infections in cancer patients bloodstream infections

Infections in cancer patients

Bloodstream infections

Nosocomial infections

Needlestick injuries

Gabrielle Haeusler, Infectious Diseases Physician


• Understanding and defining risk

• Febrile neutropenia

• Fungal infections

• Viral infections

• New diagnostics

Multiple mechanisms for infection…IMMUNE SYSTEM

Disease, chemotherapy, corticosteroids and

radiotherapy all contribute to impaired immunity

which increases the overall risk of infection.

Prolonged corticosteroids and some

chemotherapy impairs cellular immunity which

risk of viral infections. GvHD can cause

hyposplenia or asplenia which risk of infection

with encapsulated bacteria.

NEUTROPHILSMyelosuppressive chemotherapy

causes a decrease in production of

red & white blood cells & platelets.

Neutropenia risk of bacterial and

fungal infections. Effects of

neutropenia are more severe if there

are other factors contributing to

impaired immunity.

AN

C (

10

9/L

)

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.07–14 days post chemotherapy*

Depth and duration of ANC nadir are dependent upon therapy, dose and route of administration

* On average 3 weeks post radiation, case dependent

Recovery period also dependent on regimen and patient status

Time post-therapy

Infection and neutrophil nadir

Bacterial infections associated with cellular/humoral abnormalities

Humoral abnormalitiesHyposplenism, GVHD, hypogammaglobulinaemia

• Encapsulated bacteria S pneumoniae, H influenzae, malaria, capnocytophaga

Cellular/lymphoid abnormalitiesCLL, multiple myeloma, Purine analogs (fludarabine), Campath (altemtuzimab),

corticosteroids, transplant,

• Nocardia• lung/brain/skin

• Bactrim, meropenem prolonged

• Listeria monocytogenes• meningoencephalitis/bacteraemia

• Ampicillin, bactrim prolonged

• Salmonella sp• GI/endocarditis/aortitis/osteomyelitis

• CTX/ciprofloxacin

• Legionella pneumophila• urine antigen, charcoal yeast agar (specific request), PCR, serology

>1:512

• Mycobacteria TB and atypical mycobacteria: • Incidence of TB in transplant recipients 20 -100x general population

Multiple mechanisms for infection…

MUCUS MEMBRANESChemotherapy induced oral

mucositis enables oral

pathogens (esp. streptococcus

viridans group) to enter the

blood stream

GI SYSTEMColitis enables gut pathogens (esp.

anaerobes, E. coli, P. aeruginosa,

Enterococcus spp. Candida spp. ) to

enter the blood stream.

Recent antibiotic use risk of

Clostridium difficile associated

diarrhoea and infections with

antibiotic-resistant bacteria SKIN

The skin acts as the first line of defense against infection.

Disruption of the skin from CVAD, IV or recent surgery risk of

localised or systemic infection with skin organisms (esp. S.

aureus and CoNS). Radiotherapy & GvHD also disrupts skin

IMMUNE SYSTEMDisease, chemotherapy, corticosteroids and

radiotherapy all contribute to impaired immunity

which increases the overall risk of infection.

Prolonged corticosteroids and some

chemotherapy impairs cellular immunity which

risk of viral infections. GvHD can cause

hyposplenia or asplenia which risk of infection

with encapsulated bacteria.

NEUTROPHILSMyelosuppressive chemotherapy

causes a decrease in production of

red & white blood cells & platelets.

Neutropenia risk of bacterial and

fungal infections. Effects of

neutropenia are more severe if there

are other factors contributing to

impaired immunity.

Causes of fever during neutropenia

Bacteraemia

MDI

CDI

Unexplained fever

Fever not related to infection

Hann et al. Br J Haematol. 1997

MDI – microbiologically

documented infection

CDI – clinically documented

infection


Bacteraemia

MDI

CDI

Fever of unknown

origin



Bacteraemia

• Gram-negative bacteraemia (esp. Pseudomonas aeruginosa) is

the most serious

• Adequate blood volume and number of blood culture samples

are essential (i.e. minimum of 2 prior to antibiotics & from all

lumens of central line)

• Anaerobic blood cultures should be taken if there are any

gastro-intestinal symptoms or severe mucositis


Bacteraemia

MDI

CDI

Fever of unknown

origin



Sandoval et al. Pediatr Hematol Oncol. 2012

Other microbiologically

documented infection

• Bacterial infections are the

most common, followed by

viral & fungal

• Investigate according to

patients symptoms (i.e. if

skin infection take adequate

bacterial and viral swabs)

