ANTIBIOTIC UPDATE
Jon Hiles, PharmD, BCPS
Clinical Pharmacist – Infectious Diseases
Indiana University Health
Methodist and University Hospitals
Disclosure
• I have no actual or potential conflict of interest in relation
to this program or presentation.
• Special thanks to Mike Reichert, PharmD Candidate
Objectives
• Identify the pharmacologic profile and FDA-approved
indications for the following antimicrobials: telavancin,
dalbavancin, oritavancin, tedizolid,
ceftolozane/tazobactam, and ceftazidime/avibactam.
• Review efficacy data regarding the newly approved
antibiotics.
• Discuss advantages and disadvantages of the newly
approved antimicrobials and their role in therapy.
Telavancin (VIBATIV®)
Chemical structure of telavancin.
Chemical structure of vancomycin.
Antimicrobial Agents and Chemotherapy. 2004;48:3043-3050.
Telavancin (VIBATIV®)
The Assessment of Telavancin in Complicated Skin and
Skin Structure Infections (ATlaS)
• Telavancin (n=928) vs Vancomycin (n=939)
• Combination with Aztreonam (32%) and
Metronidazole (23%) when indicated
• Infections:
• Abscess (42%)
• Cellulitis (37%)
• Wound (14%)
• Infected Ulcers (5%)
• Infected Burns (1%)
Clinical Infectious Diseases. 2008;46:1683-1693
Telavancin (VIBATIV®)
The Assessment of Telavancin in Complicated Skin and
Skin Structure Infections (ATlaS)
• Vancomycin 1gm q12h adjusted as needed
• Telavancin 10 mg/kg q24h
• 7.5 mg/kg q24h for CrCl 30-50 ml/min
• 10 mg/kg q48h for CrCl <30 and HD
• Isolates Identified
MIC 90
Isolate
Number
Telavancin
Vancomycin
MSSA
336
0.5
1
MRSA
550
0.5
1
S. pyogenes
42
0.06
0.25
S. agalactiae
35
0.12
0.5
S. anginosus
18
0.06
1
E. faecalis
60
1
2
Clinical Infectious Diseases. 2008;46:1683-1693
Telavancin (VIBATIV®)
The Assessment of Telavancin in Complicated Skin and
Skin Structure Infections (ATlaS)
Test of Cure (%)
Isolates
Telavancin
Vancomycin
All
658/745 (88.3)
648/744 (87.1)
MSSA
160/181 (88.4)
154/176 (87.5)
MRSA
252/278 (90.6)
260/301 (86.4)
S. pyogenes
21/23(91.3)
23/25 (92)
S. agalactiae
15/19 (78.9)
17/19 (89.5)
S. anginosus
11/11 (100)
8/8 (100)
E. faecalis
25/27 (92.6)
28/34 (82.4)
Clinical Infectious Diseases. 2008;46:1683-1693
Telavancin (VIBATIV®)
The Assessment of Telavancin in Complicated Skin and
Skin Structure Infections (ATlaS)
Clinical Infectious Diseases. 2008;46:1683-1693
Telavancin (VIBATIV®)
The Assessment of Telavancin in Complicated Skin and
Skin Structure Infections (ATlaS)
• Side Effects
Telavancin Vancomycin
Taste disturbance
33%
7%
Nausea
27%
15%
Vomiting
14%
7%
Foamy Urine
13%
3%
Pruritus
3%
6%
Renal Dysfunction
3%
1%
Serious ADRs
7%
4%
DC’d Therapy
8%
6%
Clinical Infectious Diseases. 2008;46:1683-1693
Antimicrobial Agents and Chemotherapy. 2005;49:3163-3165
Dalbavancin (DALVANCE®)
Chemical structure of dalbavancin.
Chemical structure of vancomycin.
Drugs. 2010;70(7):859-886.
Dalbavancin (DALVANCE®)
Once Weekly Dalbavancin versus Daily Conventional
Therapy for Skin Infection (DisCover)
• Dalbavancin (n=652) vs Vancomycin-Linezolid(n=651)
• Combination with other antibiotics not reported
• Infections:
• Abscess (25%)
• Cellulitis (54%)
• Wound (21%)
New England Journal of Medicine. 2014;370(23):2169-2179.
