Yellow Card: FDA Warnings on Antibiotics · treatment plan to manage and mitigate the FDA warnings ... Ensuring safety, efficacy, and security of drugs, biologics, and medical devices

MSHP Annual Meeting 2017

Yellow Card: FDA Warnings on

Antibiotics

Monica V. Mahoney, PharmD, BCPS AQ-ID

Disclosures

In this presentation I will be:

Discussing off-label indications and uses

Challenging FDA warnings and alerts

All doses and most studies refer to adult

patients


Objectives

Identify the role the FDA plays in updating

drug warnings and communication

Evaluate the literature behind the recent FDA

antimicrobial drug interactions and adverse

drug events

Given a patient scenario, recommend a

treatment plan to manage and mitigate the

FDA warnings

FDA Background

Food and Drug Administration (1906)

Responsibilities Include:

Ensuring safety, efficacy, and security of

drugs, biologics, and medical devices

Regulates the manufacturing, marketing, and

distribution of tobacco

Involved in counterterrorism (food/drug

response to public health threats)

http://www.fda.gov/AboutFDA/default.htm


FDA Background Continued

Center for Drug Evaluation and Research

(CDER)

Pre-Clinical Clinical

Approval

Post-

Marketing

• Animal models

• PK/PD studies

• Phase 1 trials

• Phase 2 trials

• Phase 3 trials

• Voluntary reports

• Surveillance studies

• Meta-Analyses

http://www.fda.gov/AboutFDA/default.htm

Post-Marketing Surveillance

Adverse Event Reporting System (AERS)

Manufacturers required to report ADRs

MedWatch

MedWatch

Voluntary reporting by consumers and healthcare

professionals

Sentinel System

February 2016

Rapidly and securely access electronic healthcare data

from >193 million patients from multiple data partners


FDA Drug Safety Communications

Information for consumers and health

professionals on new drug warnings and

other safety information, drug label

changes, and shortages of medically

necessary drug products

http://www.fda.gov/Drugs/DrugSafety

FDA Background Continued –

Expedited Review

Fast Track Breakthrough

Therapy

Accelerated

Approval

Priority Review

• Drug txt

serious

condition +

potential to

address unmet

need

• Qualified

infectious

diseases drug

• Drug txt serious

condition +

prelim evidence

shows

improvements

over available

drugs

• Drug txt

serious

condition +

advantage over

other drugs +

surrogate

endpt predicts

clinical benefit

• NDA for drug txt

serious condition +

improvement over

other drugs

• Supplement

following pediatric

study

• Qualified infectious

diseases drug

• Priority review

voucher


A Cautionary Tale


Yahav et al. Design • Systemic review of RCT comparing cefepime (FEP) vs. other β-lactams

Patients • n=11,723 patients (7,388 all-cause mortality data)

• n=57 RCTs (41 provided all-cause mortality data)

Primary

Outcome

• 30 day, all-cause mortality

Results

Conclusions • Mortality significantly higher for FEP than comparators

• No explanations could be determined

Yahav et al. Lancet Infect Dis.2007;7:338-48


Ongoing Review

Performed literature search, requested additional information from

manufacturer, waiting on results …


All-Cause Mortality Review Yahav et al (38 trials)

Mortality: 7.86% (309/3931) FEP vs. 6.36% (220/3457) comparator

Adj Risk Diff: 17.02 per 1000 (95% CI 5.54, 28.5)

FDA Additional Trials (50 trials)


Adj Risk Diff: -2.83 per 1000 (95% CI -11.47, 5.80)

All Trials (88 trials)

Mortality: 6.21 % (588/9467) FEP vs. 6.00% (497/8288) comparator

Adj Risk Diff: 5.38 per 1000 (95% CI -1.53, 12.28)

FDA Patient-Level (35 trials)

5.63% (286/5058) FEP vs. 5.68% (226/3976) comparator




Febrile Neutropenia Review Yahav et al (19 trials)