• Asymptomatic urinary tract

infections occur in up to

10% of children with FN

and always require

treatment. Urine (mid

stream) MCS must be

done for all patients (do not

delay antibiotics for sample)


Bacteraemia

MDI

CDI

Unexplained fever



Clinically documented infection

• Requires a thorough clinical examination (i.e. don’t forget

mouth, skin, CVAD site & perineum/perianal area)

• Clinical signs may be absent in the setting of profound

neutropenia and immune suppression

• Reassess daily for any new symptoms or signs


Bacteraemia

MDI

CDI

Unexplained fever



Unexplained fever

• Diagnosis of exclusion (i.e.

ensure adequate BCs, urine

MCS +/-other investigations as

indicated)

• Severe sepsis can still occur in

the absence of a documented

infection


Bacteraemia

MDI

CDI

Unexplained fever




• Accounts for <5% of all FN

episodes

• Diagnosis of exclusion

• Causes include drug-fever (i.e.

chemotherapy such as

cytarabine), disease-related,

count recovery and blood-

transfusion reaction

Definitions

Various definitions for fever and neutropenia exist in the literature and

hospital guidelines. The impact of this variability on patient outcomes in

currently unknown.

• Fever is defined as a single temperature ≥ 38.5°C or a

sustained temperature ≥ 38.0°C over 1 hour

• Neutropenia is defined as an absolute neutrophil count < 500

cells/μL OR < 1000 cells/μL with predicted decline to < 500

cells/μL over the next 48 hours

• Neutropenia should be suspected in any oncology patient that

has received chemotherapy (oral or intravenous) within the

last 14 days

Fever during neutropenia is a medical emergency

WHY?

Delay in appropriate antibiotics = risk of poor

outcome

This retrospective study (n=1628) found that

children with FN who received 1st dose antibiotic

after 60 minutes were more likely to have a poor

outcome* compared to children who received 1st

dose antibiotic within 60 minutes.

*poor outcome defined as admission to ICU, fluid

resuscitation >40ml/kg in first 24 hrs or death

This prospective study (n=307) found that adults with FN who received 1st

dose antibiotic within 30 minutes had a lower 28-day mortality rate that

those who received 1st dose antibiotic between 30-60 minutes.

Although this study is in adult patients, it highlights the importance of early

antibiotics

Red Flags

Important Red Flags in the assessment and management

of children with fever and neutropenia include:

Sepsis

Profound neutropenia

Bodey et al. Ann Int Med. 1966

Red Flags - Sepsis

• Sepsis is a clinical syndrome that complicates severe infection

• Sepsis arises when the body’s response to an infection injures its own tissues and organs

• The sepsis cascade is progressive. It may lead to shock, multiple organ failure and death, especially if it is not recognised early.

• Children with cancer are at higher risk of sepsis during FN

SIRS SepsisSevere sepsis

Septic shock

Increasing morbidity & mortality

+ infection

Red Flags - Sepsis

Goldstein B et al. Crit Care Med. 2005; 6: 2-8

CEC, Sepsis Kills Program, 2014

RECOGNISE - Signs of sepsis in children include fever (>38°C) or

hypothermia (<36°C), tachycardia, prolonged capillary refill (>3

seconds), tachypnoea +/-hypoxia (O2 saturations <92%) , altered

conscious state, and unwell appearance. Hypotension is a late sign

as children can maintain their blood pressure by vasoconstriction

and increased heart rate.

A blood lactate level > 2mmol/L is a warning sign of severe sepsis

and a level >4mmol/L is a sign of severe illness.

Red Flags - Sepsis

CEC NSW, Sepsis Kills Program, 2014

RESUSCITATE – With rapid IV antibiotics (addressed later in this

module) and IV fluids within thirty minutes.

For patients with sepsis an initial 20ml/kg bolus of Normal Saline should be

given as a push over a maximum of 10 minutes (not through an infusion

pump). Monitor for response and if only transient improvement occurs

consider additional boluses to a maximum total volume of 40ml/kg. Total

volumes >40ml/kg should be discussed with senior clinician and inotropes

considered.

Red Flags - Sepsis

CEC NSW, Sepsis Kills Program, 2014

REFER – To specialist paediatric care and initiate retrieval if needed.

Contact the patients oncologist or haematologist at their primary

treatment centre after sepsis resuscitation (i.e. IV antibiotics and IV fluid)

has been commenced and the patient is clinically stable. For patients

presenting to hospitals other than their primary treatment centre

(including regional centres), contact the local paediatric team first.

