a r

ib r
L
BACTERIAL INFECTIONS IN SEVERELY
e r
IMMUNOSUPPRESSED PATIENTS

I D ho
Elisa Cordero Matía

M u t
Infectious Diseases Unit

C
S y a
University Hospital Virgen del Rocío

E
 a r
Sepsis in the severely immunosuppressed patient
ib r
L
e r
• Increased risk of infection by common pathogens and opportunistic
infections.

I D ho
• Increased risk of developing systemic compromise, including sepsis
and septic shock.

CM u t
• Paradoxically, in some patients as solid organ transplant recipients,
the prognosis might not be worse or perhaps even better than their

S a
nonimmunocompromised counterparts.

y
E Legrand Crit Care Med 2012, Jeddi Hematology 2010, Kalil Clin Infect Dis 2015
 a r
Sepsis in the severely immunosuppressed patient
ib r
L
• Severe and prolonged:

e r
• Cytoablative chemotherapy (e.g induction chemotherapy for acute
leukemia and lymphoreticular malignancies.

I D ho
• Delayed bone marrow recovery following allogenic hematopoietic stem cell
transplantation (HSCT).

M u t
• Solid organ transplantation.
• Non-severe and short.

C a
• Neutropenia of short duration chemotherapy in many solid malignancies.

E S • Low risk of systemic infection or sepsis.

y
• Excellent short term prognosis generally managed as outpatients.

Legrand Crit Care Med 2012, Freifeld Clin Infect Dis 2011, Kern Clin Infect Dis 2006
 a r
ib r
Sepsis in the severely immunosuppressed patient

L
e r
I D ho
febrile neutropenia in Sepsis in the solid

CM u t
hematology patients organ transplant
recipient (SOT)

S y a
E
 a r
ib r
Sepsis in the severely immunosuppressed patient

L
e r
I D ho
febrile neutropenia in Sepsis in the solid

CM u t
hematology patients organ transplant
recipient (SOT)

S y a
E
 a r
Bloodstream infections in hematologic patients
ib r
L
e r
• Incidence: 13-60%.
•  resistance to antibiotics
worldwide, including
immunosuppressed patients.

I D ho
• Mortality 12-42%
•  use of broad-spectrum
regimens, including carbapenems
and combinations

M t
• Appropriate empirical • Selection of carbapenem and
multidrug resistant pathogens,
antibiotic is critical

C a u • Fungal infections
• Clostridium difficile associated
diarrhea

E S y
Almyroudis. Transpl Infect Dis. 2005, Collin BA, Clin Infect Dis. 2001;Mikulska M, Biol Blood Marrow Transplant. 2009;
 a r
ib r
Blood stream infections and neutropenia

Mid 20th cent L

e r Gram negative bacteremia

I D ho
80´s-90´s Quinolone prophylaxis/central venous catheter

CM u t
 Gram-positive pathogens

S y
Last decade a Gram negative bacilli

E Antimicrobial resistance
 a r
Resistance rate and country
ib r
L
e r
I D ho
CM u t
S y a
E Blennow Br J Hematol 2016
 a r
Gram negative bacteremia in hematologic patients
ib r
L
• E. coli 21% (18-46%).

e r
• ESBL 11%-69%
• Ceftazidime 30-85%

D ho
• Pip/Taz: 0-51%

M I
• Carbapenems 0-18%
• K. pneumoniae 11% (4-20%)

t
• ESBL 23-69%.

u
• Ceftazidime 50-71%

C
• Pip/Taz: 25-63%

a
• Carbapenems 0-31%

S
• P. aeruginosa 10% (3-30%)

E y
• 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, 2014
 a r
ib r
Risk factors for BSI mortality in febrile neutropenia

L
e r
I D ho
CM u t
S y a
E Wang Medicine 2016
 a r
Principles of antimicrobial therapy in the
neutropenic patient
ib r
•
•
L
e r
Empirical antimicrobial therapy is always needed.
Early administration (<60 minutes).
•
I D ho
It should be active against Pseudomonas aeruginosa .

M u t
• High doses and optimized following PK/PD parameters.
• Designed to reduce antimicrobial resistance.

