Antibiotic Update

71 Pages·2016·9.46 MB·English

12/23/2016
Antibiotic Update
Prepared by: Leany Capote
University of Miami Health System PGY-1
January 2017
Goals and Objectives
Discuss the mechanism of action,
pharmacodynamics, and
pharmacokinetics of novel antibiotics
Summarize FDA-approved indications
for these novel antibiotics
Compare and contrast these novel
antibiotics and traditional agents
Abbreviations
 ESKAPE: Enterobacter  VABP: Ventilator Associated
species, Klebsiella, Bacterial Pneumonia
Pseudomonas, E. coli  PNA: Pneumonia
 GAIN: Generating Antibiotic  cIAI: Complicated intra-
Incentives Now abdominal infections
 QIDP: Qualified Infectious  ctrUaTcIt: i nCfoemctpiolincsa ted urinary
Disease Products
 MSSA: Methicillin susceptible
 ABSSSI: Acute bacterial skin staphylococcus aureus
and skin structural infections  MRSA: Methicillin resistant
 cSSSI: Complicated skin and staphylococcus aureus
skin structural infections  VRSA: Vancomycin resistant
 CAP: Community Acquired staphylococcus aureus
Pneumonia  VRE: Vancomycin resistant
 HABP: Hospital Acquired enterococcus
Bacterial Pneumonia  MOA: Mechanism of action
1
12/23/2016
Abbreviations
 DI: Drug Interactions  MAOI: Monoamine oxidase
 PO: oral, IV: Intravenously inhibitor
 RCT: Randomized controlled  Amp-c: Beta lactamase gene
trial  KPCs: Klebsiella pneumoniae
 ITT: Intended to treat group carbapenamases
 ME/CE: Experimental group  CRE: Carbapenem resistant
 n: Sample Size Enterobacteriaceae
 Crcl: Creatinine Clearance  CC: Chief Complaint
 CI: Confidence interval  HTN: Hypertension
 PT: Prothrombin time  BP: Blood Pressure
 INR: International  HR: Heart Rate
normalization ratio  Temp: Temperature
 aPPT: Activated partial  MDR: Multi drug resistant
thromboplastin time  ESBL: Extended spectrum beta
 QTc: QT-interval lactamase
 CI: Contraindicated  GNR: gram negative rods
 HNPEK: H, influenza, Neisseria,
Proteus, E. coli, Klebsiella
Background
FDA Approved Antibiotics
Boucher et al. Clinical Infectious Diseases 2013
Antibiotic Resistance
Seeing is Believing
Harvard Medical School andTechnion-Israel Institute of Technology; Sept 2016
2
12/23/2016
Background
 Infections secondary to antibiotic-resistant
bacteria are on the rise
 Gram negative bacilli, Klebsiella pneumoniae,
Acinetobacter baumannii, Pseudomonas aeruginosa
and Enterobacter species (ESKAPE)
 Innovation Act: GAIN; July 9, 2012
 Extends exclusivity to 5 years for new antibiotics to
treat serious or life-threatening infections (targeted
indications)
 Qualified Infectious Disease Products (QIDP) gain fast
track and priority review status
GAIN: Generating Antibiotic Incentives Now
ESKAPE Organisms
Bad Bugs, No Drugs: No ESKAPE!
EE SS KK AA PP EE
Enterobacter species -Klebsiella –Acinetobacter –Pseudomonas -E.coli
Qualified Infectious
Disease Products
 Acinetobacter species  Streptococcus pyogenes
 Enterobactericaceae  Aspergillus species
species  Burkholderia cepacia
 Pseudomonas species complex
 Campylobacter species  Coccidoides species
 Candida species  Crytococcus species
 Clostridium difficile  Helicobacter pylori
 Enterococcus species  Neisseria meningitides
 M. tuberculosis complex  Non-tuberculous
Mycobacteria
 Neisseria gonorrhoeae
 Staphylococcus aureus  Staphylococcus agalactiae
 Streptococcus pneumoniae  Vibrio cholera
Bold: ESKAPE; Underlined: QIDP
All listed organisms are on the Center of Disease Control (CDC) urgent threat list
3
12/23/2016
Targeted Indications
 Acute bacterial skin and skin structural infections
(aSSTI)
 Hospital acquired pneumonia/ventilator
associated pneumonia (HAP/VAP)
 Complicated intra-abdominal infections (cIAI)
 Complicated urinary tract infections (cUTI)
FDA Approved Antibiotics
Timeline
Telavancin Oritavancin
September 11, 2009 August 6, 2014
GAIN
2012
Dalbavancin Ceftolozane/
May 23, 2014 Tazobactam
December 19, 2014
Ceftazidime/
Tedizolid
Avibactam
June 20, 2014
February 25, 2015
Emerging Antibiotics
