 h (0. 5 L/kg, 8. 3 hr) § Peak : 27. 0(mcg/ml) § trough : 3. 5 (mcg/ml) day 14 18 21 22 23 24 Scr 0. 4 0. 5 0. 6 0. 7 0. 6 0. 3

Company Logo Vancomycin & NEC § 3 M/M, 4. 8 kg/60. 2 cm § Brief hx § GA 36+6 wks, 3. 08 kg, c-sec delivery 하여 whole milk feeding 하면서 지내던 중 5. 29 vomiting 2차례 있어 local PED 들러 cardiac murmur 보여 타원에서 HLHS 진단받고 강 릉아산병원 방문 evaluation 상 BNP 979 pg/ml check 되며 상지 95%, 하지 80% 로 echo 상 HLHS c PDA 로 수술위해 본원 으로 전원

Company Logo Vancomycin & NEC § Assessment § HLHS § S/P Hybris palliation OP § R/O Heart failure § Dehydration d/t AGE § 8. 14 § Sternum closure § 8. 20 § Stool hematochezia 소량

Company Logo Vancomycin & NEC § 8. 22 § Hematochezia, melena 지속 § 8. 24 § hematochezia, melena->r/o NEC § descend aorta flow 줄어든 것 의심하여 cardiac cath. 시행함 ->newly developed Co. A(juxtaductal) ->ductal stent insertion함(8 mm) § 오후에 abd. sono상 r/o intussusception ->air reduction fail ->Em. op. 시행함(ileo-lieal type intu. ->small bowel resection 시행함) PD cycling 중지 lasix-mannitol continuous infusion start

Company Logo Vancomycin & NEC § Vancomycin § 초기 regimen (8. 23) § 50 mg q 24 h § TDM (8. 28) 50 mg q 48 h § Peak : 37. 3(mcg/ml), trough : 21. 7(mcg/ml) day 6. 28 8. 11 Scr 0. 3 1. 1 8. 24 9. 2 2. 8 1. 6

Company Logo PK Parameter of theophylline Neonates 분포용적 (L/kg) 0. 8 반감기 (hr) 6 -29 Infants 0. 5 -0. 7 1. 2 -5. 9 Children 0. 5 -0. 7 1. 2 -5. 9 Adults 0. 5 6 -13

Company Logo Theophylline – viral infection § 35일된 여아 § 상병명 : RSV associated apnea § Theophylline start

Company Logo Theophylline – viral infection § 질병과 theophylline과의 interaction 모니터 theophylline의 청소율 감소 보고. infulenza B outbreak Respiratory viral infection Fever § 용량 모니터 : 2. 5 mg/kg/dose q 8 h. IV. § Recommendation TDM follow up : start 24시간 후 trough level

Company Logo Theophylline – viral infection § TDM 결과 : 5. 2 mcg/ml (non-steady state) § § Theophylline의 therapeutic range (apnea) 5 -15 mcg/ml IV aminophylline : peak/trough level 12/6. 5 fluctuation 심함. § Recommendation § § § PO theophylline : 2. 5 mg/kg q 8 h 로 전환 steady state 시 예상 농도 : 10 -11 mcg/ml 혈중농도 예상 보다 더 증가 가능성 있슴 2일 TDM follow up HR 증가시 1회 skip

Company Logo Theophylline – viral infection § Result § § § F/U TDM : 11. 8 mcg/ml 예상 보다 혈중농도 상승 Apnea control 되고 있슴 § Recommendation 2 mg/kg q 8 h로 감량

Company Logo Vancomycin & neonate Meningitis : 15 mg/kg/dose. 10 mg/kg/dose Bacteremia : PMA(weeks) PNA(days) Interval(hr) <29 0 to 14 > 14 0 to 7 >7 ALL 18 12 12 8 6 30 to 36 37 to 44 > 45

Company Logo Amikacin & neonate PMA(weeks) PNA(days) Dose (mg/kg) Interval(hr) <29* 30 to 34 >35 0 to 7 8 to 28 >29 0 to 7 >8 18 15 15 18 15 48 36 24 ALL 15 24

