Toxicity of b-Lactams

Fabio S TACCONE, MD, PhD

Hopital Erasme, ULB

Brussels, Belgium

Conflict of Interest

None to declare

Antibiotics in ICU

Infections are common in ICU patients

Associated with a significant increase in ICU mortality rate and total costs

Prescription of an adequate and appropriate antibiotic therapy is mandatory

Complex challenge for clinicians:

early identification of microorganisms

increasing prevalence of multidrug resistance pathogens

changes in pharmacokinetics and pharmacodynamics of antibiotics

Vincent JL, Lancet Respir Med 2014

Antibiotics in ICU

Infections are common in ICU patients

Associated with a significant increase in ICU mortality rate and total costs

Prescription of an adequate and appropriate antibiotic therapy is mandatory

Complex challenge for clinicians:

early identification of microorganisms

increasing prevalence of multidrug resistance pathogens

changes in pharmacokinetics and pharmacodynamics of antibiotics

Vincent JL, Lancet Respir Med 2014

Antibiotics in ICU

EARLY

THERAPY

COMBINATION

ADEQUATE

THERAPY

OPTIMAL

THERAPY

APPROPRIATE

THERAPY

Antibiotics in ICU

CIFluids

RBF

INCREASED CL

Venous Pooling

Capillary Leakage

INCREASED VD

Organ Dysfunction

REDUCED CL

TDM !!

b-Lactams

b-Lactams

POTENTIAL TOXICITY:

• Allergic: 1-10%

• Hematological: Agranulocytosis (2-15/million)

Thrombocytopenia / anemia / neutropenia

• Hepatotoxicity: 1/100000

• Nephrotoxicity: Interstitial nephritis (all)

AKI /delayed recovery (TZP)

• Neurotoxicity: Rare (CEF > others)

Park. Mayo Clin Proc. 2005

Andrès. Eur J Intern Med. 2006

Koklu Ann pharmacother 2003

Sutter Neurology 2015

• Rare (Underdiagnosed?)

• MOF/Polymedication

• Increased morbidity ?

Hematological Toxicity

A dose-dependent inhibition of granulopoiesis was found for all β-lactams

Drug-dependent antibodies to neutrophils ?

Reversible neutropenia may occur in 5-15% of patients receiving BL (>10d);

dose dependent for TZP; more frequent when endocarditis

Neftel, Infect. Dis. 1985

Peralta CID 2003

Olaison JAC 1990

Hepatic Toxicity

Amoxi-clav: Mild hepatocellular or cholestatic liver injury (1/1000); few

cases with life-threatening acute liver failure

Less frequent with TZP and CEF

Mechanism of hepatotoxicity is unclear (immuno-allergy? - Not correlated to

dosing)

Rodriguez 1996

Gresser U 2001

Larrey 1992

Zhong Fang 2013

Hepatic Toxicity

• Ceftriaxone: High biliary concentrations (150-fold blood concentrations) More

likely to induce “sludge”

Richards Drugs 1987

Nakarai Eur J Clin Pharmacol 2016

High (4g) vs normal dosing (2g)

Retrospective study

Biliary sludge or stones not assessed

Renal Toxicity

Renal Toxicity

• 1200 ICU patients – prospective randomised study

(PCT-based ATB therapy)

• More AKI among patients on TZP (“high-

exposure”): cause of delayed renal recovery in

critically ill when compared to other BL

• Not related to dosing

Jensen, BMJ 2012

Lee WL, Slutsky AS. 2010

Neuro-Toxicity

Neurons hyperexcitability

Depolarization of the PS-membrane

Seizure threshold lowered

Neuro-Toxicity

De Sarro Antimicrob Agents Chemother. 1995Sunagawa, J Antibiot 1992

Norby JAC 2000

1. Dose-dependent mechanisms: More convulsive activity at higher C Cephalosporins > Penicillins

2. Voltage-dependent mechanismsMore basic better binding to the GABAA higher neurotoxicity

Imipenem >> meropenem > doripenem

Neuro-Toxicity

RISK FACTORS• Renal failure

• Elderly patient

• Pediatric patient

• Pre-existing brain injury

Neuro-Toxicity

• Retrospective review of patients treated with meropenem or cefepime in whom EEG has been performed (42 months)

• Periodic epileptiform discharges : 5-fold more frequent in CEF group

• Blood serum creatinine concentration: elevated in 5/14 pts

• Dead 7/14 Pts

Patients treated EEG performed EDs Prevalence

(%)

CEFEPIME 1120 59 14 1.25

MEROPENEM 1572 80 3 0.25

Neuro-Toxicity

Lamoth AAC 2010

Impaired renal function

Median cefepime trough levels: 28 mg/L

Neuro-Toxicity

Chapuis, Crit Care 2010

CE

FE

PIM

E

NO DIFFERENCES !