C
S y a
• Different antimicrobials can be considered.

E
 a r
Empirical antimicrobial therapy in febrile neutropenia
ib r
• L
e r
Beta-lactam with activity against P. aeruginosa

D ho
MONOTHERAPY COMBINATION REGIMENS

M I
Cefepime (ceftazidime)

t
Piperacillin/tazobactam
aminoglycoside:
amikacin
Glycopeptide

C
Meropenem

a u vancomicyn

S
Quinolones:

y
ciprofloxacin

E Freifeld AG, IDSA guidelines 2010 up date. CID 2011; ECIL-4 Guidelines. Haematol 2013.
 a r
Empirical antimicrobial therapy in febrile
neutropenia
ib r
• L
e r
Beta-lactam with activity against P. aeruginosa

D ho
MONOTHERAPY

I
Cefepime (ceftazidime?)

M t
Piperacillin/tazobactam
Recommendation AI,
Similar efficacy,

C
Meropenem

a u mortality,
Fewer adverse

E S y
events

Freifeld AG, IDSA guidelines 2010 up date. CID 2011; ECIL-4 Guidelines. Haematol 2013.
 a r
ib
febrile cancer patients with neutropenia r
Beta-lactam monotherapy vs. beta-lactam+aminoglycoside

L
e r
I D ho
CM u t
S y a
E Paul M. Cochrane Database Syst Rev. 2013
 a r
ib
febrile cancer patients with neutropenia r
Beta-lactam+quinolones vs. beta-lactam+aminoglycoside

Outcome
L
e r RR(CI95%)

D ho
All cause mortality 0.85 (0.54-1.35)

M I
Clinical cure
Adverse events

t
Discontinuation
Nephrotoxicity
1.32 (1.00-1.74)

0.87 (0.57-1.32)
0.30 (0.16-0.59)

C a u
E S y
Bliziotis IA. Mayo Clin Proc. 2005
 a r
Empirical therapy election
ib r
L
e r
Local epidemiology
P. aeruginosa
Patients characteristics
• Opportunistic infections
S. mitis

I D ho
ESBL producer
Enterobacteriaeceae
• Prophylaxis and previous
therapy
• Previous colonization o MDR

CM
aureus
u t
Meticillin resistant S. infection
• Previous therapies

S y a • Toxicity, interaction allergies

E Focal signs and severity

 a r
ib r
L
e r
3 OPPORTUNITIES to optimize
antibiotic treatment

I D ho
CM
DIVERSIFY
u t SIMPLIFY SHORTEN

S y a
E
 a r
Diversifying the antimicrobial therapy

ib r
L
e r
1. Risk of Pseudomonas aeruginosa (neutropenia, steroids,
chemotherapy, antibiotics) mostly determine the election of

I D ho
antibiotic in the hematological unit.

M t
2. Several antibiotics can be used to treat this infection.

C u
a
3. However, the repeated use of the same antimicrobial can

E S y
lead to the development of resistance.
 a r
Risk factors for infection with MDR bacteria
ib r
L
• Patient’s prior colonization or infection by resistant pathogens, particularly:

e r
• ESBL or carbapenemase- producing Enterobacteriaceae
• Resistant non-fermenters: Acinetobacter baumannii, P. aeruginosa and Stenotrophomonas maltophilia.
• MRSA, especially with vancomycin MICs ≥2 mg/L.

I D ho
• Vancomycin-resistant enterococci.

• Previous exposure to broad-spectrum antibiotics, especially but not limited to 3rd

generation cephalosporins*.
•
•

CM u t
Serious illness (e.g. end-stage disease, sepsis, pneumonia).
Nosocomial infection.
•
•

S a
Prolonged hospital stay and/or repeated hospitalizations.
Urinary catheters.

y
E
• Older age.
• Intensive care unit stay.
F Averbuch. ECIL-4 Guidelines. Haematol 2013.
 a r
Diversifying the antimicrobial
therapy: A possible approach
ib r
L
e r
• 1. Use cefepime or piperacillin-tazobactam.