Company Logo 미숙아 & vancomycin, amikacin § GA 27+6 wk, 1214 g, AS 4 -7, em. C/S 출 생함. initial crying 있으며, HR 100회 이 상으로 cyanosis 보여 O 2만 apply 하면 서 NICU admission 함. Fi. O 2 0. 3 -0. 4정도 로 saturation 90% 가량 유지 § Assessment (8. 17) #1. prematurity #2. twin 1 st baby #3. 산모의 PROM : 2달간

Company Logo 미숙아 & vancomycin, amikacin Plan § 산모 6/9 부터 PROM 되었던 Hx 있어 amp + GM start 함. § 환아 initial crying 있었고, O 2 apply만 하면서 NICU 입원하였 음. moaning(+) retraction(+) CXR상 total hazziness(+) --> ABGA상 resp acidosis 점차 진행하는 상태로 nasal CPAP apply --> 점차 진행하면 intubation, surfactant 사용 고려. § prematurity로 w/u 진행. § 1 kg 이상으로 indocin 사용하지 않고 observation. murmur(-) § volume은 일단 70으로 restriction

Company Logo 미숙아 & vancomycin, amikacin § 8. 19 § #4. HMD --> surfactant § 8. 20 § 금일 ANC 1000미만으로 check되어 vanco+amikin으로 change 함 (10³/mm³) day 17 20 21 22 WBC 5. 8 2. 2 3. 0 13. 6

Company Logo Neonatal sepsis § Risk factor for nosocomial septicemia - the presence of IV catheters(umblical and central): major - LBW, prolonged hospital stay, prior antibiotic use, TPN, lipid emulsion, invasive procedures, the presence of other indwelling devices(e. g. , endotracheal tubes, ventriculoperitoneal shunts) § Clinical signs & Lab evidence of neonatal sepsis - poor feeding, temperature instability, lethargy, apnea: common signs - glucose instability, tachycardia, dyspnea or cyanosis, tachypnea, diarrhea, vomiting, feeding intolerance, abdominal distension, metabolic acidosis, abnormal WBC(e. g. , leukocytosis, neutropenia), elevated CRP, thrombocytopenia - jaundice, hepatosplenomegaly

Company Logo 미숙아 & vancomycin, amikacin § Vancomycin (wt ; 1072 g) § 초기 regimen (8. 20) § 10 mg q 18 h § TDM (8. 22) 현 용량 유지 § Peak : 20. 8(mcg/ml), trough : 7. 6(mcg/ml) § 분포용적 : 0. 67(L/kg), 반감기: 11. 7(hr)

Company Logo 미숙아 & vancomycin, amikacin § Amikacin (1072 g) § 초기 regimen (8. 20) § 18 mg q 36 h § TDM (8. 22) 현 용량 유지 § Peak : 27. 4(mcg/ml), trough : 4. 9(mcg/ml) § 분포용적 : 0. 74(L/kg), 반감기: 14. 3(hr)

Company Logo PK Parameter of digoxin Neonates 분포용적 (L/kg) 7. 5 -10 반감기 (hr) 44 ± 13 Infants 16. 3 ± 2. 1 18 ± 9 Children 16. 1 ± 0. 8 36 ± 11 Adults 6. 7 ± 1. 4 36 ± 8

Company Logo Regimen of digoxin (mcg/kg) Neonates 용량 (P. O. ) (mcg/kg/day) 6 -10 용량 (I. V. ) (mcg/kg/day) 5 -8 1 mo – 2 y 10 -15 7. 5 -12 2– 5 y 5 – 10 y 7. 5 -10 6 -9 4 -8 >10 y 2. 5 -5 2 -3 Adults 0. 125 -0. 5(mg) 0. 1 -0. 4(mg)

Company Logo Digoxin & 청소년 § Case § 17 yr, 34 kg, 남 § Dx § S/P TOF § 주증상 § Vomiting and nausea § Digoxin § 200 mcg bid