Adj Risk Diff: 18.99 per 1000 (95% CI 4.96, 33.02)

All Trials (24 trials)


FDA Patient-Level (7 trials)

7.86% (61/776) FEP vs. 6.55% (41/626) comparator


Most patients died from their underlying malignancies and/or

comorbid conditions


FDA Review Conclusion

FDA has finished its analysis of a possible risk of higher death with cefepime, an antibiotic,

following publication of a study that suggested a higher rate of death in patients treated with this

drug, as compared to patients treated with similar drugs. FDA has determined that the data do not

indicate a higher rate of death in cefepime-treated patients. Cefepime remains an appropriate

therapy for its approved indications.



FDA Review Conclusion

FDA has finished its analysis of a possible risk of higher death with cefepime, an antibiotic,

following publication of a study that suggested a higher rate of death in patients treated with this

drug, as compared to patients treated with similar drugs. FDA has determined that

the data do not indicate a higher rate of death in cefepime-

treated patients. Cefepime remains an appropriate therapy

for its approved indications.


Newsstand

Azithromycin

Monitor

Cefepime

Post

Quinolone

Chronicle

Linezolid

Ledger

Subscription Expired


Azithromycin TM is a 48 y/o male h/o HTN [controlled on diltiazem] and COPD, who

presents to the pharmacy with a prescription for a 3 day course of

azithromycin (500mg qDay) for a COPD exacerbation. He’s had several

days of increased dyspnea and increased sputum production. He read on

the internet that azithromycin can “kill him” and his barber recommended he

ask his doctor to switch to that “leave-a-floxa-something” drug instead.

Upon further questioning you learn that he doesn’t currently smoke, doesn’t

have diabetes, and cholesterol is normal. What antibiotic would you

recommend?

A. Azithromycin 500 mg PO qDay x 3 days

B. Levofloxacin 500 mg PO qDay x 5 days

C. Linezolid 600 mg PO q12h x 7 days

D. Amoxicillin 500 mg PO q6h x 7 days

Azithromycin: Initial FDA Alert



Ray et al.

Design • Retrospective cohort study of Tennessee Medicaid patients

Patients • Patients prescribed azithromycin (AZM) 1992-2006

• n=347,795

• Excluded high risk of death from non-cardiac dz

• Control groups

• Amoxicillin (AMX) (n=1,348,672)

• Ciprofloxacin (CIP) (n=264,626)

• Levofloxacin (LVX) (n=193,906)

• No antibiotic use (n=1,391,180)

Primary

outcome

• Cardiovascular death

• Death from any cause

Ray et al. N Engl J Med 2012;366:1881-90

Azithromycin: Cardiac Death



Comparisons Cardiovascular Death Death from Any Cause

AZM vs. No Abx

(5 days)

HR 2.88, 95% CI 1.79, 4.63 (p<0.001) HR 1.85, 95% CI 1.25, 2.75

(p=0.002)

AZM vs. No Abx

(10 days)

HR 1.86, 95% CI 1.27, 2.73 (p=0.002) Not significant

AZM vs. AMX

(5 days)

HR 2.49, 95% CI 1.38, 4.50 (p=0.002) HR 2.02, 95% CI 1.24, 3.30

(p=0.005)

AZM vs. AMX

(10 days)


AZM vs. CIP

(5 days)


AZM vs. LVX

(5 days)

Not significant Not significant

Azithromycin: Cardiac Death

Conclusion • Small absolute increase in cardiovascular death during 5 days of

azithromycin therapy, most pronounced among patients with a high

baseline risk of cardiovascular disease


Azithromycin: F/U FDA Alert


PI Update


Additional Studies

Propensity-matched Danish study comparing AZM to no antibiotics or penicillin V

in all-comers (n=~10 million)

Increased risk of CV death compared to no abx (HR 2.85, 95% CI 1.13, 7.24)

No increased risk compared to penicillin V (HR 0.93, 95% CI 0.56, 1.55)