• Criteria for escalation approach:

D ho
• Noncomplicated illness.
•
•
•

M I No resistant bacterial colonization/infection.

Fever with low probabilty of infectious etiology (drugs, tumoral fever,..).

t
Low risk patients (myeloma, CLL, lymphoma).

u
:
• 2.

S
•
C
Select cefepime or piperacillin-tazobactam according to:

aLocal epidemiology.

y
• Associated signs or symptoms.

E
 a r
Diversifying the antimicrobial
therapy: A possible approach
ib r
L
e r
3. Use meropenem as first line therapy if:

I D ho
 Severely ill patients.

CM
GNB.
u t
 Fever and previous infection/colonization with resistant

S a
 Neutropenic patients with recent therapy with

y
E piperacillin-tazobactam and recurrent fever.
 a r
Situations in which combination with an aminoglycoside is
ib r
L
indicated as the first-line regimen (BIII)

e r
• 1. Seriously-ill patients.

D ho
• 2. If resistant non-fermenters (P. aeruginosa or Acinetobacter spp.) are likely,

M I
based upon:
• a. Local epidemiology.

t
b. Previous colonization or infection with these pathogens.

u
• c. Previous use (last month) of carbapenems.

S C a
E y
 a r
When should we include GP therapy?
ib r
•

•
L
No differences in mortality, breakthrough bacteremia or time to

e r
defervescence
As initial empirical therapy
•
•
I D ho
In patients with persistent fever (>72 h)

t
More adverse events (nephrotoxicity) and selection of resistant strains

CM
(S. aureus and Enterococcus spp)

u
S a
It is not recommended to routinely add glycopeptides (DI)

y
EFreifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.
 a r
When should we consider adding empirical therapy for GPC?
ib r
1. L
e r
Hemodynamic instability or other evidence of severe sepsis, septic shock or
pneumonia.
2.
3.
I D ho
Colonization with MRSA or VRE.
Suspicion of serious catheter-related infection.
4.

M u t
Skin or soft-tissue infection at any site in areas with high index of community
acquired MRSA.

C a
5. Severe mucositis in patients receiving quinolone prophylaxis or empirical

E S therapy with cephalosporins (risk of S. mitis fulminant sepsis).

y
Freifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.
 a r
ib r
e rL
3 OPPORTUNITIES to optimize
antibiotic treatment

I D h o
M SIMPLIFY
DIVERSIFY

C u t SHORTEN

S y a
E
 a r
Escalation and de-escalation approaches
Approach Escalation
strategies Estrategias
De-escalation
de
ib r
L
Select antibiotic active against non resistant
escalada/desescalada
GNB and P. aeruginosa

e r
Select antibiotic active against resistant GNB
and MDR P. aeruginosa
Modify therapy in case of clinical deterioration Simplify if resistant infection is not
or MDR isolation confirmed.

When

I-
-D ho
Uncomplicated presentation;
No known colonization/infection with
-
-
Complicated presentation
Colonization/infection with resistant bacteria.

CM -
t
resistant bacteria;
In centers where infections due to

u
resistant pathogens are rarely seen at the
- Centers where resistant bacteria are
frequently seen at the onset of febrile
neutropenia.

a
onset of febrile neutropenia.

Options

E S y
-Anti-pseudomonal cephalosporin
(cefepime,ceftazidime)AI
- Piperacillin-tazobactam AI
-Carbapenems (BII)
-antipseudomonal betalactam + aminoglycoside
(BIII) or quinolone
-Colistin + betalactam +/- rifampicin (BIII)
Averbuch. ECIL-4 Guidelines. Haematol 2013
 a r
Reassessment of antimicrobial therapy after 2-3 days.

ib r
L
• 1. Review of systems and repeat examination daily.

e r
• New sites of infection or localizing symptoms if neutrophil count recovers
• 2. Reassess empirical antibiotic therapy after 2-3 days

I D ho
• A. Documented clinical and/or microbiological infection:
• Implement de-escalation if etiology is available:

CM u t
• Simplify therapy according to the etiology and susceptibility of the isolate (AI).
• Choose the antibiotic with the narrower spectrum.

a
• Consult with an ID expert.