Dalbavancin (DALVANCE®)
Once Weekly Dalbavancin versus Daily Conventional
Therapy for Skin Infection (DisCover)
• Vancomycin 1gm (15mg/kg) q12h x 3 days then option to
change to linezolid 600 mg PO BID x 10-14 days
• Dalbavancin 1 gm x 1 then 500 mg x 1 day 8
• CrCl <30: 750 mg x 1 then 375 mg x 1 day 8
MIC 90
• Isolates
Isolate Identified
Number
Dalbavancin
Vancomycin
MSSA
27052
0.06
1
MRSA
19721
0.06
1
S. pyogenes
5316
<0.03
0.5
S. agalactiae
2148
<0.03
1
E. faecalis
10025
0.6
NR
New England Journal of Medicine. 2014;370(23):2169-2179.
Dalbavancin (DALVANCE®)
Once Weekly Dalbavancin versus Daily Conventional
Therapy for Skin Infection (DisCover)
Test of Cure (%)
Isolates
Dalbavancin
Vancomycin Linezolid
All
547/570 (96.0)
527/545 (96.7)
Staph aureus
187/191 (97.9)
171/177 (96.6)
MRSA
72/74 (97.3)
49/50 (98)
S pyogenes
19/19 (100)
12/13 (92.3)
New England Journal of Medicine. 2014;370(23):2169-2179.
Dalbavancin (DALVANCE®)
Once Weekly Dalbavancin versus Daily Conventional
Therapy for Skin Infection (DisCover)
• Side Effects
Dalbavancin
Vancomycin Linezolid
Nausea
2.5%
2.9%
Diarrhea
0.8%
2.5%
Pruritus
0.6%
2.3%
Serious ADRs
0.3%
0.6%
DC’d Therapy
2.1%
2%
New England Journal of Medicine. 2014;370(23):2169-2179.
Antimicrobial Agents and Chemotherapy. 2004;48(3):1061-1064.
Oritavancin (ORBACTIV®)
Chemical structure of oritavancin.
Chemical structure of vancomycin.
Drugs. 2010;70(7):859-886.
Oritavancin (ORBACTIV®)
Single-Dose Oritavancin in the Treatment of Acute Bacterial
Skin Infections (SOlo)
• Oritavancin (n=475) vs Vancomycin(n=479)
• Combination with Aztreonam (10%) and
Metronidazole (3%) when indicated
• Infections:
• Abscess (30%)
• Cellulitis (50%)
• Wound (20%)
New England Journal of Medicine. 2014;370:2180-2190.
Oritavancin (ORBACTIV®)
Single-Dose Oritavancin in the Treatment of Acute Bacterial
Skin Infections (SOlo)
• Vancomycin 1gm (15mg/kg) q12h x 7-10 days
• Oritavancin 1200 mg x 1
MIC 90
Isolate
Number
Oritavancin
Vancomycin
MSSA
2958
0.06
1
MRSA
3376
0.06
1
Β-hemolytic
strep
216
0.12
1
VSE
1320
0.03
2
VRE
600
0.12
>16
Clinical Infectious Diseases. 2012;54:S203-S213.
New England Journal of Medicine. 2014;370:2180-2190.
Oritavancin (ORBACTIV®)
Single-Dose Oritavancin in the Treatment of Acute Bacterial
Skin Infections (SOlo)
Early Clinical Outcome(%)
Isolates
Oritavancin
Vancomycin
All
391/475 (82.3)
378/479 (78.9)
MSSA
96/116 (82.8)
92/110 (83.6)
MRSA
84/104 (80.8)
80/100 (80)
S. pyogenes
5/8 (62.5)
5/10 (50)
S. agalactiae
6/7 (85.7)
8/8 (100)
S. anginosus
12/13 (92.3)
14/16 (87.5)
E. faecalis
6/7 (85.7)
4/5 (80)
New England Journal of Medicine. 2014;370:2180-2190.
Oritavancin (ORBACTIV®)
Single-Dose Oritavancin in the Treatment of Acute Bacterial
Skin Infections (SOlo)
Side Effects
Oritavancin
Vancomycin
Nausea
11%
8.9%
Headache
7.2%
7.9%
Pruritus
3.4%
9.1%
LFT increase
2.3%
1%
Serious ADRs
0.6%
0.6%
DC’d Therapy
3.8%
5.8%
New England Journal of Medicine. 2014;370:2180-2190.
Journal of Antimicrobial Chemotherapy. 2009;63(6):1191-1199.
Glycopeptide Comparison
Vancomycin Telavancin
Dalbavancin
Oritavancin
T1/2
8 hrs
8 hrs
204 hrs
245 hrs
Vd
0.7 L/kg
0.13 L/kg
0.22 L/kg
1.25 L/kg
55%
90%
93%
85%
Dose
15-20 mg/kg
every 12 hrs
10 mg/kg
every 24 hrs
1000mg x1
then 500 mg x1
1 week later
1200 mg x 1
Dose Adjustments
Renal
Drug Levels
Renal
Renal
Severe Renal
Disease
Redman’s
Renal?
