critical care conference 2017 - Dammam

1. Adel Hammodi MSc. Anesth. ,MRCP
Assistant Consultant Critical Care KFSH-D
Antifungal therapy
In Sepsis

2. -60-yr-old man with a history of difficult weaning
of ventilator after CAP, tracheostomy, had a fever up
to 39, BP 80/40 HR=110 with 10 days old SC CVP
No signs of inflammation around the CVP inlet site,
minimal sputum , clear urine . the blood culture
revealed Candida Glbrata
He was on pip-tazo , vanco , fluconazol empirically :
next step is
Remove central line and replace fluconazol with
echinocandin agent

3. a 55-yr-old woman with stab wound , laparotomy
done with small bowel resection and ileostomy
Post-op she had fever38.5 hypotension with CT
abdomen some collection  drained and showed
Ecoli and bacteroids which treated acc to C/S
Along her stay in ICU progressive AKI requiring dialysis .
on day 17 she developed fever , tachycardia and hypotension
,WBC of 18000, blood culture pending,G stain of urine and
sputum showed +2 yeast so after removal of lines what next
Antifungal (caspofungin)

4. 50 year old lady admitted to ICU day 10 after OLT of
post deceased graft, with marked hypotension and
tachycardia and mottled skin
Intubated – ventilated and high dose 3 vasopressors
initiated to maintain MAP around 65 mmHG ,
imipenem, colistin , vancomycin were started and all
her immunosuppresive drugs were put to hold.
Marginal improvement in the her vitals over following
24 hrs yet still requiring high vasopressors what
antimicrobial should be considered
 add antifungal – should be earlier

5. The importance of Antifungal
Stratify your patient
Antifungal Agents
The guidelines
The Successful Way

6. fungus
Yeast
Candida
Cryptococcus
Mold
Aspergillus
fusarium
Zygomycoses
Dimorphic
Histoplasma
Coccidiodes
blastomyces

7. Systemic candidiasis
Cryptococcal menegitis , endocarditis
Rhinocerebral mucormycosis
 aspergillosis
Blastomycosis , pneumonia
Histoplasmosis
Coccidiodomycosis
Pneumocytis Jiroveci pneumonia PCP

8. The importance of Antifungal
36%
16%13%
12%
23%
Bloodstream Organisms
GNS Enterococcus Staph. Aureus Fungi Others
Prevalence Nosocomial infections in intensive care units in the USA
Crit Care Med. 1999 May;27(5):853-4.
4th leading cause of
BSI
And
4th leading cause of
mortality in sepsis

9. C. glabrata
16%
C. albicans
54%
C. parapsilosis
15%
C. tropicalis
8%
C. krusei
2%
other Candida spp
5%
Species of Candida Most Commonly Isolated
in Bloodstream Infections
In an international surveillance study 1997-1998:
Snydman DR. 2003. Chest 123(Suppl 5):500S-503S). Garbino J. et al. 2002. Medicine;81:425-433.

10. Candida Non- Albicans
UK and NrthEU C dublinesis
C. Glabrata
JAPAN
C. Tropicalis
AUST
C. Parapsillosis
US.
C.Glabrata

11. • Mortality rates associated with invasive candidiasis
(IC) have been reported to be about 40% to 60% in
ICU patients .
• Reaching 80% to 90% in patients with septic shock
The importance of Antifungal

12. • Aspergillus infections are also common among critically
ill patients.
• Traditionally, was thought to be found in neutropenic and
transplant patients.
• However, currently it is an important pathogen in non-
neutropenic critically ill patients.
• With average mortality rates up to 60% to 90%.
The importance of Antifungal

13. • Not only the use of antifungal but also its Timing
• Comparing % of Hosp. Mortality after positive fungal culture against timing of antifungal initiated
The importance of Antifungal
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
< 12hr 12-24hr 24-48 hr > 48hr
percenthospital
mortality
Antifungal therapy timing

14. • Because of
• The fungal infection has
– Nonspecific Presentation
– And not limited to patients with
severe immunosuppression.
• Critically ill patients have
– dysfunctional monocytes,
macrophages,
– and impaired neutrophils
– that put them at risk of these
opportunistic pathogens
Stratify your patient

15. • - Chemotherapy – post transplant – steroid
• - Burn – diabetic – liver – renal - malnutrition
immunocompromised
• Suppurative lung disease – COPD
• Intubation and ventilation
Respiratory
Compromise
• CVP- Urine Cath. – peritoneal dialysis – RRT
cath.
• Total parenteral nutrition
Invasive procedures
• Fecal peritonitis - antibiotic use – debilitating
disease - pancreatitis
others

16. AMPHO-B
VORICONAZOL
AMPHO-B
MICAFUNGIN
CASPOFUNGIN
NYSTATIN
K -IODIDE
FLUCYTOCIN
ITRACONAZOLE
GRESIOFULVIN
KETOCONAZOLE
TERBINAFINE
Antifungal Agents

17. Antifungal Agents
Polyene group  amphotericin
Echinocandin group caspo/mica/anidulafungin
Triazole group  fluconazole , voriconazole/posaconazole
Antimetabolite  flucytosine

18. Fungal
cell

22. Echinocandin
Inhibits the Glucan
synthase enz. weak
cell wall collapse

23. cell membrane

24. Using Azole group inhibit the production of ergosterol

34.  Members of `group:fluconazole , voriconazole and
posaconazole
 the newer agents of this group have Expanded-spectrum ,
 fungiCidal activity against moulds,
 as well as enhanced activity Against Candida species .