E S y
Freifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.
 a r
Reassessment of antimicrobial therapy in
febrile neutropenia
ib r
improvement.
•
L
B. No clinical or microbiological diagnoses but clinical

e r
We can simplify antimicrobial therapy

I D ho
• Discontinue after 48 hours
Aminoglycoside (AII)

CM u
•
t Vancomicyn (AII)
Choose a narrower spectrum betalactam (BIII)

S a
• If the wide spectrum antimicrobial therapy was used because of

y
severity, it might not be modified.

E Freifeld AG, IDSA guidelines. CID 2011; Averbuch. ECIL-4 Guidelines. Haematol 2013.
 a r
Reassessment of antimicrobial therapy
ib r
stable
L
• Unexplained persistent fever in a patient whose condition is otherwise

e r
• Rarely requires an empirical change to the initial antibiotic regimen (BII)
• Defervescence can take>5 days in hematology patients

I D ho
• Changes should be based on clinical changes o microbiological data.
• Do not add vancomycin if not indicated. (AI)

CM u t
• Continue the diagnostic workup :
• Reevaluate signs and symptoms
• Repete microbiological studies

S a
• Image tecniques

y
• Patients who remains hemodynamically unstable

E • 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.
 a r
febrile neutropenia, day +0
PIPERACILLIN/TZB + AMIKACIN
48-72h
ib r
L
e r
Microbiological
diagnosis
No microbiological
diagnosis
¿Stable?

D ho Yes No
Simplify to a narrower

M I spectrum antibiotic (AI)

t
¿Still fever? - Broaden spectrum
- Accelerate diagnosis

C a u - Continue diagnoses
Yes No
- Discontinue combination

S
therappy (BIII)
- Stop combination therapy

y
- Consider simplifying (BIII)
(BIII)

E - Considerar simplifying
(BIII)
Adaptad from 2011 ECIL Guidelines
- Consider discontinue
antibiotics after 72 hours of
defervescence (BII)
 a r
ib r
L
e r
3 OPPORTUNITIES to optimize
antibiotic treatment

I D hoSHORTEN
CM
DIVERSIFY
u t SIMPLIFY

S y a
E
 a r
ib r
L
e r
I D ho
CM u t
S y a
E Averbuch. ECIL-4 Guidelines. Haematol 2013.
 a r
ib r
L
e r
I D ho
CM u t
S y a
E Averbuch. ECIL-4 Guidelines. Haematol 2013.
 a r
•
Duration of antimicrobial therapy
ib r
L
Discontinuation of antibiotic therapy in the experimental group
after 72 hours of apirexia and disappearance of symptoms of

e r
infection independently of neutrophil cell count

D ho
EG (n=35) CG (n=45)

I
Variables P
Median (range) Median (range)

Days of neutropenia 19 (5-54) 14 (4-69) p= 0.05

M u t
PMN (*109/L) at discontinuation of

Antibiotic therapy

C
300 (0-9700) 1100 (0-13000) p<0.001

a
Duration of fever (days) 5 (1-18) 4 (1-28) p= 0.349

S
Episodes or recurrent fever 20% 24,4% p= 0.63

E y
Mortality

CT How Long EudraCT nº 2011-005152-34.

0 0
 a r
ib r
Sepsis in the severely immunosuppressed patient

L
e r
I D ho
febrile neutropenia in Sepsis in the solid

CM u t
hematology patients organ transplant
recipient (SOT)

S y a
E
 a r
Sepsis in SOT recipients
ib r
L
• Sepsis among the main causes of death among all types of organ

e r
transplants.
• Nosocomial infections: 18 times more frequent in solid organ transplant (SOT)

I D ho
recipients.
• Sepsis occurs in 20–60 % of all SOT recipients.
• Mortality ranges from 5–40 %.

CM u t
• Non classical clinical features:
• Absence of leukocytosis and fever.