Retrospective review of VA records comparing outpatient AZM, AMX, and LVX

(n=~1.75 million)

Compared to AMX, both AZM and LVX were associated with higher rates of all-

cause mortality (HR 1.48, 95% CI 1.05, 2.09 and HR 2.49, 95% CI 1.70, 3.64,

respectively)

Svanström et al. N Engl J Med 2013;368:1704-12

Rao et al. Ann Fam Med 2014;12:121-7

Patients at Highest Risk

Pre-existing QTc prolongation

Uncorrected hypomagnesemia

Uncorrected hypokalemia

Bradycardia

On concomitant Class IA or Class III

antiarrythmic agents



QTc Interval Depolarization: Na+ and Ca++ channels

Repolarization: K+ channels

QTc prolongation: excess of positively

charged ions

Risk Factors for Prolongation:

• Age

• Female gender

• Heart failure

• MI

• Hypertension

• Diabetes

• Hyperlipidemia

• ↑ BMI

• Bradycardia

• Electrolyte abnormalities

Van Noord et al. Br J Clin Pharmacol 2010;70:16-23

Tisdale. Can Pharm J 2016;149:139-52

QTc Interval Interpretation Females Males

Normal < 450 msec < 430 msec

Borderline 450 to 470 msec 430 to 450 msec

Prolonged > 470 msec > 450 msec

Alternative Treatment Options

IDSA Guidelines Available at: www.idsociety.org

Acute Bronchitis Community Acquired Pneumonia

No treatment (Pertusis →macrolide) Doxycycline 100 mg PO q12h x 7 days

Acute Sinusitis Fluoroquinolone (levo/moxi) x 5-7 days

No treatment Gonococcal Infections

Amox/clav 2g PO BID x 5-7 days Alternatives not recommended – use azithro

Doxycycline 100mg PO q12h x 5-7 days Ceftriaxone or cefixime w/ close follow-up

COPD Exacerbation MAC Prophylaxis/Treatment

Similar to CAP Alternatives not recommended – use azithro

Amox/clav 500mg PO q8h x 5-7 days

Cefpodoxime 200mg PO Q12h x 5-7 days


Role of the Pharmacist

Evaluate need for azithromycin

Recommend alternative antibiotics

Evaluate risk factors for QTc

prolongation/Torsades

Evaluate drug-drug interactions

Replete magnesium, potassium

Monitor EKG

Azithromycin TM is a 48 y/o male h/o HTN [controlled on diltiazem] and COPD, who

presents to the pharmacy with a prescription for a 3 day course of

azithromycin (500mg qDay) for a COPD exacerbation. He’s had several

days of increased dyspnea and increased sputum production. He read on

the internet that azithromycin can “kill him” and his barber recommended he

ask his doctor to switch to that “leave-a-floxa-something” drug instead.

Upon further questioning you learn that he doesn’t currently smoke, doesn’t

have diabetes, and cholesterol is normal. What antibiotic would you

recommend?






Azithromycin Does this patient have high baseline risk of cardiovascular disease?





Newsstand

No. Young, only hypertension, no diabetes, not a smoker, normal cholesterol.

Additionally, only on class IV antiarrhythmic.

Indication appropriate, Rx only for 3 days, risk of cardiovascular death low,

should be appropriate to dispense

Conflicting information on risk compared to azithromycin, pt with low risk for

cardiovascular death, FDA warning on FQs …

Inappropriate indication

One study with risk lower than azithromycin, but inappropriate for indication

DW is a 68 y/o male with a VP shunt being treated in the ICU for

post-op meningitis with cefepime 2g IV q8h, vancomycin 15 mg/kg

IV q12h, and ampicillin 2g IV q4h. On day 3 of treatment, the team

notices he is confused, pulling at his lines, and is otherwise

“altered.” They are concerned that he has developed NCSE from

the cefepime and want to change antibiotics. How do you respond?