Taste
Nausea
Foamy Urine
Renal?
None
LFTs
%Protein Bound
Side Effects
T1/2, Half-life; Vd, Volume of Distribution; LFT, Liver Function Tests
Diagnostic Microbiology and Infectious Disease. 2015. 81:275-279.
Antimicrobial Agents and Chemotherapy. 2009. 53(3):1260-1263.
Glycopeptide Comparison
Vancomycin Telavancin
MIC 50/90
MSSA
MRSA
VRSA
VRE
Dalbavancin
Oritavancin
1/1
1/1
-
0.03/0.06
0.03/0.06
0.06/0.06
-
0.06/0.06
0.06/0.06
>4/>4
0.03/0.06
0.03/0.06
0.03/0.12
SSSI
Infective
Endocarditis
LRTI
Staph
Enterocolitis
MRSA
SSSI
Nosocomial
Pneumonia
SSSI
SSSI
Cost per Dose
$2.60
$337.34
$2812.52
$2737.02
Cost per Day
$5.21
$337.34
$401.79
$391.00
FDA Indications
Diagnostic Microbiology and Infectious Disease. 2015. 81:275-279.
Antimicrobial Agents and Chemotherapy. 2009. 53(3):1260-1263.
Tedizolid (SIVEXTRO®)
Chemical structure of tedizolid-prodrug.
Chemical structure of tedizolid.
Chemical structure of linezolid.
Antimicrobial Agents and Chemotherapy. 2011;55(11):5300-5305.
Tedizolid (SIVEXTRO®)
T 1/2
Vd
% Protein Bound
Dose
MIC 50/90
MSSA
MRSA
VRSA
VRE
Dose Adjustments
Side Effects
FDA Indication
Linezolid
4-5 hrs
40-50 L
31%
IV, PO: 600 mg every 12
hours
Tedizolid
12 hrs
67-80 L
70-80%
IV, PO: 200 mg daily
2/2
1/2
0.25 (median MIC)
2/2
0.25/0.5
0.25/0.25
2 (median MIC)
0.5/0.5
None
Nausea, headache,
diarrhea, vomiting
SSTI, CAP, Nosocomial
Pneumonia, VRE faecium
None
Nausea, Vomiting,
Diarrhea, headache
SSTI
Tedizolid (SIVEXTRO®)
Tedizolid Phosphate vs Linezolid for Treatment of Acute
Bacterial Skin and Skin Structure Infections (estaBliSh-1)
• Tedizolid (n=332) vs Linezolid (n=335)
• Patients with a gram-negative pathogen suspected were
excluded
• Infections:
• Abscess (30%)
• Cellulitis (40%)
• Wound (30%)
Journal of the American Medical Association. 2013;309(6):559-569.
Tedizolid (SIVEXTRO®)
Tedizolid Phosphate vs Linezolid for Treatment of Acute
Bacterial Skin and Skin Structure Infections (estaBliSh-1)
• Linezolid 600 mg orally twice daily x 10 days
• Tedizolid 200 mg orally daily x 6 days
MIC 90
Isolate
Number
Tedizolid
Linezolid
MSSA
39
0.25
2
MRSA
124
0.25
2
S. viridans
15
0.25
1
E. faecalis
54
0.25
2
Linezolid-R
S. aureus
7
1
16
Antimicrobial Agents and Chemotherapy. 2012;56:4608-4613.
Journal of the American Medical Association. 2013;309(6):559-569
Tedizolid (SIVEXTRO®)
Tedizolid Phosphate vs Linezolid for Treatment of Acute
Bacterial Skin and Skin Structure Infections (estaBliSh-1)
Test of Cure (%)
Isolates
Tedizolid
Linezolid
All
284/332 (85.5)
388/335 (86)
MSSA
73/83 (88)
82/87 (94.3)
MRSA
75/88 (85.2)
77/90 (85.6)
S. pyogenes
7/8 (87.5)
6/8 (75)
S. agalactiae
8/9 (88.9)
3/5 (60)
S. anginosus
11/15 (73.3)
12/15 (80)
Journal of the American Medical Association. 2013;309(6):559-569.