Red Flags - Sepsis

Untreated severe sepsis and/or septic shock increases the risk of death

Oliveria et al. Pediatr Emerg Care. 2008

VOLUME OF FLUID

In a retrospective study of

children with severe sepsis

(n=90) the mortality rate was

higher for those who received

less than 40 mL/kg fluid within

the first hour

Red Flags - Sepsis

Untreated severe sepsis and/or septic shock increases the risk of death

Oliveria et al. Pediatr Emerg Care. 2008

TIMING OF FLUID

The mortality rate was also

higher for those children with

severe sepsis whose fluid

therapy was not initiated in the

first 30 minutes of diagnosis

Red Flags – Profound neutropenia

Profound neutropenia is defined as an absolute neutrophil count

< 100 cells/μL for more than 7 days

Children most likely to have profound neutropenia include those

receiving high-dose intensive chemotherapy (AML, HSCT, ALL

induction)

The duration and depth of neutropenia increases the risk of severe

infection. Examples of severe infection include bacteraemia or invasive

fungal infection

Because of the risk of severe infection, children with profound

neutropenia may be admitted to hospital for close observation

Red Flags – Profound neutropenia

The duration and depth of neutropenia increases the risk of severe

infection

Bodey et al. Ann Int Med. 1966

After 1 week the risk of

severe infection is:

>30% if N < 1000 cells/μL

>40% if N < 100 cells/μL

After 3 weeks the risk of

severe infection is approx:

80% if N remain < 100

cells/μL

Management of fever and suspected or

confirmed neutropenia

The 1st hour…

See ‘Fever and suspected or confirmed

neutropenia’

at www.rch.org.au/clinicalguide

6 0

min

ute

s

Empiric antibiotics for children with FN

• Cover Gram-negative organisms in all patients as well as viridans group

streptococci and Pseudomonas aeruginosa in high-risk patients

• Factors influencing choice - patient characteristics, clinical presentation, local

infrastructure to support different models of care, drug availability and local

epidemiology (including resistance patterns)

• Monotherapy (compared to combination therapy with an aminoglycoside) has

been shown to be safe and effective in all patients with FN

• Specific monotherapy* regimens that are recommended in children include

antipseudomonal penicillins (such as piperacillin-tazobactam) and

antipseudomonal cephalosporins (such as cefepime and ceftazidime)

*Monotherapy may not be appropriate in centres with high rates of antibiotic

resistance. In this situation combination with an aminoglycoside may be required

Lehrnbecher et al. J Clin Oncol. 2012; 30: 4427-38

Which antibiotics?

No beta-lactam hypersensitivity:

• Piperacillin-tazobactam is recommended for all patients

• If septic, inpatient onset FN or on high-risk treatment protocol

ADD amikacin*

• If suspected or proven resistant Gram-positive infection** ADD

vancomycin

*Centres may choose alternate aminoglycoside (i.e. gentamicin) depending on local

susceptibility data

**Including patients with cellulitis, obviously infected vascular devices, proven Gram-positive

bacteraemia, and known MRSA colonisation and extensive skin breaks

Which antibiotics?Non life-threatening beta-lactam hypersensitivity:

• Replace piperacillin-tazobactam with cefepime OR ceftazidime*


ADD amikacin***ceftazidime has reduced activity against viridans group streptococci. Avoid if extensive

mucositis, recent high dose methotrexate or cytarabine or ciprofloxacin prophylaxis

**Centres may choose alternate aminoglycoside (i.e. gentamicin) depending on local

susceptibility data

Life-threatening beta-lactam hypersensitivity:

• Replace piperacillin-tazobactam with ciprofloxacin AND

vancomycin


ADD amikacin**

Beyond the 1st 24 hours…

Modifying antibiotics

Stopping antibiotics

Investigating prolonged or recurrent FN

Management of fever and suspected or confirmed neutropenia

Modifying antibiotics

After 24-48 hours, discontinue amikacin and/or vancomycin (if initiated)

UNLESS:

• Patient is clinically unstable.

• An antibiotic resistant organism has been identified that requires

amikacin or vancomycin

Do not broaden initial empiric antibiotic regimen based solely on

persistent fever in children who are clinically stable

Stopping antibiotics

Appropriate cessation of antibiotics is important to minimise unnecessary exposure, avoid toxicities and reduce the risk of antibiotic resistance. Cessation of antibiotics depends on marrow recovery and risk status.