Neuro-Toxicity

Retrospective review

108 patients – 460 measurement of serum BL

concentration

96/108 : at least one supra-therapeutic level

No correlation with clinical seizure (univariate

analysis)

Beumier, Minerva Anestesiol 2015

• RETROSPECTIVE STUDY

• ALL ICU PATIENT treated with MEROPENEM (MEM), PIPERACILLIN-

TAZOBACTAM (TZP) or CEFTAZIDIME/CEFEPIME (CEF) AND AT LEAST 1

TDM PERFORMED

• HYPOTHESIS: Association of serum concentrations and with neurological

deterioration?

Neuro-Toxicity

Beumier, Minerva Anestesiol 2015

Neuro-Toxicity

Neurological evaluation

• No Brain Dysfunction -> nSOFAAdm and nSOFATDM =

0

• Brain Improvement -> nSOFAAdm 1-2 + DnSOFA = 0

• No Clinical Change -> nSOFAAdm 1-2 + DnSOFA ≤ 1

• Persistent Coma -> nSOFAAdm 3-4 + DnSOFA ≤ 2

- nSOFAAdm = 0 + DnSOFA ≥ 1

- nSOFAAdm 1-2 + DnSOFA ≥ 1

Neurological

impairement

• β-lactams concentrations:

• Minimal concentration (Cmin) was measured 30

minutes before the onset of the infusion (HPLC)

• Cmin was normalized to the clinical breakpoint of

Pseudomonas aeruginosa (as determined by

EUCAST) for each drug (Cmin/minimum inhibitory

concentration [MIC])

Neuro-Toxicity

Beumier, Minerva Anestesiol 2015

Beumier, Minerva Anestesiol 2015

(n=199) 262 TDMs

Neuro-Toxicity

Neurotoxicity Clinical assessment of neurotoxicity

is a challenge in ICU patients …

How to do it better?

Neuro-Toxicity

• Retrospective study – Dpt of Intensive Care of Erasme Hospital - Brussels, Begium (Jan

2010– Dec 2016)

Inclusion Criteria:

▪ Plasma therapeutic drug monitoring (TDM) of one of the following b-lactams:

-Meropenem (MEM)

-Piperacillin-tazobactam (TZP)

-Ceftazidime / Cefepime (CEF)

-Aztreonam (AZT)

▪ TDM concomitant to EEG monitoring

Neuro-Toxicity

Neuro-Toxicity

Altered

EEG

ALL PATIENTS

(N=276)

AGE, years (IQRs) 60 [49-69]

MALE, n (%) 107 (38)

MEDICAL ADMISSION, n (%) 168 (60)

COMORBIDITIES:

IMMUNOSUPPRESSION, n (%) 92 (33)

CANCER, n (%) 37 (13)

COPD/ASTHMA, n (%) 44 (16)

DIABETES, n (%) 76 (27)

HEART DISEASE, n (%) 105 (38)

CHRONIC KIDNEY DISEASE, n (%) 38 (14)

LIVER CIRRHOSIS, n (%) 46 (16)

PREVIOUS NEUROLOGICAL DISEASE, n (%) 105 (38)

INFECTIONS:

LUNG, n (%) 138 (50)

ABDOMEN, n (%) 66 (24)

URINARY, n (%) 11 (4)

CATHETER, n (%) 5 (2)

SKIN, n (%) 21 (8)

NEUROLOGICAL, n (%) 1 (1)

BONE, n (%) 8 (3)

ICU MORTALITY, n (%) 113 [41]

2193 TDMs analysed at

the Biochemistry Lab

1437 TDMs done in ICU

patients

391 TDMs with a

concomitant EEG

Neuro-Toxicity

276 patients

391 TDM with EEG

N=

55

N=

15

7

N=

168

N=

11

Alt

ered

EE

G (

%) p = 0.31

Altered EEG

108/391 (28%)

Neuro-Toxicity

NORMAL EEG

(N=283)

