Presented at the Egyptian African Critical care Summit, Egypt

1. Emerging
Antibiotic in ICU
Ahmed elmenshawy MD
Alexandria University

2. Disclosure
• No Conflict of interest

3. Increasing resistance
Problem
Solutions
Conclusions

4. Problem

5. Classification of Drug resistance
• XDR+
• Polymixin
Pan
PDR
• MDR+
carbapenem
Extensive
XDR
• Cephalosporins
• B-lactam/B-
lactamases
inhibitor
• Aminoglycosides
• Fluroquinolones
Multi
MDR
At least 3

6. ESKAPE pathogens
• Enterococcus faecium ….VRE
• Staphylococcus aureus ..MRSA, VISA,VRSA
• Klebsiella pneumoniae
• Acinetobacter baumanii
• Pseudomonas aeruginosa,
• Enterobacteriaceae
Gram Negative
ESBL, carbepamase
Gram Positive

7. Acientobacter resistance to
antibiotics
Journal of thoracic disease

8. Staphylococcus auresus sensitivity
to Vancomycin
100 100
90
100 100 100
100 100
100
84
86
88
90
92
94
96
98
100
102
2008 2009 2010 2011 2012 2013 2014 2015 2016
Vancomycin
Alexandria Critical Care Department

9. Klebsiella pneumonia sensitivity to
carbapenem
100 100 100
84.6
71.8
52.1
63 61.5
59 58
45
50
97.4
89.5
62.1
73.6 73
71.1 73
50
86
0
20
40
60
80
100
120
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department

10. Pseudomonas aeruginosa
sensitivity to carbapenems
42
32.5
41.3 47.6
30.6
45
51
53
35
49
38.8
40.8
48.1
24.9
28.5
41
57
31
0
10
20
30
40
50
60
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department

11. Acinetobacter baumanii
sensitivity to carbanems
22.1
17.6
14.1
3.8
8.4
6.5
29
9 8.3
39.6
34.5
16.7
11.8 13.6
22
29
9
6
0
5
10
15
20
25
30
35
40
45
2008 2009 2010 2011 2012 2013 2014 2015 2016
Meropenem Impinem
Alexandria Critical Care Department

12. Solutions

13. New antibiotic
2009 Infectious disease Society of America launched 10x20 initiatives
10 new antibiotics by year 2020
Rediscover old antibiotic
Polymoxin B chloramphenicol
Pharmacoknitics
Increasing dosage Prolonged infusion

14. •Ceftobiprole
•Ceftaroline,
Cephalsporin
•Ceftozolane/tazobactam
•Ceftazidim/Avibactam
B-lactamase inhibitors
•doripenem, biapenem, Tomopenem
•razupenem, Panipenem TebipenemCarbapenem
•telavancin, oritavancin
Dalbavancin
Glycopeptides
•Tedizolid
•Radezolid
Oxazolidinones
•Gatifloxacin Delafloxacin Nemonoxacin
•Zabofloxacin Finafloxacin ozenoxacin BesifloxacinQuinolones:
•Eravacycline
•Omadacycline
Tetracyclines:
•Plazomicin
Aminoglycosides:

15. 5th Cephalosporins
1. Ceftobiprole medocaril
2. Ceftaroline fosamil

16. Ceftobiprole medocaril
• Better than other cephalosporins aganist:
1. MRSA, VISA, VRSA, macrolide-resistant S. pyogenes
• bind to PBP2a, protein conferring ORSA resistance to b-lactam
2. Penicillin-resistant S. pneumoniae
• bind PBP2x in.
3. Enterococci (fecalis not feacium)
4. Enterobacteriaceae NOT ESBL (as ceftazidime or cefepime)
5. Pseudomonas species superior to cefepime
• Trials: (phase 3)
1. Complicated skin and soft tissue infection “cSSSI“ (MRSA)
2. CAP and HAP (not VAP) Bassetti, M. Springer 2015

17. Ceftaroline fosamil
• Similar to Ceftobiprole:
1. MRSA, heteroresistant VISA, VRSA (PBP2a inhibition )
2. No Enterococci
3. less activity against gram-ve (as ceftriaxone)
• Not ESBL-producing Enterobacteriaceae,
• Not Pseudomonas aeruginosa,
• Not Acinetobacter baumanii,
• Not Bacteroides fragilis
• FDA (2010) and European Medical Agency (EMA) (2012) for
1. SSSIs including MRSA
2. CAP including MDR S pneumonia
Bassetti, M. Springer 2015