Evidence of marrow recovery:

• Discontinue empiric antibiotics in all patients who have negative blood cultures (+/-other cultures) at 48 hours and who have been afebrile for at least 24 hours

No evidence of marrow recovery:

• Neutropenia expected to be < 7 days (ie. low risk patients) – Consider cessation of antibiotics at 72 hours if (i) cultures are negative, (ii) patient is afebrile >24 hours AND (iii) careful follow up (inc. daily review) is planned

• Neutropenia expected to be prolonged (ie. high risk patients) – The optimal duration is unknown. Cessation may be considered after 7-14 days if (i) cultures are negative, (ii) the patient is afebrile >24 hours; (iii) skin and mucous membranes are intact AND (iv) there are no impending invasive procedures or ablative chemotherapy planned.

All treatment modifications, including cessation of antibiotics, should be discussed with the patient’s primary oncology team

• Mechanisms of action

• Indications for use

• Risk factors for resistance

• Dosing and therapeutic drug monitoring

• Toxicity

• Evidence for use in febrile neutropenia

• Recommendations

Vancomycin and FN

• Glycopeptide antibiotic

• Binds irreversibly to cell wall, inhibiting synthesis and leading to cell lysis

• Bactericidal against most Gram positive bacteria• Bacteriostatic against Enterococcus spp.

• Gram positive organisms with inherent resistance:• Enterococcus spp. with vanC gene ie E. gallinarum and E. casseliflavus

• Other – Leuconostoc spp. Pedicoccus spp. and Lactobacillus spp.

• Gram positive organisms with acquired resistance:• Enterococcus spp.

• VRE with vanA gene (Teic R) or vanB gene (Teic S) [described in 1985]

• Staphylococcus aureus

• VISA [described in 1995]

• VRSA [described in 2002]

Vancomycin – Facts

Risk factors VISA:

- Low serum vancomycin levels (< 10 mg/L)- ? plasma mediated transfer from VRE- VRE and VISA/VRSA co-infection described

Risk factors VRE:

- Prolonged hospitalisation- Chronic medical illness- Vancomycin & 3rd generation cephalosporin use

• AUC/MIC correlates with treatment success

• Increased risk treatment failure when MIC > 1 ug/ml

• Trough recommendation in adults (and children):

• 15-20 mg/L for complicated infections including bacteraemia, endocarditis, osteomyelitis, meningitis and MRSA HAP

• 10-15 mg/L for all other infections

• Serum trough concentrations < 10 mg/L are associated with:

• Vancomycin resistance including hVISA, VISA and VRSA

• Treatment failureRybak et al. IDSA guidelines. 2009; 66: 82-98

Vancomycin – Drug levels

• Vancomycin has a shorter t 1/2, increased clearance and lower trough concentration c/w children without malignancy• Most studies excluded patients with significant renal impairment

• Prospective case control study (n=64)

• Children with malignancy: 71.5 mg/kg/d (±13.9) for trough 6.84 mg/l (± 2.78)

• Controls: 50.3 13 mg/kg/d (±13) for trough 8.05 mg/l (±3.01)

• Retrospective case control study found similar results in HSCT recipients

Krivoy et al. Ped Hematol Onc. 1998; 15: 333-338

Chang D. et al. PIDJ. 1994; 13: 969-47

Chang D. PIDJ. 1995; 14: 667-73

Piro et al. J Pediatr Hematol Oncol. 2009 31; 3-7

Vancomycin – Dosing in malignancy

No clear relationship between serum levels and ototoxicity or nephrotoxicity

• Ototoxicity:

• Available data does not support vancomycin induced ototoxicity

• Most reports of tinnitus and/or deafness include patients that have also received aminoglycosides

• Nephrotoxicity:

• Conflicting data re risk of renal impairment with vancomycin therapy

• True incidence of nephrotoxicity of vancomycin monotherapy is low

• Most available data suggest a 3- to 4- fold increase in nephrotoxicity when aminoglycosides are combined with vancomycin

Vancomycin – Toxicity

- n=165

- Vancomycin or placebo introduced after 48-60 h of

Tazocin monotherapy in persistently febrile patients

The empiric addition of vancomycin in

persistent fever in DOES NOT reduce

time to defervescence or improve

outcome

Cometta et al. Clin Infect Dis. 2003; 37: 382-9

Excluded patients with septic shock, catheter related

infection, lung infiltrates, infection with tazocin

resistant Gram positive bacteria

• No increase in treatment failure

• No increase in duration of fever

• No increase in morbidity

• Retrospective review of 550 FN episodes (321 children)

• Vancomycin commenced after G+ organism identified in 39/75 (overall vancomycin used to treat 43/75)

• No mortality secondary to G+ infection

• Failure to eradicate Enterococcus spp. in 1 pt at 48h (improved with ampicillin+gent)

• RCT of 747 FN episodes (? number children)

• Ceftazadime/amikacin (G+ 68) versus ceftazidime/amikacin + vancomycin (G+ 67)

