bacterialinfectionsin severely immunosuppressed patients
TRANSCRIPT
BACTERIAL INFECTIONS IN SEVERELY
IMMUNOSUPPRESSED PATIENTS
Elisa Cordero Matía
Infectious Diseases Unit
University Hospital Virgen del Rocío
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• Increased risk of infection by common pathogens and opportunistic
infections.
• Increased risk of developing systemic compromise, including sepsis
and septic shock.
• Paradoxically, in some patients as solid organ transplant recipients,
the prognosis might not be worse or perhaps even better than their
nonimmunocompromised counterparts.
Legrand Crit Care Med 2012, Jeddi Hematology 2010, Kalil Clin Infect Dis 2015
Sepsis in the severely immunosuppressed patient
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• Severe and prolonged:
• Cytoablative chemotherapy (e.g induction chemotherapy for acute
leukemia and lymphoreticular malignancies.
• Delayed bone marrow recovery following allogenic hematopoietic stem cell
transplantation (HSCT).
• Solid organ transplantation.
• Non-severe and short.
• Neutropenia of short duration chemotherapy in many solid malignancies.
• Low risk of systemic infection or sepsis.
• Excellent short term prognosis generally managed as outpatients.
Legrand Crit Care Med 2012, Freifeld Clin Infect Dis 2011, Kern Clin Infect Dis 2006
Sepsis in the severely immunosuppressed patient
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febrile neutropenia in
hematology patients
Sepsis in the solid
organ transplant
recipient (SOT)
Sepsis in the severely immunosuppressed patient
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febrile neutropenia in
hematology patients
Sepsis in the solid
organ transplant
recipient (SOT)
Sepsis in the severely immunosuppressed patient
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Bloodstream infections in hematologic patients
• Incidence: 13-60%.
• Mortality 12-42%
• Appropriate empirical antibiotic is critical
• resistance to antibiotics worldwide, including immunosuppressed patients.• use of broad-spectrum
regimens, including carbapenemsand combinations • Selection of carbapenem and
multidrug resistant pathogens,
• Fungal infections
• Clostridium difficile associated diarrhea
Almyroudis. Transpl Infect Dis. 2005, Collin BA, Clin Infect Dis. 2001;Mikulska M, Biol Blood Marrow Transplant. 2009;
Ninin E, Clin Infect Dis. 2001, Poutsiaka DD,. Bone Marrow Transplant. 2007, Trecarichi EM, J Infect. 2009;. ESCMID eLibrary
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Blood stream infections and neutropenia
Mid 20th cent Gram negative bacteremia
80´s-90´s Quinolone prophylaxis/central venous catheter
Gram-positive pathogens
Last decade Gram negative bacilli
Antimicrobial resistanceESCMID eLibrary
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Resistance rate and country
Blennow Br J Hematol 2016ESCMID eLibrary
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Gram negative bacteremia in hematologic patients
• E. coli 21% (18-46%).
• ESBL 11%-69%
• Ceftazidime 30-85%
• Pip/Taz: 0-51%
• Carbapenems 0-18%
• K. pneumoniae 11% (4-20%)
• ESBL 23-69%.
• Ceftazidime 50-71%
• Pip/Taz: 25-63%
• Carbapenems 0-31%
• P. aeruginosa 10% (3-30%)
• Multiresistant: 30-70%
• Carbapenem 44% (3-66%)
Pagano 2014, Trecarichi 2015, Prabhash et al, 2010; Sood et al, 2012; Metan et al, 2013; Miedema et al, 2013; Bousquet et al, 2014ESCMID eLibrary
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Risk factors for BSI mortality in febrile neutropenia
Wang Medicine 2016ESCMID eLibrary
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Principles of antimicrobial therapy in theneutropenic patient
• Empirical antimicrobial therapy is always needed.
• Early administration (<60 minutes).
• It should be active against Pseudomonas aeruginosa .
• High doses and optimized following PK/PD parameters.
• Designed to reduce antimicrobial resistance.
• Different antimicrobials can be considered.
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MONOTHERAPY
Cefepime (ceftazidime)
Piperacillin/tazobactam
Meropenem
COMBINATION REGIMENS
aminoglycoside:
amikacin
Glycopeptide
vancomicyn
Quinolones:
ciprofloxacin
WITH
Empirical antimicrobial therapy in febrile neutropenia
• Beta-lactam with activity against P. aeruginosa
Freifeld AG, IDSA guidelines 2010 up date. CID 2011; ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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MONOTHERAPY
Cefepime (ceftazidime?)