Meropenem + RPX7009 (Carbavance)
Imipenem/Relebactam (MK7655)
Plazomicin (ACHN-4901)
 All cover Qualified Infectious Disease Products
(QIDP)
4
12/23/2016
Telavancin (Vibativ®)
 September 11, 2009
 Coverage: Gram Positives
 Staphylococcus aureus
•Methicillin susceptible staphylococcus aureus + Methicillin
resistant staphylococcus aureus (MSSA + MRSA)
 Streptococcus pyogenes
 Streptococcus agalactiae
 Streptococcus anginosus group
 Enterococcus faecalis
•Vancomycin resistant enterococcus (VRE)
Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
Telavancin
Pharmacology and Pharmacokinetics
 Class: Synthetic lipoglycopeptide
 Mechanism of Action (MOA):Interferes with cell
wall synthesis and depolarizes the bacterial
membrane
 Metabolites: None detectable
 Metabolism: Non-significant
 Excretion: Kidney (76% excreted in urine)
 Half-life: ~8 hours
 Drug interactions: Non-significant
Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
Telavancin Trials
Two Phase 3 Trials
Design Sample Intervention Infections
RCT 1867 - Telavancin10 mg/kg IV Cellulitis,major
every 24 hours abscesses, wound
- Vancomycin1000 mg IV infections, burn and
every 12 hours ulcer
Clinical Response Rates in ABSSSI Trials using Responders at 48-
72 Hours after Initiation of Therapy
Trial VIBATIV Vancomycin Difference
n/N% n/N (%) 95%CI
1: ITT 72.5% (309/426) 71.6% (307/429) 0.9 (-5.3, 7.2)
1:CE 84.3% (289/343) 82.8% (288/348) 1.5 (-4.3, 7.3)
2: ITT 74.7% (342/458) 74.0% (356/481) 0.7 (-5.1, 6.5)
2:CE 83.9% (302/360) 87.7% (315/359) -3.8 (-9.2, 1.5)
Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
5
12/23/2016
Telavancin Trials
Two Phase 3 Trials
All-Cause Mortality at Day 28 in Patients with at least One Baseline
Gram-Positive Pathogen
Trial VIBACTIV Vancomycin Difference 95%CI
1 28.7% (n= 187) 24.3 (n=180) 4.4% (-4.71, 13.5% )
CrCl ≤ 50 41.8% (n=63) 35.4% (n=68) 6.4% (-10.4-23.2%)
CrCl > 50 22.0% 17.6% (n=112) 4.4% (-5.9-14.7%)
2 24.3% (n=22) 22.3% (n=206) 2.0% (-6.1%, 10%)
CrCl ≤ 50 43.9% (n=53) 29.6% (n=58) 14.3% (-3.6, 32.2)
CrCl > 50 18.2% (n=171) 19.3% (n=148) -1.1% (-9.8, 7.6)
Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
Telavancin
Indications and Dosages
 Complicated skin and skin structure infection
(CSSSI)
 10 mg/kg IV over 60 minutes every 24 hours for 14
days
 HABP/VABP
 10 mg/kg IV over 60 minute every 24 hours for 21 days
 Renal or hepatic dose adjustments:
 Renal adjustment is required once CrCl < 50 mL/min
 Formulations:
 Solution for injection
•750 mg/vial
Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
Telavancin
Adverse Events, Warnings and
Precautions
 Adverse Events:
 Taste disturbance (33%)
 Nausea (5-27%)
 Vomiting (5-14%)
 Foamy urine (13%)
 Diarrhea (7%)
 Contraindications:
 Hypersensitivity to telavancin
•Potential to cross-react with vancomycin
Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
6
12/23/2016
Telavancin
Adverse Events, Warnings and
Precautions
 Warning and Precautions:
 Decreased efficacy in moderate/severe pre-existing
renal impairment
 Hypersensitivity reactions
 Infusion-related reactions
•To avoid “Red-man syndrome”: Administer over 60
minutes
 Clostridium difficile-associated diarrhea
 Coagulation test interference
•Falsely elevates PT, INR, aPPT
 QTc prolongation
Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
Telavancin
Adverse Events, Warnings and
Precautions
 Black Box Warning:
 Use in moderate/severe renal impairment
(CrCl < 50 ml/min) should only be considered if benefit
outweighs risk
•Increased mortality observed
 Nephrotoxicity
 Avoid use in pregnancy
•Pregnancy test should be administered prior to initiation
•Potential fetal risk
 REMS program
 Requires a medication guide and communication plan
REMS: Risk Evaluation and Mitigation Strategies Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
Telavancin
Advantages and Disadvantages
Advantages: Disadvantages
 Effective against  Only available as IV