• No difference in duration of fever

• No mortality in 1st 3 daysRubin and Pizzo et al. Annal Internal Med. 1988; 108: 30-35

EORCT. J. Infect Dis 1991; 163: 951

Gram-positive directed therapy

Indications for vancomycin

1. Proven Gram positive bacteraemia

• Vancomycin should be ceased if susceptibilities indicate an alternative agent can be used

2. Catheter related infection including:

• Onset of fever and/or sepsis directly related to CVAD access

• Exit site infection

• Tunnel infection (NB treatment failure common)

3. Severe sepsis / septic shock

4. Known MRSA colonisation

Prolonged or recurrent fever

• Prolonged neutropenia is an important risk factor for invasive fungal infections

• Children with prolonged fever (>72-96 hours) OR recurrent fever despite

broad spectrum antibiotics should be evaluated for IFI and empiric treatment

considered

• Risk of IFI is modified by antifungal prophylaxis (type, dose, frequency, levels,

compliance)

• Patients considered high-risk for IFI include those with (i) relapsed acute

leukemia; (ii) AML; (iii) Graft versus Host Disease (GvHD); (iv) allogeneic

stem cell transplant; (v) severe aplastic anaemia; (vi) prolonged corticosteroid

use and (vii) prolonged ICU admission.

• All other patients should be categorised as low-risk for IFI (note that low-risk

does not equal no-risk)

Regional centres should consider transferring patients with prolonged or

recurrent fever to their primary treatment centre for further investigations

• CT of lungs and CT sinuses (age >2y) and targeted imaging of

other clinically suspected areas of infection

• Bronchoscopy and lavage (BAL) if pulmonary infiltrates

detected on CT lungs (consult micro and ID to ensure

appropriate Ix are performed)

• Fungal cultures from blood, BAL and other sterile sites as

indicated

• Galactomannan (+/- aspergillus PCR if available) on blood and

BAL fluid

• GM (antigen in cell wall of Aspergillus spp. Penicillium and

Alternaria spp)

• The combined Se and Sp from paediatric studies is 0.76 (95% CI, 0.62

to 0.87) and 0.86 (95% CI, 0.68 to 0.95)

Prolonged or recurrent fever – Ix

Lehrnbecher et al. J Clin Oncol. 2012; 30: 4427-38

• Proven – Fungal elements in biopsy of tissue with corresponding tissue damage OR mold or yeast cultured from sterile site (exc. BAL, sinus, urine)

• Probable – Host factors + radiology + mycological criteria (mold or yeast cultured from non-sterile site OR indirect tests inc. GM)

• Possible – Host factors + radiology in absence of mycological criteria

De Peuw, EORTC, CID. 2008; 48: 1813-21

Prolonged or recurrent fever – Dx IFI

LRT Ix in cancer patients

Localised vs. diffuse

• Non-neutropenic (similar to that of immunocompetent child)

• Bacterial > viral or fungal

• Atypical bacteria inc Legionella

• Dx – culture on charcoal yeast agar (let lab know); urinary antigen (specific for Legionella pneumophilia type 1 only (80% illnesses)

• Neutropenic



• Non-neutropenic (similar to that of immunocompetent child)

• Bacterial > viral or fungal

• Atypical bacteria inc Legionella

• Dx – culture on charcoal yeast agar (let lab know); urinary antigen (specific for Legionella pneumophilia type 1 only (80% illnesses)

• Neutropenic• Early – Bacterial

• Late –fungal +/- viral

• 2ndary causes - angioinvasion, thrombosis, infarction and haemorrhage

• CT – changes suggestive of fungal infection include nodules (ddx. Nocardia, malignancy); halo sign (early); air crescent sign (late); cavitation (late)



• Non-infectious

• Anti-neoplastic agents – bleomycin, cyclophosphamide, methotrexate

• Neoplastic process

• Radiotherapy

• Infectious

• Viral – Herpes viruses (CMV, VZV, HSV, HHV-6), Influenza, AV, RSV

• Dx – IF or PCR (NB can have prolonged shedding)

• Rx – role for antivirals

• Atypical pneumonia – Mycoplasma pneumoniae or Chlamydia pneumoniae

• Rx - macrolide

• Other – PCP

• Sx - fever, non-productive cough, tachypnoea, dypnoea, hypoxaemia;

• Ix - CXR diffuse infiltrate (localised infiltrate or effusion is rare)

• Rx - Bactrim

Herpes viruses

• 3 Subfamilies

• Alphaherpesvirus: HSV-1, HSV-2, Varicella zoster (VZV)