Tedizolid (SIVEXTRO®)
Tedizolid Phosphate vs Linezolid for Treatment of Acute
Bacterial Skin and Skin Structure Infections (estaBliSh-1)
• Side Effects
Tedizolid
Linezolid
Nausea
8.5%
13.4%
Vomiting
2.7%
6%
Headache
6.3%
5.1%
Diarrhea
4.5%
5.4%
Pruritus
0.9%
2.4%
Plt <150
3.2%
5.6%*
Serious ADRs
1.5%
1.2%
DC’d Therapy
0.6%
0.6%
*Includes data from both ESTABLISH 1 and 2
Journal of the American Medical Association. 2013;309(6):559-569.
Lancet Infectious Diseases. 2014;14:696-705.
Tedizolid (SIVEXTRO®)
Parameter
Tedizolid (200 mg daily)
Linezolid (600 mg BID)
Cmax
6.5
63.8
Protein Binding %
80
31
fCmax
1.3
43.4
IC50
8.7
46
fCmax/IC50
0.15
0.94
IC50
5.7
2.1
fCmax/IC50
0.23
21
MAO-A
MAO-B
Cmax, Concentration Maximum; fCmax, free Cmax; IC50, Inhibitory
Concentration 50%; MAO, Monoamine Oxidase
Antimicrobial Agents and Chemotherapy. 2013;57(7):3060-3066.
Acquisition Costs
Drug
Dosage Form Cost/Unit
Units/Day*
Cost/Day
Telavancin
750mg vial
$337.34
1
$337.34
Dalbavancin
500 mg vial
$1406.26
0.3**
$401.79
Oritavancin
400 mg vial
$912.34
0.4**
$391.00
Tedizolid
200 mg vial
$235.00
1
$235.00
Tedizolid
200 mg tablet
$295.00
1
$295.00
Linezolid
600 mg vial
$147.42
2
$294.84
Linezolid
600 mg tablet
$138.68
2
$277.36
Daptomycin
500 mg vial
$379.20
1
$379.20
Synercid
500 mg vial
$304.27
3
$912.80
Ceftaroline
600 mg vial
$107.40
2
$214.80
Vancomycin
1 gm vial
$2.60
2
$5.21
*70 kg patient
** Doses averaged over a 1 week duration of treatment
Patient Case
Patient presents to the ED with cellulitis. What can we
discharge him/her on.
A) Place PICC start Vancomycin
B) Oritavancin
C) Dalbavancin
D) Place PICC Telavancin
E) Bactrim PO
F) Keflex PO
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftazidime
Ceftolozane
Tazobactam
Drugs. 2014;74:31-51.
Ceftolozane/Tazobactam (ZERBAXA®)
MIC 50 / 90 of various clinical isolates
Organism
Ceftazidime
Ceftolozane
Ceftolozane/
Tazobactam
A. baumannii
8 / 16
-/-
0.5 / 2
Citrobacter spp
Ceftazidime R
0.25 / 64
>64 / >64
0.5 / 16
32 / >32
0.25 / 8
16 / >16
Enterobacter spp
Ceftazidime R
0.25 / >32
>32 / >32
0.5 / 16
>32 / >32
0.25 / 8
8 / 32
Escherichia coli
ESBL
0.25 / 8
16 / >32
0.12 / 0.5
64 / >64
0.12 / 0.5
0.5 / 4
Klebsiella spp
ESBL
0.12 / 32
32 / >32
0.25 / >32
>32 / >32
0.25 / 4
2 / >32
Pseudomonas
2 / 32
0.5 / 2
0.5 / 2
S. pneumoniae
0.25 / 8
<0.12 / 4
<0.12 / 4
Drugs. 2014;74:31-51.
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftolozane-tazobactam compared with levofloxacin in the
treatment of complicated urinary-tract infections, including
pyelonephritis (ASPECT-cUTI)
• Ceftolozane/tazobactam (n= 398) vs Levofloxacin (n=
402)
• Patients included if they had positive UA and clinically
diagnosed with complicated urinary tract infection or
pyelonephritis and identified pathogen.
Lancet. 2015;385;1949-1956.
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftolozane-tazobactam compared with levofloxacin in the
treatment of complicated urinary-tract infections, including
pyelonephritis (ASPECT-cUTI)
• Ceftolozane/tazobactam 1.5 gm IV every 8 hours x 7 days
• Levofloxacin 750 mg IV once daily x 7 days
Resistance at baseline:
• Ceftolozane/tazobactam 20/731 (2.7%)
• Levofloxacin 195/731 (26.7%)
Lancet. 2015;385;1949-1956.
Ceftolozane/Tazobactam (ZERBAXA®)
Lancet. 2015;385;1949-1956.