Piperacillin/tazobactam
Meropenem
Empirical antimicrobial therapy in febrile
neutropenia
• Beta-lactam with activity against P. aeruginosa
Recommendation AI,
Similar efficacy,
mortality,
Fewer adverse
events
Freifeld AG, IDSA guidelines 2010 up date. CID 2011; ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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febrile cancer patients with neutropeniaBeta-lactam monotherapy vs. beta-lactam+aminoglycoside
Paul M. Cochrane Database Syst Rev. 2013ESCMID eLibrary
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Outcome RR(CI95%)
All cause mortality 0.85 (0.54-1.35) Clinical cure 1.32 (1.00-1.74) Adverse events Discontinuation 0.87 (0.57-1.32) Nephrotoxicity 0.30 (0.16-0.59)
febrile cancer patients with neutropeniaBeta-lactam+quinolones vs. beta-lactam+aminoglycoside
Bliziotis IA. Mayo Clin Proc. 2005ESCMID eLibrary
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Empirical therapy election
Local epidemiologyP. aeruginosa
S. mitis
ESBL producer
Enterobacteriaeceae
Meticillin resistant S.
aureus
Patients characteristics• Opportunistic infections
• Prophylaxis and previous
therapy
• Previous colonization o MDR
infection
• Previous therapies
• Toxicity, interaction allergies
Focal signs and severityESCMID eLibrary
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3 OPPORTUNITIES to optimize
antibiotic treatment
DIVERSIFY SIMPLIFY SHORTEN
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1. Risk of Pseudomonas aeruginosa (neutropenia, steroids,
chemotherapy, antibiotics) mostly determine the election of
antibiotic in the hematological unit.
2. Several antibiotics can be used to treat this infection.
3. However, the repeated use of the same antimicrobial can
lead to the development of resistance.
Diversifying the antimicrobial therapy
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Risk factors for infection with MDR bacteria
• Patient’s prior colonization or infection by resistant pathogens, particularly: • ESBL or carbapenemase- producing Enterobacteriaceae
• Resistant non-fermenters: Acinetobacter baumannii, P. aeruginosa and Stenotrophomonas maltophilia.
• MRSA, especially with vancomycin MICs ≥2 mg/L.
• Vancomycin-resistant enterococci.
• Previous exposure to broad-spectrum antibiotics, especially but not limited to 3rd
generation cephalosporins*.
• Serious illness (e.g. end-stage disease, sepsis, pneumonia).
• Nosocomial infection.
• Prolonged hospital stay and/or repeated hospitalizations.
• Urinary catheters.
• Older age.
• Intensive care unit stay.
F Averbuch. ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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Diversifying the antimicrobial
therapy: A possible approach
• Criteria for escalation approach:
• Noncomplicated illness.
• No resistant bacterial colonization/infection.
• Fever with low probabilty of infectious etiology (drugs, tumoral fever,..).
• Low risk patients (myeloma, CLL, lymphoma).
:
• Local epidemiology.
• Associated signs or symptoms.
• 1. Use cefepime or piperacillin-tazobactam.
• 2. Select cefepime or piperacillin-tazobactam according to:
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3. Use meropenem as first line therapy if:
Severely ill patients.
Fever and previous infection/colonization with resistant
GNB.
Neutropenic patients with recent therapy with
piperacillin-tazobactam and recurrent fever.
Diversifying the antimicrobial
therapy: A possible approach
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Situations in which combination with an aminoglycoside is
indicated as the first-line regimen (BIII)
• 1. Seriously-ill patients.
• 2. If resistant non-fermenters (P. aeruginosa or Acinetobacter spp.) are likely,
based upon:
• a. Local epidemiology.
b. Previous colonization or infection with these pathogens.
• c. Previous use (last month) of carbapenems.
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When should we include GP therapy?
• No differences in mortality, breakthrough bacteremia or time to
defervescence
• As initial empirical therapy
• In patients with persistent fever (>72 h)
• More adverse events (nephrotoxicity) and selection of resistant strains
(S. aureus and Enterococcus spp)
It is not recommended to routinely add glycopeptides (DI)
Freifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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When should we consider adding empirical therapy for GPC?