• Betaherpesvirus: CMV, HHV-6, HHV-7

• Gammaherpesvirus: EBV,HHV-8

• Ubiquitous up to 80% population

• Latent in PBMC, macrophages, salivary glands,

nasopharynx, nerve ganglia

• Reactivation with defects cell mediated immunity

• accompanied by viral shedding

Herpes viruses: Infection versus disease

• Asymptomatic infection – active viral replication in the blood (detected by PCR) in the absence of clinical manifestations or organ failure abnormalities. Diagnosis by PCR in blood or serum

• Disease - infection with clinical symptoms or organ function abnormalities. Diagnosed by PCR in blood or serum PLUS evidence of end organ damage. Disease is ‘proven’ if biopsy shows typical changes of infection – ie. inclusion bodies for CMV

• Syndrome – some herpes viruses present with a typical syndrome (see next slide) that should prompt investigation of disease

• Greatest risk for serious disease is post allogeneic transplant – see next slide for timing of reactivations

Herpes viruses: syndromes & disease

• HSV:• Disease: mucositis, oesophagitis, hepatitis, pneumonitis, hemocytophagic,

encephalitis

• CMV:• Typical syndrome: fever, neutropenia, hepatitis

• Disease: hepatitis, colitis, encephalitis, pneumonitis, retinitis,

• Other associations: rejection, GvHD, invasive fungal infection (CMV often a marker of underlying immune deficiency – diagnosis of CMV should prompt search for other opportunistic infections such as PJP

• VZV:• Disease: disseminated zoster, retinitis, encephalitis

• EBV:• Disease: post transplant lymphoproliferative syndrome, NPC

• HHV 6• Syndrome: fever, rash, reversal of sleep/wake cycle

• Disease: encephalitis, neutropenia, fever, rash

• HHV 8• Disease: Kaposi’s sarcoma, Castleman’s disease,

CDC Recommendations Prevention of infection among HSCT recipients 2000

HHV-6

Herpes viruses: syndromes & disease

• HSV:• Disease: mucositis, oesophagitis, hepatitis, pneumonitis, hemocytophagic,

encephalitis

• CMV:• Typical syndrome: fever, neutropenia, hepatitis

• Disease: hepatitis, colitis, encephalitis, pneumonitis, retinitis,

• Other associations: rejection, GvHD, invasive fungal infection (CMV often a marker of underlying immune deficiency – diagnosis of CMV should prompt search for other opportunistic infections such as PJP

• VZV:• Disease: disseminated zoster, retinitis, encephalitis

• EBV:• Disease: post transplant lymphoproliferative syndrome, NPC

• HHV 6• Syndrome: fever, rash, reversal of sleep/wake cycle

• Disease: encephalitis, neutropenia, fever, rash

• HHV 8• Disease: Kaposi’s sarcoma, Castleman’s disease,

Herpes viruses: DiagnosisViral culture not readily available (useful to test antiviral resistance)

Histology tissue inclusions:• gold std demonstrating active disease rather than latent infection

Antigen detection: • CMV pp65Ag blood less sensitive than molecular detection (ie PCR) for detection of

active infection

Molecular detection:• Blood or serum PCR (quantitative assays available for most) = HSV1, HSV2, CMV,

VZV, HHV-6• preferred method for HSV and VZV - vesicle, CSF

CMV PCR: • blood, CSF, tissue• Qualitative DNA or RNA assays (+ or neg) • Quantitative viral load - High levels associated with higher risk of active infection

therefore VL may guide preemptive treatment

Serology:• Nonspecific and unreliable in immunocompromised patients especially CMV• Pre- transplant screening may be useful

1st line treatments for herpes virus disease

Treatments used for cancer patients

• HSV and VZV – acyclovir (requires infected cell to produce thymidine kinase to activate acyclovir)

• CMV – ganciclovir (GCV)• Resistance mutations - Monitoring CMV load is a useful approach for assessing the likelihood of drug

resistance. Markers suggestive of CMV resistance include a rising viral load, rebounding viral load, and a persistently elevated viral load in the setting of antiviral therapy.

