Management of Infection after Liver Transplantation

-Review of SNUH Protocol-

서울대학교 의과대학 외과학교실

이 남 준, 신 우 영, 이 해 원, 서 경 석, 이 건 욱

Incidence of Infection

• 60-80% LT recipients

• Contribution to mortality• Uncommon 6 mo. after LT

Infections after LT, Transplantation of the Liver, 2005

New Engl J Med 338:1741, 1998

Usual Sequence of Infections after Transplantation

Am J Med 70:405, 1981

Risk Factors for Infection

CMV, HSV, VZV, Endemic mycosis, Pneumocystis, Tuberculosis

ImmunosuppressionLatent infection

Resistant bacteriaAspergillusLegionella

CMV, HSV, HIVPreop. antibiotics↑ Hospital stay

Hospital floraDonor graftColonization

Prolonged indwelling catheterProlonged antibiotics administrationRepeat laparotomy or transplantation

↑ Operation time↑TransfusionGraft ischemia or injuryIntraabdominal bleeding GI contamination

Corticosteroid therapyPoor nutritional statusChronic lung diseaseDM

Postop. managementSurgery Underlying condition

Post-transplantTransplantPre-transplant

Contents

1. Anti-microbial prophylaxis protocol of SNUH

2. Infection during early post-LT period in SNUH

- Bacterial - Fungal

3. Clinical significance of VRE in LT4. Management of fungal infection

Anti-microbial Prophylaxis-SNUH Protocol-

Bacterial Prophylaxis• Routine

– Preop. GI decontamination with Kanamycin (1g qid+hs) for 3 days

– Preop. Hibitan shower– Intraop.: Unasyn (Ampicillin+sulbactam, 3.0g ivs q 8hr)– Postop.-POD2: Unasyn (3.0g ivs q 6hr)

• Bacterial infection– 이식 전 colonization 환자 (-)– Preop. antibiotics 사용하고 휴지기가 없었던 환자 (+)– Intraop. peritonal infection & contamination 환자 (+)– ~ POD 5/7 – 1차적으로 경험적 항생제 또는 사용하던 항생제 이후 동정 결과에

따라 조정

Fungal Prophylaxis

• 이득과 손해의 저울질

– 침습적 진균감염증의 예방

– 약물 부작용, 내성발현, 약물 상호작용

• 예방적 항진균제

– 모든 이식환자에게 예방적 항진균제 투여? * 진균감염증의 고위험군에게만?* 단위 이식병원에 대한 자료?

김 남 중, 2007 SUNH Transplant Symposium

이식장기 발병까지 평균시간

간 17일(6-1,197일)

Fungal Prophylaxis• Pre-LT. GI decontamination with Nystatin (15mL

qid) for 3 days• Routine

– Fluconazol• Low risk patients: 퇴원할 때까지, 100-200 mg po qd• High risk patients: 퇴원할 때까지, Fluconazol 400 mg iv po qd• 추가 항생제 치료 기간이 일주일이상 예상되는 경우

– Nystatin gargle • 수술 직후부터 6mo.까지

– Bactrim (Trimethoprim/sulfamethoxazole)• 수술 후 경구 투여가 가능한 시점부터 12mo.까지, 1- 2T biw

– No amphotericin B

High Risk Patients in Fungal Infection

•Candida 감염증

– 재수술을 한 경우

– choledochojejunostomy

– 수술 중 수혈요구량이 많은 경우

– 수술시간이 긴 경우

– 신부전이 있는 경우

•Aspergillus 감염증

– 이식간의 기능이 나쁜 경우

– 이식전의 질병이 전격성 간염인 경우

– 재이식한 경우

– 투석을 받는 경우

김 남 중, 2007 SUNH Transplant Symposium

Viral Prophylaxis• HBIG & Nucleos(t)ide

– Combined therapy for Hepatitis B related recipients

– Only HBIG monoprophlyaxis according to antiHBc status for Hepatitis B naïve patients

• D (+) or R (+)

• Cytomegalovirus (CMV)/Epstein-Barr virus (EBV) prophylaxis– D (-), R(-) no – D (-) or (+), R (+) no – D (+), R (-)

수술 직후부터 퇴원할 때까지 Ganciclovir 6mg/kg iv qd퇴원 후 3mo.까지 acyclovir 200mg tid po

Routine Culture

• Pre-LT– General organism, tuberculosis, fungus– Skin, nasal swab, sputum, throat swab, urine,

urethral discharge, stool (parasite)

• Post-LT– General organism, tuberculosis, fungus– Tip of catheter, content of abdominal drain– Additional culture, if indicated: blood, sputum,

urine, ascites, stool, wound, ect.