39. 6mg/kg for 2 doses followed by 4mg/kg twice daily

41.  Conclusions :
Voriconazole is a suitable alternative to amphotericin B
preparations for empirical antifungal therapy in patients
with neutropenia and persistent fever.

42. CASPOFUNGIN
• DOSE 35-70 MG/DAY -
• hypotension ,low K – headache and GI – fever >26%
• Require dose adjustment in Hepatic disease
Micafungin
• Dose 100 mg/day
• neutropenia – low Mg /K
• minimal drug interaction – no adjustment
Anidulafungin
• Dose 200 mg first dose then 100 mg OD.
• Minimal interaction – no dose adjustment
Echinocandins
exhibit fungicidal activity against many fungal species

45. • In summary, caspofungin was as effective as
liposomal amphotericin B in patients with
persistent fever and neutropenia .
• better tolerated than liposomal amphotericin B.

46. Spectrum of activity
Fluconazole Voriconazole Flucytosine Ampho-B Echinocandin
C. Albicans S S S S S
C. Tropicalis S S S S S
C. Parapsillosis S S S S S/
C. Glabrata SR SR S SI S
C. Krusei R (Intrinsic) S R S>I S
C. Lusitaniae S S S S
Aspergillosis R S I SR S
Crytptococus S S S+ S
ZYGOMYCOSIS R R (S
Posaconazol)
I S (LIPID) R

47. Prophylaxis:
Reduces the rate
of colonization
and its conversion
to candidemia +/-
mortality
Preemptive
Piarrux 2004
proposed  to
decrease
incidence of
candidemia
Based on Candida
colonization index
Therapeutic
Either
empirical or
culture based

48. The guidelines

49. What Is the Treatment for Candidemia in Non-neutropenic
Patients?
 An echinocandin
daily blood cultures .
 Recommended duration 2 weeks after documented
cleared infection.
The guidelines
Should Central Venous Catheters Be Removed in Nonneutropenic
Patients With Candidemia?
Central venous catheters (CVCs) should be
removed as early as possible.

50. What Is the Treatment for Candidemia in Neutropenic
Patients?
• An echinocandin
• Lipid formulation AmB, 3–5 mg/kg daily, is an
effective but less attractive alternative because of
the potential for toxicity.
The guidelines

51. What Is the Role of Empiric Treatment for Invasive
Candidiasis in Non-neutropenic Patients in the
Intensive Care Unit?
• Empiric antifungal therapy should be considered
in critically ill patients with risk factors for invasive
Candidiasis
• Preferred empiric therapy is echinocandin
The guidelines

52. • What Is the Treatment for Intra-abdominal
Candidiasis?
• Empiric antifungal therapy should be considered
for patients with clinical evidence of intra-
abdominal infection and significant risk factors for
candidiasis, including recent abdominal surgery,
anastomotic leaks, or necrotizing pancreatitis .
• Source control with appropriate drainage is crucial
The guidelines

53. What Is the Treatment for Candida Intravascular
Infections, Including Endocarditis?
• Lipid formulation AmB, 3–5 mg/kg daily, with or
without flucytosine, 25 mg/kg 4 times daily,
OR
• High-dose echinocandin
The guidelines

54. What Is the Treatment for Central Nervous
System Candidiasis?
• Liposomal AmB, 5 mg/kg daily, with or
without oral flucytosine, 25 mg/kg 4 times
daily is recommended.
The guidelines

55. • Triazoles are preferred agents for treatment and prevention
of IA in most patients.
• Treatment of IPA for a minimum of 6–12 weeks is required
• Serial monitoring of serum GalactoM can be used in the
appropriate patient subpopulations (hematologic
malignancy, HSCT)
– to monitor disease progression
– and therapeutic response,
– and predict outcome

56. for CNS aspergillosis.
• Voriconazole is the primary therapy
• Lipid formulations of AmB are reserved for
those intolerant or refractory to voriconazole.

57. How to improve the success rate of
antifungal treatment ?Optimize the all factors
• Drug related
– Decrease time to
initiate therapy
– Optimal
drug/dose/duration
– Monitoring with or
without TDM
– Role of adjuvant eg
GCSF, interferon,
– Role of combination
• Patient related
– Reversal of risk
factors
– Source control

58. Combination therapy
• Use amphotericinB (AmB) plus fluconazole
• is as least as effective as higher dose (800 mg
daily) fluconazole given alone
• for patients with candidemia ,
• but there is little role for this combination in
current practice,
• especially as echinocandins are such a safe and
effective alternative.

59. Candida endocarditis
• Caspofungin has been used as monotherapy
and
• In combination with AmB, azoles, or
flucytosine
in
• single case reports, but data are limited for
the other echinocandins.

60. Invasive Aspergillosis (IA) 2016 IDSA
• Echinocandins are effective as salvage therapy in
combination with voriconazole against IA.
• Echinocandins in Combinations with polyenes or
azoles suggest additive or synergistic effects in
some preclinical studies.
• In vitro studies demonstrate that the combination
of triazole and polyene may be antagonistic

61. Take home message