• (i) UL97 phosphotransferase mutations, which confer resistance to ganciclovir – treat with high dose GCV or foscarnet

• (ii) UL54 DNA polymerase mutations (occur as second-step mutations in patients who already have a UL97 mutation) and confers high level GCV resistance. Treat with foscarnet, cidofovir or combination

• HHV-6 – ganciclovir (foscarnet 2nd line). HHV-6 infected cells do not produce TK therefore acyclovir is not active)

• EBV – antiviral treatment rarely useful. Need to reduce immunosuppression. Role for rituximab for post transplant lymphoproloferative disease

• For up to date summaries of diagnosis and treatment of herpes viruses in cancer patients see guidelines by the European Conference in Infections in Leukaemia (ECIL) - http://www.kobe.fr/ecil/publications.htm

http://www.kobe.fr/ecil/publications.htm


• Understanding and defining risk ✔

• Febrile neutropenia ✔

• Fungal infections ✔

• Viral infections ✔

• New diagnostics - PET

Positron emission tomography (PET)

• Radio-isotope: 18F-FluoroDeoxyGlucose (FDG)

• Glucose analogue

• Actively transported into cells via GLUT

Malignant cells


• Radio-isotope: 18F-FluoroDeoxyGlucose (FDG)

• Glucose analogue

• Actively transported into cells via GLUT

• FDG-PET:

• Functional plus semi-quantitative image

• FDG-PET/CT:

• As above plus more precise anatomical information

• Effective radiation dose: 13 to 30 mSv

• Background radiation: 2.4 mSv per yr

• AP and lateral CXR: 0.1 mSv

Bingsheng et al. Radiology. 2009; 25: 166-174


Use in malignancy:

• False positive

• Infection

• Inflammation

• Other – brown fat, thymic tissue, brain, heart

• False negative

• Tumours with slow growth and low metabolism –

carcinoid tumours, well differentiated adenoca

• Small tumours <7mm

• Hyperglycaemia

Role of FDG-PET in infection

Diagnostic tool:

•Pyrexia of unknown origin

•Prolonged fever and neutropenia

•Chronic osteomyelitis

•Infected prostheses

•Complicated diabetic foot infections

•Vascular infections

Impact on antimicrobial use

Monitoring response to treatment

Pyrexia of Unknown Origin

• Meta-analysis of FDG-PET and FDG-PET/CT for the Ix of PUO

• FDG-PET

• 5 studies involving 214 adult patients

• FDG-PET abnormal in 55% and 32.2% contributed to the final diagnosis

Dong et al. Eur J Radiology. 2011; 80: 834-44

Pyrexia of Unknown Origin

• Meta-analysis of FDG-PET and FDG-PET/CT for the Ix of PUO

• FDG-PET +CT

• 4 studies involving 117 adult patients

• FDG-PET abnormal in 67.2% and 62.1% contributed to the final diagnosis

Dong et al. Eur J Radiology. 2011; 80: 834-44

PUO: FDG-PET vs leucocyte scintigraphy

• Prospective study of non-IC patients with PUO (n= 23)

• 111In-labelled LS plus FDG-PET within 7 days

• Abnormal uptake: FDG-PET 14 (61%) and LS 3 (13%)

• Advantages of FDG-PET over LS:

• Higher sensitivity (although less specific)

• Semi-quantitative

• Less preparation and results available within 1h v 24h

• Not affected by leukopeniaSeshadri et al. J Infect. 2012; 1-9

Prolonged fever and neutropenia

• Prospective study at PMCC of FDG-PET/CT for evaluation of D+5 fever despite antibiotics (n=20)

• 16 (80%) positive scans:

• Sensitivity 92.9% compared to conventional Ix (1 URTI not found)

• Located 9 additional sites of infection

• Contributed to the management of 15/20 (75%) pts, inc:

• Altered antimicrobial therapy in 9 pts

• Prolonged Ab for liver abscess 1

• Antifungal commenced 1

• Other directed therapy 2

• Antifungal withheld 5

Guy et al. Eur J Nuc Med Mol Imag. 2012; 39: 1348-55

Prolonged fever and neutropenia

• Prospective study at PMCC of FDG-PET/CT for evaluation of D+5 fever despite antibiotics (n=20)

• 16 (80%) positive scans:

• Sensitivity 92.9% compared to conventional Ix (1 URTI not found)

• Located 9 additional sites of infection not found on conventional Ix

• Contributed to the management of 15/20 (75%) pts, inc:

• Altered antimicrobial therapy in 9 pts

• Prolonged Ab for liver abscess 1

• Antifungal commenced 1

• Other directed therapy 2

• Antifungal withheld 5

Guy et al. Eur J Nuc Med Mol Imag. 2012; 39: 1348-55

Children

• PUO or unexplained fever (n=69)

• Dx established in 53% of cases and FDG-PET +/-CT

contributed to diagnosis in 73%

• CT improved the sensitivity (100%) and PPV (82.4%)

• PUO pre liver transplant (n=11)

• Increased FDG-PET uptake in liver in 5 pts

• Transplanted despite fever (1 death due to graft failure)