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftolozane-tazobactam compared with levofloxacin in the
treatment of complicated urinary-tract infections, including
pyelonephritis (ASPECT-cUTI)
• Side Effects
Ceftolozane/
tazobactam
Levofloxacin
Headache
5.8%
4.9%
Constipation
3.9%
3.2%
Nausea
2.8%
1.7%
Diarrhea
1.9%
4.3%
3%
1.3%
Pyrexia
1.5%
0.7%
Insomnia
1.3%
2.6%
Incr AST/ALT
1.7%
0.9%
Hypertension
Lancet. 2015;385;1949-1956.
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftolozane-tazobactam plus metronidazole for
complicated intra-abdominal infections in an era of
multidrug resistance (ASPECT-cIAI)
• Ceftolozane/tazobactam (n= 389) vs Meropenem (n= 417)
• Patients included if they had clinical evidence of a
complicated intra-abdominal infection and had operative
or percutaneous drainage of an infectious focus
confirming the presence of infection.
Clinical Infectious Diseases. 2015;Advanced Access:1-10.
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftolozane-tazobactam plus metronidazole for
complicated intra-abdominal infections in an era of
multidrug resistance (ASPECT-cIAI)
• Ceftolozane/tazobactam 1.5 gm IV every 8 hours plus
metronidazole 500 mg every 8 hours x 4 - 14 days
• Meropenem 1 gm IV every 8 hours x 4 - 14 days
Resistance at baseline:
• Ceftolozane/tazobactam
• Enterobacteriaceae 2.6%, Pseudomonas 1.4%
• Meropenem
• Enterobacteriaceae 0.1%, Pseudomonas 10.1%
Clinical Infectious Diseases. 2015;Advanced Access:1-10.
Ceftolozane/Tazobactam (ZERBAXA®)
Clinical Infectious Diseases. 2015;Advanced Access:1-10.
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftolozane-tazobactam plus metronidazole for
complicated intra-abdominal infections in an era of
multidrug resistance (ASPECT-cIAI)
• Side Effects
Ceftolozane/
tazobactam
Meropenem
Headache
2.5%
1.8%
Hypokalemia
2.9%
1.6%
Nausea
7.9%
5.8%
Diarrhea
6.2%
5%
Hypertension
1.9%
2%
Pyrexia
5.2%
4%
Insomnia
3.5%
2.2%
Clinical Infectious Diseases. 2015;Advanced Access:1-10.
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftolozane-tazobactam plus metronidazole for
complicated intra-abdominal infections in an era of
multidrug resistance (ASPECT-cIAI)
• Decreased efficacy in patients with CrCl <50
Dose
CrCl
Successful Outcome n/N (%)
Ceftolozane/
tazobactam
Meropenem
Ceftolozane/
tazobactam
Meropenem
>50
1.5 gm q8
1 gm q8
312/366 (85.2%)
355/404 (87.9%)
30-50
750 mg q8
1 gm q12
11/23 (47.8%)
9/13 (69.2%)
Clinical Infectious Diseases. 2015;Advanced Access:1-10.
Ceftolozane/Tazobactam (ZERBAXA®)
62 yo WM with a complex history of biliary fistula after a
necrotic gall bladder s/p resection and frequent stenting for
biliary obstruction presenting with increasing RUQ pain and
subjective fever
Ceftolozane/Tazobactam (ZERBAXA®)
A) Start Ceftolozane/Tazobactam
immediately
B) Start Colistin if patient becomes septic
and shows systemic sings of infection
C) Ask lab to place a
Ceftolozane/Tazobactam Etest to confirm
susceptibility
D) Both B and C
Ceftolozane/Tazobactam (ZERBAXA®)
Ceftazidime/Avibactam (AVYCAZ®)
Ceftazidime
Proceedings of the National Academy of Sciences. 2012;109(29):11663-11668.
Ceftazidime/Avibactam (AVYCAZ®)
MIC 50 / 90 of various clinical isolates
Organism
Ceftazidime
Ceftazidime/
Avibactam
Ceftolozane/
Tazobactam
Acinetobacter spp
32 / >32
16 / >32
0.5 / 2*
Enterobacter spp
Ceftazidime R
0.25 / 32
32 / >32
0.12 / 0.5
0.5 / 1
0.25 / 8
8 / 32
Escherichia coli
ESBL
0.12 / 2
16 / >32
0.06 / 0.12
0.12 / 0.25
0.12 / 0.5
0.5 / 4
Klebsiella spp
ESBL
Meropenem R
0.12 / 32
>32 / >32
>32 / >32
0.12 / 0.5
0.5 / 1
0.5 / 2
0.25 / 4
2 / >32
Pseudomonas
Ceftazidime R
Meropenem R
2 / 32
32 / >32
16 / >32
2/4
4 / 16
4 / 16
2 / 32
4/8
*Drugs 2014; 74:31-51.