1. Hemodynamic instability or other evidence of severe sepsis, septic shock or
pneumonia.
2. Colonization with MRSA or VRE.
3. Suspicion of serious catheter-related infection.
4. Skin or soft-tissue infection at any site in areas with high index of community
acquired MRSA.
5. Severe mucositis in patients receiving quinolone prophylaxis or empirical
therapy with cephalosporins (risk of S. mitis fulminant sepsis).
Freifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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3 OPPORTUNITIES to optimize
antibiotic treatment
DIVERSIFY SIMPLIFY SHORTEN
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Escalation and de-escalation approaches
strategies Estrategias de
escalada/desescalada
Averbuch. ECIL-4 Guidelines. Haematol 2013.
Approach Escalation De-escalation
Select antibiotic active against non resistant
GNB and P. aeruginosa
Modify therapy in case of clinical deterioration
or MDR isolation
Select antibiotic active against resistant GNB
and MDR P. aeruginosa
Simplify if resistant infection is not
confirmed.
When - Uncomplicated presentation;
- No known colonization/infection with
resistant bacteria;
- In centers where infections due to
resistant pathogens are rarely seen at the
onset of febrile neutropenia.
- Complicated presentation
- Colonization/infection with resistant bacteria.
- Centers where resistant bacteria are
frequently seen at the onset of febrile
neutropenia.
Options -Anti-pseudomonal cephalosporin
(cefepime,ceftazidime)AI
- Piperacillin-tazobactam AI
-Carbapenems (BII)
-antipseudomonal betalactam + aminoglycoside
(BIII) or quinolone
-Colistin + betalactam +/- rifampicin (BIII)ESCMID eLibrary
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Reassessment of antimicrobial therapy after 2-3 days.
• 1. Review of systems and repeat examination daily.
• New sites of infection or localizing symptoms if neutrophil count recovers
• 2. Reassess empirical antibiotic therapy after 2-3 days
• A. Documented clinical and/or microbiological infection:
• Implement de-escalation if etiology is available:• Simplify therapy according to the etiology and susceptibility of the isolate (AI).
• Choose the antibiotic with the narrower spectrum.
• Consult with an ID expert.
Freifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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Reassessment of antimicrobial therapy in
febrile neutropenia
B. No clinical or microbiological diagnoses but clinicalimprovement.• We can simplify antimicrobial therapy
• Discontinue after 48 hours
Aminoglycoside (AII)
Vancomicyn (AII)
• Choose a narrower spectrum betalactam (BIII)
• If the wide spectrum antimicrobial therapy was used because of severity, it might not be modified.
Freifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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Reassessment of antimicrobial therapy
• Unexplained persistent fever in a patient whose condition is otherwise
stable
• Rarely requires an empirical change to the initial antibiotic regimen (BII)
• Defervescence can take>5 days in hematology patients
• Changes should be based on clinical changes o microbiological data.
• Do not add vancomycin if not indicated. (AI)
• Continue the diagnostic workup :
• Reevaluate signs and symptoms
• Repete microbiological studies
• Image tecniques
• Patients who remains hemodynamically unstable
• Broaden their antimicrobial regimen to include coverage for resistant gram-negative,
gram-positive, and anaerobic bacteria and fungi Freifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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febrile neutropenia, day +0
PIPERACILLIN/TZB + AMIKACIN
No microbiological
diagnosis
Yes
¿Still fever?
¿Stable?
- Broaden spectrum
- Accelerate diagnosis
No
- Continue diagnoses
- Stop combination therapy
(BIII)
- Considerar simplifying
(BIII)
Yes- Discontinue combination
therappy (BIII)
- Consider simplifying (BIII)
- Consider discontinue
antibiotics after 72 hours of
defervescence (BII)
No
48-72hMicrobiological
diagnosis
Simplify to a narrower
spectrum antibiotic (AI)
Adaptad from 2011 ECIL Guidelines ESCMID eLibrary
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3 OPPORTUNITIES to optimize
antibiotic treatment
DIVERSIFY SIMPLIFY SHORTEN
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Averbuch. ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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Averbuch. ECIL-4 Guidelines. Haematol 2013.ESCMID eLibrary
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• Discontinuation of antibiotic therapy in the experimental group
after 72 hours of apirexia and disappearance of symptoms of
infection independently of neutrophil cell count
CT How Long EudraCT nº 2011-005152-34.