A. Change cefepime to 1g IV q12h

B. Keep cefepime at 2g IV q8h

C. Change to ceftriaxone 2g IV q12h

D. Change to meropenem 2g IV q8h

Cefepime

WBC: 18.6 Wt: 76 kg Scr: 1.2 mg/dL CrCl: 64 mL/min


Cefepime


Cefepime AERS Review Data search 1996 through 2012

59 cases of nonconvulsive status epilepticus (NCSE) during

cefepime (FEP) treatment identified

Altered mental status

Confusion

Decreased responsiveness

Risk Factors:

Age > 50 years

Renal dysfunction

Dose inappropriately high for renal function

NCSE reversible upon FEP discontinuation and/or hemodialysis

Activity verified by

EEG



Mayo Clinic Review Design • Retrospective review

Patients • ICU adults treated with FEP 2009-2011

• n=100 patients

Methods • Primary outcome = FEP neurotoxicity

• Encephalopathy, delirium, altered mental status, confusion, acute

confusional state

Results • 15 patients met criteria for neurotoxicity

• Impaired consciousness (n=13)

• Myoclonus (n=11)

• Disorientation (n=6)

• NCSE (n=1)

• Risk factors:

• Inappropriate high dose (62.4%. Vs 24.7%, p=0.001)

• History of chronic kidney disease (66.7% vs. 35.3%, p=0.04)

Conclusions • FEP-associated seizures may be rare, but other manifestations of CNS

toxicity may not be

Fugate et al. Crit Care 2013;17:R264

β-Lactams

Cross the BBB

Renally excreted

Dosage adjustment in renal impairment

Cockcroft-Gault:

Modification of Diet in Renal Disease (MDRD):

140 – (age) x (weight)

72 x (Scr) (x 0.85 if female)

186.3 x Scr -1.154 x age -0.203 x 0.742 (if female) x 1.212 (if black)


Antibiotics and Status Epilepticus

Review of 117 patients with SE Jan 2003-Jan 2008

12 (10%) temporally related to antibiotics

Misra et al. Neurol Sci 2013;34:327-331

Antibiotics and Status Epilepticus

Multiple mechanisms:

High serum drug levels

Intrinsic seizurogenic activity

Four classes of antibiotics most frequently reported:

1. Penicillins … block GABA and benzodiazepine receptors

2. Cephalosporins … block GABA and benzodiazepine receptors

3. Carbapenems … activate NMDA induced epileptogenesis

4. Quinolones … activate NMDA induced epileptogenesis

Misra et al. Neurol Sci 2013;34:327-331


Alternative Treatment Options Gram-Positive Activity

Staphylococcus aureus, Streptococcus pneumoniae

β-lactams (ampicillin/sulbactam, ceftriaxone, ertapenem, meropenem)

Glycopeptides (vancomycin, daptomycin)

Oxazolidinones (linezolid, tedizolid)

Gram-Negative Activity

Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes*, etc

β-lactams (ampicillin/sulbactam, ceftriaxone*, ertapenem, meropenem)

Aminoglycosides (gentamicin, tobramycin)

Glycylcycline (tigecycline)

Pseudomonas aeruginosa Activity

β-lactams (ceftazidime, meropenem, piperacillin/tazobactam)

Aminoglycosides (gentamicin, tobramycin)

Colistin

*potentially avoid 3rd generation cephalosporins for

SPICE organisms due to inducible β-lactamases


Evaluate need for cefepime


Evaluate risk factors for neurotoxicity

Calculate renal function and continue to

monitor

Adjust cefepime dose accordingly

Recommend EEG in appropriate patients


DW is a 68 y/o male with a VP shunt being treated in the ICU for

post-op meningitis with cefepime 2g IV q8h, vancomycin 15 mg/kg

IV q12h, and ampicillin 2g IV q4h. On day 3 of treatment, the team

notices he is confused, pulling at his lines, and is otherwise

“altered.” They are concerned that he has developed NCSE from

the cefepime and want to change antibiotics. How do you respond?





