bacterialinfectionsin severely immunosuppressed patients

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


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febrile neutropenia in

hematology patients

Sepsis in the solid

organ transplant

recipient (SOT)


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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).


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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.


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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.


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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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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)


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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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bacterialinfectionsin severely immunosuppressed patients

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