ALTERED EEG

(N=108)p

NEUROLOGIACL DISEASE, n (%) 101 (34) 47 (43) 0.154

SEDATIVE, n (%) 93 (33) 35 (32) 0.932

FK506/CsA, n (%) 38 (13) 17 (16) 0.556

MECHANICAL VENTILATION, n (%) 207 (73) 82 (74) 0.576

FiO2, % [IQs] 37 [30-45] 35 [30-50] 0.302

PaO2, mmHg [IQs] 81 [69-94] 79 [68-94] 0.450

PaO2/FiO2, [IQs] 230 [162-314] 231 [166-297] 0.480

PaCO2, mmHg [IQs] 38 [33-45] 35 [31-42] 0.011

pH, [IQs] 7.42 [7.37-7.47] 7.42 [7.37-7.47] 0.361

SODIUM, mmol/l 139 [136-142] 138 [134-141] 0.543

LACTATE, mmol/l [IQs] 1.4 [1.0-2.0] 1.5 [1.1-2.5] 0.062

HEMOGLOBIN, g/dl [IQs] 8.6 [7.8-9.5] 8.6 [7.7-9.8] 0.930

PLATELETS, count [IQs] 126 [53-238] 131 [59-226] 0.989

CRP, mg/dl [IQs] 110 [61-220] 110 [49-210] 0.573

UREA, mg/dl [IQs] 51 [32-76] 43 [27-83] 0.866

CREATININE, mg/dl [IQs] 0.9 [0.6-1.5] 1.1 [0.6-1.7] 0.229

BILIRUBINE, mg/dl [IQs] 0.76 [0.38-1.90] 0.67 [0.37-2.8] 0.212

AMMONIA, mg/dl [IQs] 63 [44-88] 67 [53-90] 0.717

Cmin, [IQs] 10.4 [3.1-36.6] 25.8 [6.9-66.4] 0.002

Cmin/MIC, [IQs] 2.5 [1.0-5.0] 3.7 [1.5-6.1] 0.003

SEIZURES, n (%) - 66 (52) -

GPEDs, n (%) - 50 (46) -

SOFA, [IQs] 9 [5-13] 10 [7-13] 0.147

CARDIOVASCULAR SOFA 1 [0-4] 3 [0-4] 0.087

RENAL SOFA, [IQs] 0 [0-2] 1 [0-2] 0.322

GCS ADMISSION, [IQs] 9 [3-14] 8 [3-14] 0.524

GCS DOSAGE, [IQs] 9 [5-14] 7 [4-10] 0.002

Neurological worsening, n (%) 61 (22) 20 (18) 0.390

Neuro-Toxicity

0

10

20

30

40

50

< 1 1- 1.9 2-3.9 4-7.9 > 8

All TDMs

N= 57 N= 94 N= 96 N= 99 N= 45

p = 0.017

Cmin/MIC

Alt

ered

EE

G (

% o

f T

DM

)

Neuro-Toxicity

0

10

20

30

40

50

60

70

80

< 1 1- 1.9 2- 3.9 4- 7.9 > 8

Patients without preexisting neurological disease

Cmin/ MIC

p= 0.023

Alt

ered

EE

G (

% o

f T

DM

)

N= 22 N= 58 N= 61 N= 66 N= 36Cmin/MIC

Neuro-Toxicity

TZP MEM

0

5

10

15

20

25

30

35

40

< 1 1- 1,9 2- 3,9 4- 7,9 > 8

Cmin/MIC

p = 0.09

N = 10 N = 63 N = 44 N = 37 N = 14

Alt

ered

EE

G

(% o

f T

DM

)

0

5

10

15

20

25

30

35

40

45

50

< 1 1- 1,9 2- 3,9 4- 7,9 > 8

Cmin/MIC

p = 0.019

N = 43 N =23 N = 36 N = 38 N = 17

Alt

ered

EE

G

(% o

f T

DM

)

Cmin/MIC Cmin/MIC

For CEF and AZT, no relation between Cmin/MIC and EEG abnormalities

Neuro-Toxicity

A multivariate analysis (adjusted for patients) to identify the independent risk factors for the

occurrence of EEG abnormalities was performed using a multivariable generalized linear

mixed models for binary responses (cut-off in the univariate analysis – p<0.1)

p value OR (95% CI)

Previous Neurological Disease 0.003 1.71 [1.03-2.83]

PaCO2, mmHg 0.007 0.96 [0.93-0.99]

Cmin/MIC <0.001 1.16 [1.07-1.25]

Neuro-Toxicity

• The AUC of Cmin/MIC to predict “altered EEG” was 0.60 (95% CIs 0.53-0.66; p=0.002)

• A Cmin/MIC > 4 enabled prediction of altered EEG during β-lactam therapy with a sensitivity of 48%

and a specificity of 68%

• Cmin/MIC > 8 predicted altered EEG with a sensitivity of 17%, a specificity of 91%

• The AUC of the multivariable model was 0.71

AUC = 0.60 [0.53-0.66] AUC = 0.71 [0.65-0.77]

Cmin/MICModel

Neuro-Toxicity

• b-lactams= « safe ” drugs

• Toxicity is rare and difficult to recognize

• High doses vs. high blood concentrations

• High b-lactam concentrations may increase the risk of neurological complications (EEG

abnormalities)

• Monitoring of β- lactam levels should be considered when neurological and/or EEG

alterations occur in patients with sepsis

Conclusions

β-lactams