Cefepime

WBC: 18.6 Wt: 76 kg Scr: 1.2 mg/dL CrCl: 64 mL/min

Is this presentation consistent with the case reports?





Cefepime

Newsstand

Pt is >50 years but doesn’t have renal dysfunction nor is cefepime inappropriately

high (CrCl >60 mL/min, dose appropriate for renal function and indication).

Dose is too low for meningitis, pt’s CrCl doesn’t warrant dosage adjustment.

Dose is appropriate for indication and CrCl. Multiple other reasons for AMS (VP

shunt, CNS infection, ICU, delirium). Could perform an EEG to definitively r/o

Drug is inappropriate (need pseudomonal coverage) and other β-lactams can

also cause NCSE

Unnecessary broadening, other β-lactams can also cause NCSE


PG is a 38 y/o female diagnosed with her 2nd UTI in 2 years. She

has no urogenital abnormalities, is allergic to “sulfa”, and takes

migraine medicine as needed. She is finishing a prednisone taper

for an unknown indication. She complains of 2 days of urinary

frequency and “burning.” A dipstick urinalysis shows + leukocyte

esterase, 40 WBC, and + nitrites. Which of the following treatments

would you recommend?

A. Sulfamethoxazole/trimethoprim 1 DS PO BID x 3 days

B. Ciprofloxacin 250 mg PO BID x 5 days

C. Fosfomycin 3g PO x 1

D. Treat symptoms only: phenazopyridine + ibuprofen

Fluoroquinolones

Fluoroquinolones



Fluoroquinolone FDA Update


November 2015 Special Meeting

• Acute bacterial sinusitis

(ABS)

• Acute bacterial

exacerbation of chronic

bronchitis (ABECB)

• Uncomplicated urinary

tract infection (uUTI)

• Nov 1997 to May 2015

• 178 cases of healthy

pts who developed

irreversible ADRs


Placebo-

Controlled

Trials

AERS

Review

FDA Safety

Communication


Placebo-Controlled Trials: ABS 20 placebo-controlled trials

6 showed statistically significant differences

Cochrane Review 2012 Acute rhinosinusitis (adults) concluded

there is “no place for antibiotics for the patient with clinically

diagnosed, uncomplicated acute rhinosinusitis”

Cochrane Review 2014 Acute maxillary sinusitis (adults)

concluded “there is moderate evidence that antibiotics provide a small

benefit … however about 80% improved within 2 weeks” with no

antibacterial therapy

IDSA Guidelines 2012 Acute bacterial rhinosinusitis (adults/kids)

comment that 90% ABS is caused by viruses and antibiotics should

be reserved for “patients with greater severity of symptoms”

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesM

eetingMaterials/Drugs/Anti-

InfectiveDrugsAdvisoryCommittee/UCM472655.pdf

Placebo-Controlled Trials: ABECB

15 placebo-controlled trials

6 showed statistically significant differences

Cochrane Review 2009 Antibiotics for exacerbations of

COPD supports “antibiotics for patients who are moderately

or severely ill”

Multiple societal/organizational position papers echo finding

for moderately/severely ill patients

FDA definitions:

Mild: patients treated as outpatients

Moderate to severe: pts needing hospitalization for txt of ABECB





Placebo-Controlled Trials: uUTI

5 RCT:

4 placebo-controlled, 1 ibuprofen-controlled

Microbiologic eradication was higher in Abx treated

patients (n=3)

Symptom improvement/resolution differed

Higher in abx vs. placebo (n=2)

Higher in ibuprofen vs. abx (n=1)

Microbiologic and symptom improvement (both) was

higher in abx treated patients (n=2)




Fluoroquinolone Prescriptions

0.0

5.0

10.0

15.0

20.0

25.0

2010 2011 2012 2013 2014

Ciprofloxacin

Levofloxacin

Moxifloxacin

Gemifloxacin

Ofloxacin

23.3M 23.1M 23.2M 23.0M 22.2M

Outpatient accounts for the majority (82%)

Females comprise 65% (14.5 million)

Top Indications:

UTI, Prostatitis, Pneumonia, Bronchitis

Outpatient Prescriptions (million) for Fluoroquinolones per Year





Fluoroquinolone ADRs

Existing Warnings:

Tendinitis and tendon rupture

Cardiac arrhythmia

Peripheral neuropathy





Existing Warnings:


Age > 60 years

Concomitant corticosteroids

Kidney, heart, lung transplant?