Antimicrobial Agents and Chemotherapy. 2014;58(3):1684-1692.
Ceftazidime/Avibactam (AVYCAZ®)
KPC
Eastern, USA
VIM
Japan
NDM
Sweden (Indian patient)
NmcA
Paris, France
1985
Imipenem
FDA Approval
1991
1993
OXA-48
Turkey
1996
2001
Meropenem
FDA Approval
2003
Ertapenem
FDA Approval
VIM – Verona integron-encoded metallo-beta-lactamase
NmcA – Not metalloenzyme carbapenemase A
KPC – Klebsiella pneumoniae carbapenemases
OXA-48 – Oxacillinase-48
NDM – New Dehli metallo-beta-lactamase
2007 2008
Doripenem
FDA Approval
(Ambler Class B)
(Ambler Class A)
(Ambler Class A)
(Ambler Class D)
(Ambler Class B)
Emerging Infectious Diseases. 2011;17(10):1791-1798.
Ceftazidime/Avibactam (AVYCAZ®)
KPC-2
Colistin
Tetracycline
e
Cefepime
Tigecycline
Fosfomycin
Gentamicin
Emerging Infectious Diseases. 2011;17(10):1791-1798.
Ceftazidime/Avibactam (AVYCAZ®)
NDM-1
Colistin
Tetracycline
e
Tigecycline
Fosfomycin
Emerging Infectious Diseases. 2011;17(10):1791-1798.
Ceftazidime/Avibactam (AVYCAZ®)
OXA-48
Colistin
Rifampin
Ceftazidime
Cefotaxime
Aztreonam
Cefepime
Gentamicin
Emerging Infectious Diseases. 2011;17(10):1791-1798.
Ceftazidime/Avibactam (AVYCAZ®)
Ceftazidime/Avibactam (AVYCAZ®)
Efficacy and safety of ceftazidime-avibactam versus
imipenem-cilastatin in the treatment of complicated urinary
tract infections
• Ceftazidime/Avibactam (n= 27) vs
Imipenem/Cilastatin (n= 35)
• Patients included if they had positive UA and clinically
diagnosed with complicated urinary tract infection or
pyelonephritis and identified pathogen.
Current Medical Research and Opinion. 2012;28(12):1921-1931.
Ceftazidime/Avibactam (AVYCAZ®)
Efficacy and safety of ceftazidime-avibactam versus
imipenem-cilastatin in the treatment of complicated urinary
tract infections
• Ceftazidime/Avibactam 500/125mg IV every 8 hours x 714 days
• Imipenem/Cilastatin 500 mg IV every 8 hours x 7-14 days
(switch to oral ciprofloxacin was allowed after 4 days both groups)
Resistance at baseline:
• Ceftolozane/tazobactam 0%
• Imipenem/Cilastatin 0%
Current Medical Research and Opinion. 2012;28(12):1921-1931.
Ceftazidime/Avibactam (AVYCAZ®)
Current Medical Research and Opinion. 2012;28(12):1921-1931.
Ceftazidime/Avibactam (AVYCAZ®)
Efficacy and safety of ceftazidime-avibactam versus
imipenem-cilastatin in the treatment of complicated urinary
tract infections
• Side Effects
Ceftazidime/
Avibactam
Imipenem/
Cilastatin
Headache
19.1%
31.3%
Constipation
10.3%
3%
Diarrhea
8.8%
10.4%
Hypertension
5.9%
3%
Insomnia
5.9%
6%
Incr AST/ALT
2.9%
6%
Current Medical Research and Opinion. 2012;28(12):1921-1931.
Ceftazidime/Avibactam (AVYCAZ®)
Comparative study of the efficacy and safety of
ceftazidime/avibactam plus metronidazole versus
meropenem in the treatment of complicated intraabdominal infections in hospitalized adults
• Ceftazidime/Avibactam (n= 101) vs Meropenem (n= 102)
• Patients included if they had clinical evidence of a
complicated intra-abdominal infection and had operative
or percutaneous drainage of an infectious focus
confirming the presence of infection.
Journal of Antimicrobial Chemotherapy. 2013;68:1183-1192.