18. B-lactam &B-
lactamase inhibitor
1. Tazobactam: Ceftozolane/tazobactam
2. Avibactam: Ceftazidime/avibactam
3. MK-7655

19. Target for beta-
lactamase enzymes
B- lactamases
bacterial enzymes able to hydrolyse a wide
variety of penicillins and cephalosporins
 Class A -
• penicillinases
• ESBL
• Carbapenemases
 Class C –
 Amp C enzymes – not inhibited by clavulanic acid
 Class D –
 Oxacillinases, some are carbapenemases
 Class B –
 Metallo betalactamases [MBL] -inhibited by metal ion
chelators
inhibited by
clavulanic acid

20. Ceftozolane/tazobactam
• Superior to ceftazidime in:
1. Greater gram –ve coverage
• Most ESBL producing enterobactracae
• Bacteroides spp
2. Unique anti-Psuedomonal
• superior to ceftazidime, carbapenem, piperacillin/tazobactam
• ability to escape various resistance mechanisms (e.g., PBP
mutations, efflux pumps)
• Not to carbapemenases or metallo-B-lactamases (MBL)
• Trial: (Phase 3)
1. Complicated intrabdominal infections (as meropenem) cIAI
2. Complicated UTI (superior to levofloxacin) “cUTI”
3. Ongoing for HAP/VAP
Zhanel,GG. Springer 2013

21. New B-lactamases inhibitors
• Avibactam
• beta-lactamase inhibitor characterized by
• high affinity with class A and C and some D B-lactamases
• potential to inhibit ESBLs, KPCs, OXA, and AmpC
• Combinations
1. with ceftazidime (Phase 3)
2. with ceftaroline (Phase 1)
3. With aztreonam (phase 1)
• MK-7655 another novel beta-lactamase inhibitor under
investigation
• activity against class A and class C carbapenemases
• Ongoing phase 2 trials for cIAIs and cUTIs (with imipenem/cilastatin)
• BLI-489 inhibit Class A,C,D lactamases (with piperacillin)

22. Ceftazidime/avibactam
• Active against:
1. ESBL
2. AmpC strains
3. OXA-48, and Klebsiella carbamases (KPC)
4. MDR psuedomonas
• not metallo-beta-lactamase, not likely Acinetobacter
• Trials:
1. Phase 3 in cIAIs, cUTIs, HAP, and VAP.
2. cIAIs (as to meropenem) in combination with
metronidazole
Sharma R, Clin Ther 2016

23. Carbapenem
S aureus MRSA Strep Entero GNR Anaerobe Pseud/Acinet
Impinem ++++ - +++ Fecalis +++ ++++ ++
Meropenem ++++ - ++ Fecalis +++ ++++ +++
Doripenem +++ - +++ Fecalis +++ ++++ ++++
Biapenem +++ - +++ - +++ ++++ ++
tomopenem +++ ++ ++++ ++ ++ ++
razupenem +++ ++ ++++ fecium ++ ++ ++
Panpenem ++++ - ++ Fecalis ++++ ++++ +++
Ertapenem +++ - ++++ Fecalis ++++ ++++ -
tebipenem +++ - ++++ Fecalis ++++ ++++ -
Sulopenem +++ - +++ +++ ++++ -
Bassetti, M. Springer 2015

24. Clinical indications
Carbapenem Clinical indications
Meropenem/impinem HAP, cUTIs, cIAIs, and BSI FDA
Doripenem
0.5 G/8 hr
pyelonephritis, cUTI, and cIAI,
HAP,VAP
FDA,
EMA
doripenem + colisitin colistin-resistant, carbapenemase
producing K. pneumoniae (KPC)
RCT
Tebipenem/pivoxil (oral)
Sulopenem (oral)
Upper resp tract infection
still undergoing trials
Jaban 3rd phase
Panipenem/betamipron
0.5g/12 hr
UTIs, lower RTI,
obstetrical/gynaecological, and
surgical infections.
FDA China, Korea
Japan
Biapenem 0.3g/12 hr RTIs and UTIs RCT
Tomopenem cSSSI and HAP. RCT
Razupenem cSSSI RCT
Bassetti, M. Springer 2015