• No increased FDG-PET uptake in liver in 6 pts

• Targeted antibiotics and transplanted when afebrile

• Case reports of use in dx PUO in neonatesJasper et al. Eur J Nucl Med Mol Imaging. 2010; 37: 136-145

Sturm et al. Liver Trans. 2006; 12: 1698-1704

FDG-PET and antimicrobial use

Retrospective case control study at PMCC

• Compared antimicrobial usage following FDG-PET/CT (n=37) vs conventional imaging (n=76) for high risk FN

• Cases matched according to malignancy, duration FN, time of admission

• FDG-PET/CT had a significant impact on:

• Antimicrobial utilisation (35.1% vs 11.8%, p=0.003)

• Duration of amphotericin B (median 4.0 days vs 10 days; p=0.001)

• Equated to cost savings of AUD 7,440 – 14,455 per pt

(cost of FDG-PET/CT approx AUD 1,000 per scan)

Koh et al. Leuk Lymphoma 2012

Summary

• Fever and suspected of confirmed neutropenia is a medical emergency

• A severe infection occurs in >40% of patients with profound neutropenia

lasting more than 1 week

• Antibiotics within 60 minutes improves outcome in patients with FN

• Early and appropriate fluid resuscitation (ie. 20ml/kg normal saline bolus)

improves outcome in children with severe sepsis

• Antibiotics should NOT be delayed while awaiting neutrophil count or to

contact the oncology unit

• Indication for vancomycin include proven G+ infection, known MRSA

colonisation, suspective or proven CVAD associated infection and severe

sepsis/septic shock

BLOODSTREAM INFECTIONS

Blood cultures

• Culture of blood is the most sensitive method for the detection

of bacteraemia of fungaemia

• An adequate number of blood cultures (BC) and volume of

blood improves the sensitivity:

• Number – At least 2 sets of BC from separate sites should be taken

before antibiotics (note – BC taken from 2 lumens of a CVAD are

considered ‘separate sites’)

• Volume – The volume of blood required depends on the age of the

patient and type of BC bottles used. Too little blood will not detect low

levels of circulating bacteria and an excess volume relative broth will

also decrease the sensitivity

• Yellow is paediatric aerobic (0.5-4 mL)

• Green is adult aerobic (5-10 mL)

• Both contain the same culture media in

different volumes

• Orange is anaerobic (5-10 mL)

• G+ Actinomyces, Clostridium, Peptostreptococcus

• G- Bacteroides, Fusobacterium, Prevotella

• An excess volume, relative to broth,

decreases the sensitivity of BC results

Blood cultures

Take if suspected anaerobic infections – oral/GI or intra-

abdominal focus, necrotic lesions, gaseous lesions

Number of blood cultures

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 BC 2 BC 3 BC 4 BC

Number BC in 24hrs

Washington 1975 Weinstein 1983 Cockerill 2004 Lee 2007

Connell et al. Pediatrics 2007

35% adequate volume 64% adequate volume

BC +Adequate vol. 5.2%

Inadequate vol. 2.1%

S. aureus bacteraemia (SAB)

• Treatment – 2 weeks uncomplicated and 4-6 weeks if

complicated SAB

• S. aureus in urine is a sign of staphylococcal bacteraemia

until proven otherwise

• Never underestimate a SAB – look for sites of seeding

• S. aureus meningitis without preceding CNS

instrumentation indicates the presence of endocarditis

until proven otherwise

Catheter related BSI

• Culture of the catheter tip (line removal)

• Quantitative blood cultures

• Differential time to positivity (DTP) of blood cultures drawn

from different sites

• Limitations – identical blood volume, simultaneous culture and

continuously monitored blood culture system is needed

• In pediatric oncology pts - a DTP of ≥150 minutes had a Sp of

100% and Se of 89% for CRBSI. For cultures from both lumens

of a double-lumen catheter, a DTP of ≥180 minutes had a

specificity of 94% and sensitivity of 61%

Wolf, PIDJ, 2013. 32:905-910

Catheter related BSI

• Look for complications - tunnel or port pocket, endovascular

and metastatic

• Treatment – line removal v’s salvage (25% failure rate).

• Salvage – systemic Ab +/- lock therapy

• Failures due to biofilm, intermittent Ab exposure

• Indications for removal:

• Relapse of CLABSI with an identical organism

• Infection with mycobacteria (relapse rate 70%), fungi such as Candida spp.

(relapse rate 70%), S. aureus (relapse rate 50%), Bacillus cereus and

some multiresistant bacteria

Wolf, PIDJ, 2013. 32:905-910

infections in cancer patients bloodstream infections

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