lung infections  More nephrotoxic
 Less monitoring  QTc Prolongation
required
 CI in pregnancy
 Acodvdeitriaogneal MRSA  Coagulation test
interference
Telavancin [package insert] San Francisco, CA; Theravance Biopharma antibiotics INC; 2009
7
12/23/2016
Comparator
Considerations Telavancin Vancomycin
Coverage • MRSA, VRE • MRSA
Side Effects • BBW: nephrotoxic, • Nephrotoxic
contraindicated in
pregnancy
• QTc Prolongation
AWP/day • $449.93 (75 kg) • $9.12 (75 kg)
• (10 mg/kg) • (15 mg/kg)
Other • Less monitoring • More monitoring
• Only indicated for • Additional indications
SSTI and for PNA , endocarditis,
nosocomial PNA osteomyelitis,
• Coagulation test septicemia
interference
AWP: Average wholesale price
Dalbavancin (Dalvance®)
 Approved May 23, 2014
 Coverage: Gram Positives
 Staphylococcus aureus (MSSA + MRSA)
 Streptococcus anginosus
 Streptococcus pyogenes
 Streptococcus agalactiae
Dalbavancin [package insert] Chicago,IL;Durata therapeutics INC;2014
Dalbavancin
Pharmacology and Pharmacokinetics
 Class: Semisynthetic lipoglycopeptide
 Mechanism of Action: Disrupts cell wall synthesis
by binding D-alanyl-D-alanine terminus of
peptidoglycan
 Excretion: Evenly excreted in urine (30%) and
feces (20%)
 Minor metabolite excreted in urine
 Half-life: ~346 hours (~2 weeks)
 Drug Interactions (DI): Non-significant
Dalbavancin [package insert] Chicago,IL;Durata therapeutics INC;2014
8
12/23/2016
Dalbavancin Trials
Two Phase 3 Trials
Design Sample Intervention Infections
Randomized 1312 - Dalbavancin1000 mg IV x 1, then Cellulitis, major
control trial 500 mg IV x 1 7 days later abscesses and
(RCT) - Vancomycin1000 mg or 15 mg/kg wound infections
IV q12h x 3 days then switched to
linezolid 600mg PO q12h
Clinical Response Rates in ABSSSI Trials at 48-72 Hours after
Initiation of Therapy
Trial DALVANCE Vancomycin/Linezolid Difference
n/N (%) n/N (%) 95%CI
1 240/288 (83.3%) 233/285 (81.8%) 1.5% (-4.6. 7.9)
2 285/371 (76.8%) 288/368 (78.3%) -1.5% (-7.4, 4.6)
Dalbavancin [package insert] Chicago,IL;Durata therapeutics INC;2014
Dalbavancin
Indications and Dosages
 Acute bacterial skin and skin structure infections
(ABSSSI)
 Regimen:
•1000 mg IV over 30 minutes one time then
•500 mg IV over 30 minutes one time
 Administered one week after first infusion
 Dalbavancin 1500mg delivered as a single dose was
noninferior to a 2-dose regimen
 Renal Adjustment
•Renal adjustment is required once CrCl < 30 mL/min
 Formulations
 Solution for injection (500 mg/vial)
Dalbavancin [package insert] Chicago, IL; Durata therapeutics INC;2014
Dunne, M. Clinical Infectious Diseases, 62(5), 545-551; 2016
Dalbavancin
Adverse Events, Warning and
Precautions
 Adverse Events
 Headache (3.8-4.7%)
 Diarrhea (3.4-4.4%)
 Nausea (2.0-5.5%)
 Hypersensitivity Reactions
 Cross-sensitivity with other glycopeptides
 Infusion-related reactions (<2%)
 Hepatic effects (<2%)
 Clostridium difficile associated diarrhea
Dalbavancin [package insert] Chicago,IL;Durata therapeutics INC;2014
9
12/23/2016
Dalbavancin
Advantages and Disadvantages
Advantages Disadvantages
Commonly used Lacks
 
Minimal drug Enterococcus sp.

interactions coverage
 Dosing regimen  Hepatic
impairment
Reduced

nephrotoxicity  Only available IV
Dalbavancin [package insert] Chicago,IL;Durata therapeutics INC;2014
Comparator
Considerations Dalbavancin Vancomycin
Coverage • MRSA • MRSA
• Enterococcus sp.
Side Effects • Hepatic impairment • More nephrotoxic
• Nephrotoxic
AWP/week • $5,364 • $63.84 (75kg)
Other • Simple dosing • More monitoring
regimen • Additional indications
• Only indicated for for PNA, endocarditis,
SSTIs osteomyelitis,
septicemia
AWP: Average wholesale price
Tedizolid (Sivextro®)
 Approved June 20, 2014
 Coverage: Gram Positives
 Staphylococcus aureus (MSSA + MRSA)
 Streptococcus anginosus
 Streptococcus pyogenes
 Streptococcus agalactiae
 Enterococcus faecalis and faecium (VRE)
Tedizolid [package insert] Ferentino, Italy; Merck and CO; 2014
10