Existing Warnings:


Cardiac arrhythmia

Risk of serious arrhythmia low

Underlying cardiovascular disease increased risk





Existing Warnings:

Tendinitis and tendon

rupture

Cardiac arrhythmia

Peripheral

neuropathy





Fluoroquinolone-Associated Disability (FQAD)

Reviewed AERS Nov 1997-May 2015

FQAD: ADRS from ≥ 2 body systems

ADRs persist for >30 days after d/c FQ

• Musculoskeletal

• Neuropsychiatric

• Cardiovascular

• Senses

• Skin

• Peripheral Nervous System

Organ System Cases Involved (n=178)

Musculoskeletal (tendon/joint/muscle) 173 (97%)

Neuropsychiatric 121 (68%)

Peripheral Nervous System 113 (63%)

Senses (vision, hearing, etc) 57 (32%)

Skin 27 (15%)

Cardiovascular 22 (12%)




FDA Recommendations

“… serious side effects associated with

fluoroquinolone antibacterial drugs

generally outweigh the benefits for patients

with acute sinusitis, acute bronchitis, and

uncomplicated urinary tract infections who

have other treatment options”



Alternative Treatment Options Acute Sinusitis

No treatment

Amoxicillin/clavulanate 2g PO BID x 5-7 days

Doxycycline 100 mg PO q12h x 5-7 days

Acute Bronchitis

No treatment

Pertussis → macrolide

Uncomplicated Urinary Tract Infections

No treatment

Symptomatic management (ibuprofen, phenazopyridine)

Nitrofurantoin 100 mg PO BID x 5 days

Fosfomycin 3g PO x 1

Sulfamethoxazole/trimethoprim 1 DS PO BID x 3 days

IDSA Guidelines Available at: www.idsociety.org


Evaluate need for fluoroquinolone

Recommend alternative antibiotics or no antibiotics

(per indication)

Counsel patients on symptom management (per

indication)

Evaluate risk factors for tendinitis

Evaluate drug-drug interactions

Recommend appropriate use of fluoroquinolone


PG is a 38 y/o female diagnosed with her 2nd UTI in 2 years. She

has no urogenital abnormalities, is allergic to “sulfa”, and takes

migraine medicine as needed. She is finishing a prednisone taper

for an unknown indication. She complains of 2 days of urinary

frequency and “burning.” A dipstick urinalysis shows + leukocyte

esterases, 40 WBC, and + nitrites. Which of the following

treatments would you recommend?




D. Treat symptoms only – phenazopyridine + ibuprofen

Fluoroquinolones

Fluoroquinolones Is this an uncomplicated UTI?




D. Treat symptoms only – phenazopyridine + ibuprofen

Newsstand

No structural abnormalities, young healthy female, last UTI 1-2 years ago.

Yes, this is uncomplicated.

Patient endorses allergy to “sulfa”. Since alternative options exist, would

not want to challenge patient.

As this is uUTI, FDA warns against using this agent if alternatives exist. If

we were to use, increased risk of tenditinis, given concomitant steroids.

Appropriate option with no contra-indications

Also appropriate option if patient willing to “watch and wait”


Linezolid A prescription for linezolid 600 mg PO q12h x 5 days is transmitted to your

pharmacy for JM, a 55 y/o female. She was diagnosed with sputum-

confirmed MRSA pneumonia and received 3 days of vancomycin in the

hospital. Her WBC improved (18.6 →12.3), no longer requires

supplemental oxygenation, and fever has resolved.

What do you do?

