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AMPHOTERICIN B NEPHROTOXICITY . GILBERT DERAY PARIS , FRANCE. * Amphotericin B (AmB) remains the most effective drug in treating systemic fungal infections. * Amphotericin B can produce a wide variety of acute and chronic side effects, the most important of which is nephrotoxicity .

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slide1

AMPHOTERICIN B NEPHROTOXICITY

GILBERT DERAY

PARIS , FRANCE

slide2

*Amphotericin B (AmB) remains the most effective drug in treating systemic fungal infections

*Amphotericin B can produce a wide variety of acute and chronic side effects, the most important of which is nephrotoxicity

slide3

INCIDENCE OF AMPHOTERICIN B NEPHROTOXICITY

Authors Rate of nephrotoxicity

1998 White 64 %

1999 Walsh 49 %

1999 Wingard 53 %

slide4

RATE AND SEVERITY OF NEPHROTOXICITY AND HEMODIALYSIS IN PATIENTS TREATED WITH AMPHOTERICIN

Creatinine values Dialysis required

(% patients) (% patients)

Doubled Increased to

> 2.5 mg/dl

53 % 29 % 15 %

Wingard et al, J Clin Inf Dis, 1999

pharmacoeconomics of hospital costs according to amphotericin b renal toxicity
PHARMACOECONOMICS OF HOSPITAL COSTS ACCORDING TO AMPHOTERICIN B RENAL TOXICITY

Greenberg et al ,ICAAC,2000

the effects of acute renal failure on mortality
THE EFFECTS OF ACUTE RENAL FAILURE ON MORTALITY

Odds ratio of dying = 3.09

80

76 %

Mortality

(%patients)

*

70

57 %

* p < 0.05

vs NO

60

50

40

0

Hemodialysis

Wingard JR, Clin Infect Dis, 1999

amphotericin b nephrotoxicity
AMPHOTERICIN B NEPHROTOXICITY

IS

* Frequent

* Severe

* Associated with an increase in hospital costs

* Associated with an increase in the risk of death

Therefore we must

If possible, prevent Amphotericin B nephrotoxicity.

slide8

Prevention of Amphotericin B nephrotoxicity

* Intralipid

* Risk factors

* Early detection of renal toxicity

* New formulations

amphotericin b and intralipid
AMPHOTERICIN B AND INTRALIPID

* We lower the price but...

* Do we lower the renal toxicity ?

*And even so should we do it ?

slide10

PROSPECTIVE TRIALS COMPARING RENAL TOXICITY OF AMPHOTERICIN B IN EITHER GLUCOSE OR INTRALIPID

Authors Patients Less nephrotoxicity

with intralipid

Moreau 1992 Haematological YES

malignancies

Caillot 1994 Haematological YES

malignancies

Sorkine 1996 ICU critical ill patients YES

Schöffski 1998 Neutropenic patients NO

Nucci 1999 Cancer NO

slide11

THE USE OF LIPID EMULSION WITH AMPHOTERICIN B

Benefit ? Risks

* Price * Effect on amphotericin B * Lower antimycotic nephrotoxicity ? activity * Cholestasis

* Thrombocytopenia

* Hepatic function

abnormalities

* Pulmonary toxicity

we should NOT !!

slide12

Prevention of Amphotericin B nephrotoxicity

* Intralipid

* Risk factors

* Early detection of renal toxicity

* New formulations

slide13

RISK FACTORS FOR AMPHOTERICIN B NEPHROTOXICITY

* Use of diuretics

* Abnormal baseline renal function

* Cumulative dose of Amphotericin B

* Concomitant nephrotoxic drugs (cyclosporin,FK506,aminoglycosides...)

* Dehydration

* Patient category

slide14

AMPHOTERICIN B AND DIURETICS

* There is no clinical evidence that diuretics prevent Amphotericin B nephrotoxicity.

* Mannitol and Furosemide will aggravate hypokalemia and hypomagnesemia.

* Diuretics are a risk factor for amphotericin B nephrotoxicity.

* I do not recommend their use in this indication.

slide15

HYDRATION AND AMPHOTERICIN B

*Dehydration is a key factor for the renal tolerance of all potential nephrotoxic drugs,

*All patients should received 1 to 2 liters of isotonic saline prior to each amphotericin B infusion

slide16

RATE OF NEPHROTOXICITY AND HEMODIALYSIS IN 4 PATIENTS GROUPS

Patients groups Nephrotoxicity Dialysis

(CR x 2)(%) required (%)

Allogenic BMT 61 20

Autologous BMT 80 19

SOT 35 18

Non Transplantation 54 7

Wingard JR, Clin Inf Dis, 1999

slide17

Prevention of Amphotericin B nephrotoxicity

* Intralipid

* Risk factors

* Early detection of renal toxicity

* New formulations

slide18

TUBULAR DYSFUNCTION INDUCEDBY AMPHOTERICIN B

Incidence

HypoK+ 25 - 75 %

HypoMg 30 - 75 %

Renal tubular acidosis 50-100 %

Renal concentrating defects (polyuria) 50- 100 %

* Usually before renal insufficiency

* After 7 to 14 days of treatment

* Dose-dependant response

slide19

AZOTEMIA

*Is caracterized by a decrease in creatinine clearance and an increase in serum creatinine

*Is preceded by tubular dysfunction

*May be irreversible with large cumulative doses

* Is underestimated with serum creatinine assessment

slide20

WHAT CHANGE IN SERUM CREATININE SHOULD BE CONSIDERED AS SIGNIFICANT ?