Post-LT Infection-2006 SNUH Experience-

SNUH Experience

• Between Jan. and Dec. 2006.• 53 recipients of adult-to-adult LDLT

– In-patient data– Age: 49.9±8.8 (19-63) years– Gender (M:F): 43:10– Hospital stay: 23.4±10.5 (14-65) days– Mortality

• No operative mortality• 1 hospital mortality

Pre-LT Culture• Culture (+) for general organism

– 40 (75.9%) out of 53 patients– 137 pairs of bacteria

skin, 30,34%

sputum,7, 8%

throat swab,8, 9%

urethraldischarge,

37, 41%

urine,voided, 7,

8%

streptococc17, 14%

corynebacter11, 8%

enterococc 13, 11% staphylococ

80, 66%

others , 16,12%

Post-LT Culture• Culture (+) for general organism

– 38 (72.2%) out of 53 patients– 72 pairs of bacteria

vascularcath, 14,

23%

blood,7, 8%

drain, 13,21% foley tip, 27,

43%

sputum, 1,2%

enterococc13, 18%

stenotrophomonas, 11, 8%

pseudomonas, 8, 11%

staphylococ36, 50%

others , 8,16%

Fungus Culture

• Pre-LT 13 pairs of fungus in 10 (16.7%) of 53 patients– Throat swab (n=5), sputum (n=4), urethral

discharge (n=3), skin (n=1) – Yeast (n=8), Candida sp.(n=4), Rhodotorula

glutinis (n=1)

• Post-LT 3 pairs of fungus in 3 (5.6%) of 53 patients – Candida sp. (n=3)– Foley tip (n=3)

0

5

10

15

20

25

30

35

40

urethraldischarge(foley tip)

skin(vascular

cath)

throatswab

sputum urine,voided

drain blood

Pre-LT Gram

Post-LT Gram

Pre-LT Fungus

Post-LT Fungus

Post-LT Infection• 13 cases in 9 (17.0%) out of 53 patients

– 9 (23.7%) of 38 culture positive patients– No fungal infection

• Most common site: peritoneal infection (drain)

0

1

2

3

4

5

6

intra

abdom

ina

resp

irato

ry

bile le

akage

urinary

CRIFUO

Staphylococcus (n=5)Enterococcus (n=1)

Stenotrphomas, Staphylococcus, Citrobacter, VRE

Factors ass. Post-LT Infection

• No difference in– Age, gender, Pre-LT MELD score, Child-Pugh

class, Hb, Albumin, Bilirubin, operation time, ischemic time, transfusion amount

.00484%33%Pre-LT culture (+) rate

.01120 days31 daysHospital stay post-LT

.1700%11%Hospital mortality

.15016%44%UNOS status 1/2A

P-value

Non-Infection(n=44)

Infection(n=9)

Variables

Summary (I)Under SNUH prophylactic protocol for bacterial and

fungal infection

• Peri-transplant bacterial culture (+) rate– Pre-LT: 75.9% of patients, mc. Staphylococcus (66%), skin,

urethra– Post-LT: 72.2% of patients, mc. Staphylococcus (50%),

indwelling catheter

• Post-LT bacterial infection – Incidence 17% (n=9, 12 cases), mc. peritoneal infection– Not associated with rate of pre-LT colonization, disease

severity index– Increased hospital stay in infected patients’ group, but not

increased early post-LT mortality rate

• No fungal infection during the early post-LT period

Vancomycin Resistant Enterococcus (VRE)

• VRE(+) 18 (4%) of 450 recipients

• Sites of VRE isolates: urine > GI, drain > blood > wound, …

• Associated microbials: MRSA, VSE, E.coli, ect.

• Infection rate: 20%• Cause of death:

associated morbidity

최은경 외, 대한 이삭학회지 20:241, 2006

최은경 외, 대한 이삭학회지 20:241, 2006

Fever after Aplastic Anemia Therapy M/46, HBV-LC with HCC, with DM (8 years) bronchitis (5 years) 2001.8.27.LDLT Aplastic anemia (2006.5.)

Aspergillus 감염증 치료 프로토콜

• Voriconazole을 추천하는 경우

– 배양검사로 “invasive aspergillosis”가 확진된 환자

– 6 mg/kg, every 12 hour, 이후 4 mg/kg, every 12 hour 정주

• Amphotericin B를 추천하는 경우

– 방사선검사로 진단되었으나 배양검사로 입증되지 않은 환자

– 1.0 – 1.5 mg/kg/day

질환 1차 약제 2차 약제

침습성아스페르길루스증

Amphotericin B 1.0-1.5 mg/kg/dayVoriconazole 4 mg/kg, q 12 hour

ItraconazoleCaspofungin

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Candida 감염증 치료 프로토콜

• Fluconazole을 추천하는 경우

– 임상적으로 안정되어 있고, fluconazole 감수성인 candida

• Amphotericin B를 추천하는 경우

– 임상적으로 불안정한 환자

– C. glabrata 혹은 C. krusei가 자란 경우

질환 1차 약제 2차 약제

심부칸디다 감염증

Amphotericin B ≥ 0.7 mg/kg/dayFluconazole ≥ 400 mg/dayCaspofungin 50 mg/day

Voriconazole

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기타 진균증 치료 프로토콜

질환 1차 약제 2차 약제

P. cariniipneumonia Trimethoprim/sulfamethoxazole Pentamidine

MucormycosisAmphotericin B ≥ 1.0 mg/kg/day +Surgical treatment

Cryptococcalmeningitis Amphotericin B +/- Flucytosine

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Summary (II)

• Fungal infection during long-term f/u– Asscoiated with underlying

immunosuppressive status & mortality– 조기에 임상증상을 의심하여 치료 시작