Ceftazidime/Avibactam (AVYCAZ®)
Comparative study of the efficacy and safety of
ceftazidime/avibactam plus metronidazole versus
meropenem in the treatment of complicated intraabdominal infections in hospitalized adults
• Ceftazidime/Avibactam 2.5 gm IV ever 8 hours plus
metronidazole 500 mg every 8 hours x 5 - 14 days
• Meropenem 1 gm IV every 8 hours x 5 - 14 days
Resistance at baseline:
• Ceftazidime/Avibactam 6/147 (4.1%)
• Meropenem 2/151 (1.3%)
Journal of Antimicrobial Chemotherapy. 2013;68:1183-1192.
Ceftazidime/Avibactam (AVYCAZ®)
Comparative study of the efficacy and safety of
ceftazidime/avibactam plus metronidazole versus
meropenem in the treatment of complicated intraabdominal infections in hospitalized adults
Ceftazidime/
Avibactam
Meropenem
n = 101
n = 102
Cure
84
91
Failure
17
11
n = 68
n = 76
Cure
62
71
Failure
6
5
MITT population
ME population
Not reported
-2.2% (95% CI: -20.4%, 12.2%)
Journal of Antimicrobial Chemotherapy. 2013;68:1183-1192.
Ceftazidime/Avibactam (AVYCAZ®)
Comparative study of the efficacy and safety of
ceftazidime/avibactam plus metronidazole versus
meropenem in the treatment of complicated intraabdominal infections in hospitalized adults
• Side Effects
Ceftazidime/
Avibactam
Meropenem
Nausea
9.9%
5.6%
Vomiting
13.9%
4.9%
Abdominal Pain
7.9%
2.9%
Pyrexia
8.9%
10.8%
Incr AST
8.9%
14.7%
Ceftazidime/Avibactam (AVYCAZ®)
Comparative study of the efficacy and safety of
ceftazidime/avibactam plus metronidazole versus
meropenem in the treatment of complicated intraabdominal infections in hospitalized adults
• Decreased efficacy in patients with CrCl <50
Dose
CrCl
>50
30-50
Mortality n/N (%)
Ceftazidime/
Avibactam
Meropenem
Ceftazidime/
Avibactam
Meropenem
2.5 gm q8
1 gm q8
5/498 (1%)
5/494 (1%)
940 mg q8
1 gm q12
8/31 (25.8%)
3/35 (8.6%)
Recommended dose for Ceftazidime/Avibactam in patients with
a CrCl 30-50 has ben adjusted to 1.25 gm q8 as a result
Journal of Antimicrobial Chemotherapy. 2013;68:1183-1192.
Acquisition Costs
Drug
Dosage Form Cost/Unit
Units/Day*
Cost/Day
Ceftolozane/
Tazobactam
1.5 gm vial
$83.00
3
$249.00
Ceftazidime/
Avibactam
2.5 gm vial
$268.98
3
$806.95
Cefepime
1 gm vial
$2.59
3
$7.77
Piperacillin/
Tazobactam
3.375 gm vial
$3.54
3
$10.62
Meropenem
1 gm vial
$8.87
3
$26.62
Tigecycline
50 mg vial
$111.37
2
$222.74
*70 kg patient
Ceftazidime/Avibactam (AVYCAZ®)
Ceftazidime/Avibactam (AVYCAZ®)
Which would NOT be an alternative to
Ceftazidime/Avibactam?
A) Tigecycline
B) Colistin
C) Gentamicin
D) Amikacin
E) Cefepime
F) Fosfomycin
The moment a new antibiotic enters widespread use, its days are numbered.
References
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•
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novel bactericidal agent, against gram-positive bacteria. Antimicrobial Agents and
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Stryjewski ME, Graham DR, Wilson SE, et al. Telavancin versus vancomycin for the
treatment of complicated skin and skin structure infections caused by gram-positive
organisms. Clinical Infectious Diseases. 2008;46:1683-1693.
Zhanel GG, Calic D, Schweizer F et al. New lipoglycopeptides A comparative review of
dalbavancin, oritavancin and telavancin. Drugs. 2010;70(7):859-886.
Boucher HW, Wilcox M, Talbot GH et al. Once-weekly dalbavancin versus daily
conventional therapy for skin infections. New England Journal of Medicine.
2014;370(23):2169-2179.
Lefort A, Pavie J, Garry L et al. Activities of dalbavancin in vitro and in a rabbit model of
experimental endocarditis due to Staphylococcus aureus with or without reduced
susceptibility to vancomycin and teicoplanin. Antimicrobial Agents and Chemotherapy.