  • A 25% rise in serum creatinine level may appear to be small but actually represents a substantial fall in GFR -perhaps as much as a 50% reduction because of the exponential rise in serum creatinine level with declining renal function ,
  • In addition, renal function and muscle mass decline more or less in parallel with advancing age or severe disease, so that the little old lady and your very sick patients with a mild increase in serum creatinine have a GFR only about 30% of that of a young healthy adult
slide21

EARLY DETECTION OF AMPHOTERICIN B NEPHROTOXICITY

  • Tubular dysfunction: hypokalaemia; hypomagnesemia; polyuria; tubular acidosis .

And \ or

  • Renal insufficiency: a 25% rise in serum creatinine .

Stop the drug...

slide22

Prevention of Amphotericin B nephrotoxicity

* Intralipid

* Risk factors

* Early detection of renal toxicity

* New formulations

slide23

Randomized, double blind clinical trial of Amphotericin B colloidal dispersion vs amphotericin B in the empirical treatment of fever and neutropenia.

White et al. Clin Inf Dis, 1998.

* 213 neutropenic patients

* Hematologic malignancy or marrow transplantation

* Treatment

ABCD (4 mg/kg/d) vs conventional amphotericin B (0.8 mg/kg/d)

slide24

ABCD vs AMPHO B :RENAL INSUFFICIENCY

% of patients

with serum

creatinine

> 2 times baseline

*

* p < 0.05

vs ABCD

ABCD

Ampho B

White M et al, Clin Inf Dis, 1998

slide25

ABLC for cryptococcal meningitis in AIDS patients

Sharkey et al, CID, 1996 ; 22 : 315-321

* 55 AIDS patients

* Cryptococcal meningitis

* Treatments

- Amphotericin B : 1 mg/kg/day

- Abelcet® : 5 mg/kg/day

2.5 mg/kg/day

1.2 mg/kg/day

slide26

Comparative nephrotoxicity of Abelcet® and conventional Amphotericin B

Ampho B Abelcet ®

(5 mg/kg/day)

Doubling in SCR 53 % 50 %

HypoK+ 24 % 24 %

HypoMg 24 % 24 %

Sharkey et al, CID, 1996 ; 22 : 314-321

Luke R et al, Am J Kidney Dis, 1998 ; 31 : 780-785

slide27

Liposomal amphotericin B for empirical therapy

in patients with persistent fever and neutropenia

Walsh et al, N Engl J Med, 1999

* Double blind randomized study (n = 683)

* Persistent fever and neutropenia (cancer, lymphoma, bone marrow transplantation)

* Treatments

- Ampho B : 0.6 mg/kg/day or

- Ambisome : 3.0 mg/kg/day

slide28

AMBISOME® vs AMPHO B :RENAL INSUFFICIENCY

% of patients

with serum

creatinine

> 2 times baseline

* p < 0.05

vs Ampho B

*

AmBisome®

Ampho B

Walsh et al, N Engl J Med, 1999

slide29

AMBISOME® vs AMPHO BHYPOKALEMIA (K+ < 2.5 mEq/l)

% of patients

with serum K+

< 2.5 mEq/l

*

* p < 0.05 vs

Ampho

Ambisome®

Ampho B

Walsh et al, N Engl J Med, 1999

slide30

A randomized double blind comparative trial

evaluating the safety of Ambisome® versus Abelcet®

in the empirical treatment of febrile neutropenia.

Wingard et al, 9th focus on fungal infections, 1999

* Double blind randomized study (n = 250)

* Neutropenic patients with unresolved fever

* Treatments

- Abelcet® : 5 mg/kg/day

- Ambisome® : 3 mg/kg/day or 5 mg/kg/day

slide31

AMBISOME VS ABELCET:RENAL INSUFFICIENCY

%

patients with serum

creatinine > 2 times baseline

*

*

* p < 0.05 vs Abelcet ®

Wingard et al, 9th focus on fungal infections, 1999

slide32

AMBISOME VS ABELCET:RENAL INSUFFICIENCY

*

%

patients

*

2 x baseline

serum creatinine

1.5 x baseline

serum creatinine

* p < 0.05 vs Ambisome ®

Wingard et al, 9th focus on fungal infections, 1999

slide33

CONCLUSIONS

* Amphotericin B nephrotoxicity remains frequent and severe

* Amphotericin B-induced acute renal failure is not a benign complication :

-It increases hospital costs

-It increases patient mortality

slide34

CONCLUSIONS

The prevention of Amphotericin B nephrotoxicity

rely on :

*The detection and if possible the suppression of risk factors,

*The use of liposomal formulation of Amphotericin B : (at least)

- in high risk patients,

- in patients with Amphotericin B nephrotoxicity.