Duration of antimicrobial therapy
Variables EG (n=35)
Median (range)
CG (n=45)
Median (range) P
Days of neutropenia 19 (5-54) 14 (4-69) p= 0.05
PMN (*109/L) at discontinuation of
Antibiotic therapy 300 (0-9700) 1100 (0-13000) p<0.001
Duration of fever (days) 5 (1-18) 4 (1-28) p= 0.349
Episodes or recurrent fever 20% 24,4% p= 0.63
Mortality 0 0
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febrile neutropenia in
hematology patients
Sepsis in the solid
organ transplant
recipient (SOT)
Sepsis in the severely immunosuppressed patient
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Sepsis in SOT recipients• Sepsis among the main causes of death among all types of organ
transplants.
• Nosocomial infections: 18 times more frequent in solid organ transplant (SOT)
recipients.
• Sepsis occurs in 20–60 % of all SOT recipients.
• Mortality ranges from 5–40 %.
• Non classical clinical features:
• Absence of leukocytosis and fever.
• More frequent organ failure.
• Hospital-acquired microorganism -> More MDR bacteria.
Bodro Transplantation 2013, Linares Transplant Proc 2009 Malinis Transplantation 2012 Hsu Eur J Cardiothoracic Surg 2011, Candel
Transplant Proc 2005, Wan Exp Clin Trans 2013, Kalil Clin Infect Dis 2015 ESCMID eLibrary
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Nosocomial bloodstream infections
Transplant recipients vs. others
Crude mortality 34.5% vs. 40.5%
Camargo Transplant Infect Dis 2015ESCMID eLibrary
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Resistant bacteremia in SOTr
19.6% episodes of bacteremia due to rESKAPE
Risk factors:
Prior transplantation,
Septic shock
Prior antimicrobial therapy
Bodro Transplantation 2013ESCMID eLibrary
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XDR P. aeruginosa bacteremia in SOT
Bodro Transplantation 2015
Risk factors:
Prior transplantation,
Septic shock
Hospital acquiredESCMID eLibrary
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Predisposing factors of bacterial sepsis
• CMV serology mismatch.
• CMV disease.
• Predisposes to higher rates of bacterial and fungal sepsis
• Prolonged duration of graft cold ischemia.
• Prolonged duration of surgical transplantation procedure.
• Requirement of large amounts of blood transfusion.
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Sepsis in SOT: Differential diagnosis • Allograft rejection
• Allograft thrombosis
• Post-transplantation lymphoproliferative disease
• Acute pancreatitis
• Cytomegalovirus disease
• Pulmonary embolism
• Myocardial infarction
• Cerebral-vascular accident
• Pulmonary calcinosis
• Bronchiolitis obliterans
• Intrathoracic hemorrhage
• Hypersensitivity drug reaction
• Acute respiratory distress syndrome
• Acute arterial or venous occlusion
• Acute viral colitisESCMID eLibrary
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Septic shock in kidney transplant
recipients
Respiratory60%
Urinary 17%
Abdominal9%
Other14%
Carvalho Plosone 2014ESCMID eLibrary
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Typeofinfection FrequencyUTI 47%Cistitis 33.5%Pyelonephritis 13%CMV 22%Surgicalsiteinfection
8%
Pneumonia 6%Skininfection 4%Acutegastroenteritis
0.5%
Source of sepsis in kidney transplant
recipients• Urinary tract: most common site of infection.
• Respiratory source: similar to general population
• Abdominal source: more frequent:
• Pericolic abscess
• Bowell perforation (elderly)
• Hepatic cysts infection
• Cholecystitis and pancreatitis
Garcia-Prado Enf Infec Microbiol Clin 2009 Kalil, Curr Infect Dis Rep 2015,
Koneru Arch Surg 1990, Andreoni Transplantation 1999. Dominguez Transplant Int 1998.ESCMID eLibrary
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Urinary tract infections in SOT
Vidal Transplant Infect Dis 2012ESCMID eLibrary
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UTI in kidney recipients
Predisposing factors
Vidal et al. GESITRA consensus document. EIMC 2015ESCMID eLibrary
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UTI in kidney recipients• It is crucial an adequate source control in septic patients
• Abdominal ultrasounds should be routinely performed in all kidney
recipients with sepsis of urinary source
• Rule out pyelonephritis, perinephric abscess, fungal balls, and ureteral
obstruction;
• In case of negative ultrasound and non satisfactory clinical course
consider other techniques .