S a
• More frequent organ failure.
• Hospital-acquired microorganism -> More MDR bacteria.

y
E
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
 a r
Nosocomial bloodstream infections
Transplant recipients vs. others ib r
L
e r
I D ho
CM u t
S y a
Crude mortality 34.5% vs. 40.5%

E Camargo Transplant Infect Dis 2015

 a r
Resistant bacteremia in SOTr
ib r
L
e r
19.6% episodes of bacteremia due to rESKAPE

I D ho
M
Risk factors:

u t
Prior transplantation,

C a
Septic shock

S
Prior antimicrobial therapy

E y Bodro Transplantation 2013

 a r
XDR P. aeruginosa bacteremia in SOT
ib r
L
e r
I D ho
CM u t
Risk factors:

S y a Prior transplantation,
Septic shock

E Hospital acquired

Bodro Transplantation 2015

 a r
Predisposing factors of bacterial sepsis
ib r
L
• CMV serology mismatch.

e r
• CMV disease.

I D ho
• Predisposes to higher rates of bacterial and fungal sepsis
• Prolonged duration of graft cold ischemia.

CM u t
• Prolonged duration of surgical transplantation procedure.
• Requirement of large amounts of blood transfusion.

S y a
E
 a r
Sepsis in SOT: Differential diagnosis
ib r
•
•
•
•
L
Allograft rejection

e r
Allograft thrombosis
Post-transplantation lymphoproliferative disease
Acute pancreatitis
•
•
•
D ho
Cytomegalovirus disease

I
Pulmonary embolism
Myocardial infarction
•
•
•
M t
Cerebral-vascular accident
Pulmonary calcinosis

C u
Bronchiolitis obliterans

a
• Intrathoracic hemorrhage

S
• Hypersensitivity drug reaction
• Acute respiratory distress syndrome
•
•

E y
Acute arterial or venous occlusion
Acute viral colitis
 a r
Septic shock in kidney transplant
recipients ib r
L
e r Other

I D ho
Abdominal
9%
14%

CM u t Urinary Respiratory
60%

a
17%

E S y Carvalho Plosone 2014

 a r
Source of sepsis in kidney transplant
recipients ib r
L
e r
• Urinary tract: most common site of infection.
• Respiratory source: similar to general population

I D ho
• Abdominal source: more frequent:
• Pericolic abscess Type of infection
UTI
Frequency
47%

t
Cistitis 33.5%

M
• Bowell perforation (elderly) Pyelonephritis 13%
CMV 22%
• Hepatic cysts infection

u
Surgical site 8%

C
infection
• Cholecystitis and pancreatitis Pneumonia 6%

a
Skin infection 4%

S
Acute 0.5%
gastroenteritis

E y
Garcia-Prado Enf Infec Microbiol Clin 2009 Kalil, Curr Infect Dis Rep 2015,
Koneru Arch Surg 1990, Andreoni Transplantation 1999. Dominguez Transplant Int 1998.
 a r
Urinary tract infections in SOT
ib r
L
e r
I D ho
CM u t
S y a
E Vidal Transplant Infect Dis 2012
 a r
UTI in kidney recipients
Predisposing factors ib r
L
e r
I D ho
CM u t
S y a
E
Vidal et al. GESITRA consensus document. EIMC 2015
 a r
UTI in kidney recipients
ib r
L
• It is crucial an adequate source control in septic patients

e r
• Abdominal ultrasounds should be routinely performed in all kidney
recipients with sepsis of urinary source

I D ho
• Rule out pyelonephritis, perinephric abscess, fungal balls, and ureteral
obstruction;

CM u t
• In case of negative ultrasound and non satisfactory clinical course
consider other techniques .

S a
• In cases of recurrent UTI consider:
• Ureteral reflux,

y
E• Uretero-vesicle junction strictures
• Neurogenic bladder
 a r
Sepsis and liver transplantation
ib r
L
• 30% of liver transplant in the first 3 months.

e r
• Most frequent -> intraabdominal:

I D ho
• Intra-extrahepatic abscess
• Secondary peritonitis

t
Type of infection Frequency

CM
• Cholangitis

u
• Surgical site infection
Surgical site
infection
CMV
UTI
16%

14%
11%

a
Bacteremia 10%
• Clostridium difficile colitis Cholangitis 8%

S
Pneumonia 7%
Liver abscess 6%

y
• Respiratory infections: Peritonitis 4%

E
CRB 2%

• First month
García-Prado EIMC 2009, Paya Mayo Clin Proc 1999, George Rev Infect Dis 1991
 a r
Biliary infections in liver transplant
recipients ib r
L
e r
• Lack of classic Charcot´s triade
• Frequently absence of fever, pain, jaundice.