2004;48(3):1061-1064.
Corey GR, Kabler H, Mehra P et al. Single-dose oritavancin in the treatment of acute
bacterial skin infections. New England Journal of Medicine. 2014;370:2180-2190.
Mendes RE, Farrell DJ, Sader HS et al. Oritavancin microbiologic features and activity
results from the surveillance program in the United States. Clinicial Infectious Diseases.
2012;54:S203-S213.
McKay GA, Beaulieu, Arhin FF et al. Time-kill kinetics of oritavancin and comparator
agents against Staphylococcus aureus, Enterococcus faecalis and Enterococcus
faecium. Journal of Antimicrobial Chemotherapy. 2009;63(6):1191-1199.
References
• Mendes RE, Farrell DJ, Sader HS et al. Update of the telavancin activity in vitro tested
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against a worldwide collection of Gram-positive clinical isolates (2013), when applying the
revised susceptibility testing method. Diagnostic Microbiology and Infectious Disease.
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Biedenbach DJ, Bell JM, Sader HS et al. Activities of dalbavancin against a worldwide
collection of 81,673 gram-positive isolates. Antimicrobial Agents and Chemotherapy. 2009.
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Drusano GL, Liu W, Kulawy R et al. Impact of granulocytes on the antimicrobial effect of
tedizolid in a mouse thigh infection model. Antimicrobial Agents and Chemotherapy.
2011;55(11):5300-5305.
Prokocimer P, De Anda C, Fang E et al. Tedizolid phosphate vs linezolid for treatment of
acute bacterial skin and skin structure infections. Journal of the American Medical
Association. 2013;309(6):559-569.
Prokocimer P, Bien P, Deanda C et al. In vitro activity and microbiological efficacy of
tedizolid (TR-700) Against gram-positive clinical isolates from a phase 2 study of oral
tedizolid phosphate (TR-701) in patients with complicated skin and skin structure infections.
Antimicrobial Agents and Chemotherapy. 2012;56:4608-4613.
Moran GJ, Fang E, Corey GR et al. Tedizolid for 6 days versus linezolid for 10 days for
acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, doubleblind, phase-3, non-inferiority trial. Lancet Infectious Diseases. 2014;14:696-705.
References
• Moran GJ, Fang E, Corey GR et al. Tedizolid for 6 days versus linezolid for 10 days for
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acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, doubleblind, phase-3, non-inferiority trial. Lancet Infectious Diseases. 2014;14:696-705.
Flanagan S, Bartizal K, Minassian SL et al. In vitro, in vivo, and clinical studies of
tedizolid to assess the potential for peripheral or central monoamine oxidase
interactions. Antimicrobial Agents and Chemotherapy. 2013;57(7):3060-3066.
Zhanel GG, Chung P, Adam H et al. Ceftolozane/tazobactam a novel
cephalosporin/beta-lactamase inhibitor combination with activity against multidrugresistant gram-negative bacilli. Drugs. 2014;74:31-51.
Wagenlehner FM, Umeh O, Steenbergen J et al. Ceftolozane-tazobactam compared
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References
• Nordmann P, Nass T, and Poirel L. Global spread of carbapenemase-producing
enterobacteriaceae. Emerging Infectious Diseases. 2011;17(10):1791-1798.
• Vazquez JA, Patzan LDG, Stricklin D et al. Efficacy and safety of ceftazidime-avibactam
versus imipenem-cilastatin in the treatment of complicated urinary tract infections,
including acute pyelonephritis, in hospitalized adults: results of a prospoective,
infestigator-blinded, randomized study. Current Medical Research and Opinion.
2012;28(12):1921-1931.
• Lucasti C, Popescu I, Ramesh MK et al. Comparative study of the efficacy and safety of
ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of
complicated intra-abdominal infections in hospitalized adults: results of a randomized,
double-blind, phase II trial. Journal of Antimicrobial Chemotherapy. 2013;68:1183-1192.
Acquisition Costs
Drug
Dosage Form Cost/Unit
Units/Day*
Cost/Day
Isavuconazole 186 mg cap
$48.00
2
$96
Isavuconazole 372 mg vial
$225.00
1
$225.00
Posaconazole 100mg ER tab $54.76
3
$164.28
Posaconazole 300 mg vial
$500.00
1
$500.00
Voriconazole
200 mg vial
$75.52
3
$226.56
Voriconazole
200 mg tab
$15.09
3
$45.28
Micafungin
100 mg vial
$61.78
1
$61.78
*70 kg patient