• In cases of recurrent UTI consider:
• Ureteral reflux,
• Uretero-vesicle junction strictures
• Neurogenic bladderESCMID eLibrary
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Typeofinfection FrequencySurgicalsiteinfection
16%
CMV 14%UTI 11%Bacteremia 10%Cholangitis 8%Pneumonia 7%Liverabscess 6%Peritonitis 4%CRB 2%
Sepsis and liver transplantation• 30% of liver transplant in the first 3 months.
• Most frequent -> intraabdominal:
• Intra-extrahepatic abscess
• Secondary peritonitis
• Cholangitis
• Surgical site infection
• Clostridium difficile colitis
• Respiratory infections:
• First monthGarcía-Prado EIMC 2009, Paya Mayo Clin Proc 1999, George Rev Infect Dis 1991 ESCMID eLibrary
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Biliary infections in liver transplant
recipients• Lack of classic Charcot´s triade
• Frequently absence of fever, pain, jaundice.
• Must be suspected in case of fever without focal signs or symptoms together with CMV.
• Process microbiological samples:
• Blood cultures.
• CMV RT-PCR.
• Others if symptoms: urine culture, respiratory samples, ….
• Image studies
• Frequently associated to:
• Biliary strictures.
• Intrahepatic abscesses
• Hepatic artery thrombosis (recurrent hepatic abscess)ESCMID eLibrary
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Infected bilomas• Frequency 10% of liver transplantation.
• High morbidity: resource consumption, readmission, retransplantation
if associated to hepatic artery thrombosis.
• Gram positive bacteria the most common, followed by Candida spp.,
Enterobaceriaceae and P. aeruginosa.
• Treatment:
• Drainage.
• Antimicrobial therapy: generally prolonged (4-6 weeks).
• Caution: risk of MDR bacteria
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Recurrent cholangitis• Structural lesions of the biliary tree:
• Bile leak.
• Anastomotic and non-anastomotic strictures.
• Ampullary dysfunction.
• Consider ischaemic cholangiopathy in cardiac-death donor or hepatic artery
thrombosis.
• Less frequent: recurrence of primary sclerosing cholangitis or secondary sclerosing
cholangitis.
• Few information available despite its frequency
• Frequent broad spectrum antimicrobials-> Increased MDR infections.
deOliveira ML, Ann Surg 2011,Seehofer D. Am J Transplant 2013, Vrochides D.Transpl Infect Dis 2007ESCMID eLibrary
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Hepatic artery thrombosis
• Poor perfusion of the bile ducts: strictures and leaks
• Abscesses.
• Require multiple drainage.
• Frequently need retransplantation.
Source control is a crucial part
of the treatment if biliary or vascular changes
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Treatment of MDR bacterial infection in
SOT
• Source control is critical Associated with survival.
• Catheter removal.
• Wound debridement.
• Abscess, biliary tree, urinary tract drainage.
• Therapeutic options are expensive, toxic and of limited efficacy.
• Explore combination therapies.
• Optimize PK/PD.
Patel. Infect Control Hosp Epidemiol 2008, Cervera Clin Microbiol Infect 2014
Clancy Am J Transplant 2013ESCMID eLibrary
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Ideas to take home• Bacterial infection in severely immunosuppressed patients is a frequent
request for the ID consultant.
• It requires a rapid diagnostic workup and prompt therapeutic
recommendations.
• The attenuation of signs / symptoms of infection require an "aggressive”
diagnostic attitude.
• The best diagnostic tool is the detailed history and daily detailed clinical examination.
• Wide differential diagnosis with non-infectious diseases.
• The empirical approach should be early and directed to the most likely
etiology.ESCMID eLibrary
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• In this setting MDR bacteria are an important challenge.
• Antimicrobial stewardship is possible despite underlying illness.
• Diversify
• Select according to the severity, source of infection and local epidemiology
• Limit broad spectrum treatment and especially carbapenems in first line to seriously ill
patients or at risk of infection with resistant bacteria
• Simplify whenever it is possible
• Reduce the duration of empirical treatments
• Persistent fever alone does not justify adding treatment against Gram-positive
or antifungal treatment empirical
• Source control is crucial, especially in SOT recipients.
Ideas to take home
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