D ho
• Must be suspected in case of fever without focal signs or symptoms together with CMV.

M I
• Process microbiological samples:
• Blood cultures.
• CMV RT-PCR.

t
u
• Others if symptoms: urine culture, respiratory samples, ….

C
• Image studies

a
• Frequently associated to:

S • Biliary strictures.

E y
• Intrahepatic abscesses
• Hepatic artery thrombosis (recurrent hepatic abscess)
 a r
Infected bilomas
ib r
L
• Frequency 10% of liver transplantation.

e r
• High morbidity: resource consumption, readmission, retransplantation
if associated to hepatic artery thrombosis.

I D ho
• Gram positive bacteria the most common, followed by Candida spp.,
Enterobaceriaceae and P. aeruginosa.

CM
• Treatment:
• Drainage.

u t
S a
• Antimicrobial therapy: generally prolonged (4-6 weeks).
• Caution: risk of MDR bacteria

y
E
 a r
Recurrent cholangitis
ib r
L
• Structural lesions of the biliary tree:

e r
• Bile leak.
• Anastomotic and non-anastomotic strictures.

I D ho
• Ampullary dysfunction.
• Consider ischaemic cholangiopathy in cardiac-death donor or hepatic artery

t
thrombosis.

CM
• Less frequent: recurrence of primary sclerosing cholangitis or secondary sclerosing

u
cholangitis.

S a
• Few information available despite its frequency
• Frequent broad spectrum antimicrobials-> Increased MDR infections.

y
E
deOliveira ML, Ann Surg 2011,Seehofer D. Am J Transplant 2013, Vrochides D.Transpl Infect Dis 2007
 a r
Hepatic artery thrombosis
ib r
L
• Poor perfusion of the bile ducts: strictures and leaks

e r
• Abscesses.

D ho
• Require multiple drainage.

M I
• Frequently need retransplantation.

t
C a u
Source control is a crucial part

E S
of the treatment if biliary or vascular changes
y
 a r
Treatment of MDR bacterial infection in
SOT ib r
L
e r
• Source control is critical Associated with survival.

D ho
• Catheter removal.

M I
• Wound debridement.
• Abscess, biliary tree, urinary tract drainage.

t
• Therapeutic options are expensive, toxic and of limited efficacy.

C u
• Explore combination therapies.

a
S
• Optimize PK/PD.

E y
Patel. Infect Control Hosp Epidemiol 2008, Cervera Clin Microbiol Infect 2014
Clancy Am J Transplant 2013
 a r
Ideas to take home
ib r
L
• Bacterial infection in severely immunosuppressed patients is a frequent

e r
request for the ID consultant.

D ho
• It requires a rapid diagnostic workup and prompt therapeutic

M I
recommendations.

t
• The attenuation of signs / symptoms of infection require an "aggressive”

u
diagnostic attitude.

S C
• The best diagnostic tool is the detailed history and daily detailed clinical examination.

a
• Wide differential diagnosis with non-infectious diseases.

E y
• The empirical approach should be early and directed to the most likely
etiology.
 a r
Ideas to take home
ib r
L
• In this setting MDR bacteria are an important challenge.

e r
• Antimicrobial stewardship is possible despite underlying illness.
• Diversify

D ho
• Select according to the severity, source of infection and local epidemiology

M I
• Limit broad spectrum treatment and especially carbapenems in first line to seriously ill
patients or at risk of infection with resistant bacteria

t
• Simplify whenever it is possible
• Reduce the duration of empirical treatments

C a u
• Persistent fever alone does not justify adding treatment against Gram-positive

E S
or antifungal treatment empirical

y
• Source control is crucial, especially in SOT recipients.