A. Fill linezolid

B. d/c citalopram, fill linezolid

C. d/c sumatriptan and citalopram, fill linezolid

D. Call the physician and change back to vancomycin

Multivitamins 1 PO qDay Fexofenadine 180 mg PO qDay PRN

Lisinopril 20 mg PO qDay Citalopram 10 mg PO qDay

Sumatriptan 50 mg PO PRN migraine; may repeat x 1 Omeprazole 20 mg PO qDay

Linezolid and CNS Reactions



Linezolid: FDA Update


Antipsychotic Review Agent Half-life (hrs) Agent Half-life (hrs)

SSRIs Tricyclic Antidepressants

Citalopram 24-48 Amitriptyline 9-27

Escitalopram 27-32 Clomipramine 19-37*

Fluoxetine 96-144* Desipramine 15-24

Fluvoxamine 15-16 Doxepin 15*

Paroxetine 21 Imipramine 8-21

Sertraline 26 Nortriptyline 28-31

Vilazodone 25 MAOIs†

SNRIs Phenelzine 12

Desvenlafaxine 10-11 Selegiline 10

Duloxetine 12 Other

Venlafaxine 5* Bupropion 14*

Mirtazapine 20-40

SSRI: Selective Serotonin Reuptake Inhibitors; SNRI: Serotonin Norepinephrine

Reuptake Inhibitors; MAOI: monoamine oxidase inhibitors; *active metabolite

with additional activity; †may irreversibly bind with weeks of activity



Excess serotonin

Mental status changes

Autonomic hyperactivity

Neuromuscular abnormalities

Symptoms:

Agitation, tachycardia, diaphoresis, tremor,

restlessness, muscular rigidity, hyperreflexia, clonus

Life threatening:

Metabolic acidosis, rhabdomyolysis, seizures, renal

failure, disseminated intravascular coagulation

Serotonin Syndrome

Woytowish et al. Ann Pharmacother 2013;47:388-97

Butterfield et al. Design • Review of Phase 3 and 4 comparator-controlled trials

Methods • Intensive word search algorithms for serotonin syndrome

• Sternbach Criteria

• Hunter Serotonin Toxicity Criteria

• Compared linezolid (n=5426) vs. comparator study drug (n=5058)

Sternbach Criteria

1. Recent addition of serotonergic

medication

2. At least 3 serotonergic

symptoms: MS changes, agitation, myoclonus,

hyperreflexia, diaphoresis,

shivering, tremor, diarrhea, fever,

and/or incoordination

3. All other causes ruled out

Hunter Criteria

1. Recent addition of serotonergic

medication

2. At least 1 of the following: Spontaneous clonus,

Inducible clonis + agitation/diaphoresis,

Ocular clonus + agitation/diaphoresis,

Tremor + hyperreflexia,

And/or hypertonia plus T>100.4⁰F +

ocular clonus/inducible clonus

Butterfield et al. J Antimicrob Chemother 2012;67:494-502


Butterfield et al continued Methods • Included FDA medications

• Also included analgesics, anti-Parkinson’s medications, migraine

medications, atypical antipsychotics, antiemetics, and other

serotonergic agents (SA)

Results

• ≥3 SA more likely + any criteria than ≤2 SA, but NS

• Comorbidities of + Criteria:

• Hepatic failure, renal failure, cerebrovascular events

Conclusions • Risk of SS is low

• Risk with linezolid is no different than comparators

Outcome Linezolid Comparator RR

Serotonin syndrome 0 0 N/A

Hunter & Sternbach 0 0 N/A

Any one scale 13 (0.24%) 6 (0.12%) RR 2.02, 95% CI 0.77,5.31

SA & any one scale 12 (0.54%) 4 (0.19%) RR 2.79, 95% CI 0.90, 8.65)

FDA Recommendations

Linezolid should generally not be given to patients

taking serotonergic drugs

Emergency Situations:

Consider availability of other abx

Stop SA immediately and closely monitor patient for 2

weeks (5 weeks) or until 24h after last linezolid dose

Non-Emergency Situations:

Stop SA at least 2 weeks (5 weeks) in advance

Resume SA 24h after last dose of linezolid



Linezolid & SA in Practice Alternative Abx:

Emergent discontinuation of SA:

Should be tapered

Discontinuation syndrome

Dizziness, nausea, lethargy, headache, sleep disturbance, GI upset,

exacerbation of psychiatric issues

Concomitant linezolid and SA:

SS onset: 30 min to 21 days

Time to resolution: 48h (2h to 9 days)

Antibiotic Indication* Dose and Routes

Linezolid MRSA, VRE, aBSSSI, PNA 600 mg IV/PO q12h

Daptomycin MRSA, VRE, aBSSSI, NOT PNA! 4 or 6 mg/kg IV q24h

Tedizolid MRSA, VRE, aBSSSI, maybe PNA 200 mg IV/PO q24h

Vancomycin MRSA, NOT VRE, aBSSSI, PNA 15-20 mg/kg IV q12h

Haddad. Drug Safety 2001;24:183-97

Woytowish et al. Ann Pharmacother 2013;47:388-97

*not necessarily FDA-approved


Evaluate need for linezolid


Evaluate concomitant SA

Discontinue unnecessary SA

Educate patients/caregivers about SS

symptoms


Linezolid A prescription for linezolid 600 mg PO q12h x 5 days is transmitted to your

pharmacy for JM, a 55 y/o female. She was diagnosed with sputum-

confirmed MRSA pneumonia and received 3 days of vancomycin in the

hospital. Her WBC improved (18.6 →12.3), no longer requires

supplemental oxygenation, and fever has resolved.

What do you do?

A. Fill linezolid




Multivitamins 1 PO qDay Fexofenadine 180 mg PO qDay PRN

Lisinopril 20 mg PO qDay Citalopram 10 mg PO qDay

Sumatriptan 50 mg PO PRN migraine; may repeat x 1 Omeprazole 20 mg PO qDay

Linezolid A. Fill linezolid




One, low dose SSRI. Butterfield et al found no increased risk. Counsel

patient on s/sx of serotonin syndrome

Worry about discontinuation syndrome, will still be in system for 5-10 days,

cannot delay pneumonia treatment

Same as above, plus 5HT3 antagonists not proven to be correlated, taking

as a PRN only, offering no alternative for migraine txt

Not a viable option given patient is discharged home. Want an oral option


Linezolid A. Fill linezolid



D. Call the physician and change back to vancomycin to

tedizolid 200 mg PO qDay

One, low dose SSRI. Butterfield et al found no increased risk. Counsel

patient on s/sx of serotonin syndrome

Worry about discontinuation syndrome, will still be in system for 5-10 days,

cannot delay pneumonia treatment

Same as above, plus 5HT3 antagonists not proven to be correlated, taking

as a PRN only, offering no alternative for migraine txt

Newsstand

Parting Words …

25-40% of hospitalized patients receive antibiotics

75% of those are empiric and often not de-

escalated

Up to 50% of antibiotic use is inappropriate

Once started on the inpatient side, patients often

discharged home to finish a course

Emerging literature shows that shorter may be

better

Dellit et al. Clin Infect Dis 2007;44:159-77


More Parting Words …

Document, document, document

Pharmacist/technician malpractice insurance

available from multiple sources

Affordable

$100-150/year

Always a good idea

Compare to physician: $5,000-10,000/year

In Conclusion

FDA will release warnings and alerts

Contain broad statements and

recommendations

Important to understand the details

Treat each patient and situation as a unique

encounter

It is ok to deviate from FDA recommendations in

patient specific scenarios


Yellow Card: FDA Warnings on

Antibiotics

Monica V. Mahoney, PharmD, BCPS AQ-ID

Documents

Yellow Card: FDA Warnings on Antibiotics · treatment plan to manage and mitigate the FDA warnings ... Ensuring safety, efficacy, and security of drugs, biologics, and medical devices