25. Glycopeptide
Dosing Tissue
penetration
Renal
toxicity
MRSA VISA VRE MDR S
Pne
CoNS
vancomycin 8-12 h + +++ ++ - - ++ ++
teicoplanin 24 hr ++ - ++ +/- - ++ ++
telavancin 24 hr ++++ ++++ ++++ ++ Van-
A
+++ +++
oritavancin 1 dose ++++ - ++++ +++ Van-
A/B
++++ ++++
dalbavancin q 1W ++++ - ++++ +++ Van-
A
++++ ++++
Devasahayam G, Expert Opin Investig Drugs. 2010

26. Clinical indications
• *Telavancin has good penetration in the alveolar
macrophages, and unlike daptomycin, its activity is not
affected by pulmonary surfactant
Telavancin cSSSI FDA
MRSA HAP and VAP* EMA
S. aureus bacteremia 3rd phase trial
oritavancin SSSIs due to MSSA, MRSA, Strep & E. faecalis. FDA
dalbavancin SSSI, including those caused by MRSA.
Catheter- related BSI
FDA
Phase 2 trial
Devasahayam G, Expert Opin Investig Drugs. 2010

27. Oxazolidinones
Tedizolid
• oral and IV
• superior than linezolid
1. Staphylococcus spp.,
2. Streptococcus spp.,
3. Enterococcus spp.
4. Anaerobes
• once daily
• Better safety profile.
• No hematological Side effects
• does not inhibit the
monoamine oxidase pathway
• FDA approved for SSSI
Radezolid
• higher efficacy than linezolid
1. S. pneumoniae , S. pyogenes.
2. Staphylococci
3. Enterococci
4. GNR: H. influenzae & Moraxella
catarrhalis (commonly in CAP)
• Phase 2 trial: uncomplicated
SSSI, CAP

28. Quinolones
Gram+ve MRSA Gram-ve Psued Acine VRE
norfloxacin,
ciprofloxacin
ofloxacin
++ - ++ +++ - -
moxifloxacin ++ - ++ + -
gatifloxacin ++ ++ +++ -
*Delafloxacin ++++ ++++ +++ + -
*Nemonoxacin ++++ ++++ +++ + ++
*Zabofloxacin ++++ ++++ +++ +
*Finafloxacin +++ ++++ +
*JNJ-Q2 ++++ ++++ +++ - - _
*WCK771 ++++ ++++ ++ - - -
ozenoxacin ++++ ++++ ++ - - -
besifloxacin +++ ++++ ++ - - ++
*Low potential for development of resistance due to multiple mechanisms of action

29. Clinical indications
Quinolones RTIs, UTIs, SSSI, and IAIs FDA
moxifloxacin
gatifloxacin
CAP and HAP FDA,
EMA
Delafloxacin CAP (oral/iv) and HAP
SSSI 3rd phase trial
Nemonoxacin CAP (oral/iv) 3rd phase trial
Zabofloxacin CAP 2nd phase trial
Finafloxacin cUTI and acute pyelonephritis 2nd phase trial
JNJ-Q2 SSSI
CAP
2nd phase trial
underway
ozenoxacin cSSSI RCT
besifloxacin Bacterial conjuctivitis RCT

30. Plazomicin
• new aminoglycoside against both gram-positive and gram
negative pathogens
1. In combination
• against MRSA and VISA with daptomycin / ceftobiprole
• against P. aeruginosa with doripenem/ imipenem/
piperacillin/tazobactam, cefepime
2. cUTI and acute pielonephritis
• Phase 2 study (As to levofloxacin)
3. BSI or HAI due to carbapenem-resistant
Enterobacteriaceae
• Phase 3 clinical trial for (as to colistin) with a tigecycline or
meropenem

31. Glycylcyclines (new Tetracyclines)
Eravacycline
• Broad-spectrum gram-
positive and gram-negative
against
1. MRSA, VRE,
2. Enterobacteriaceae
(ESBL or
carbapenemases) more
than tigecycline
3. Not P. aeruginosa
• Phase 3 clinical trials for
cIAIs and cUTIs
Omadacycline
• Active against both gram
positive and gram-negative
bacteria.
1. MRSA, VRE, S. pneumonia,
2. Enterobacteriaceae &
Bacteroides fragilis
• Phase 2 study in SSSI

32. Other classes
• Macrolides:
1. Telithromycin:
• FDA approval for chronic bronchitis exacerbation and sinusitis was
withdrawn in 2006
2. Cethromycin:
• very potent against macrolide-resistant strep and enterococci
• More potent against S. aureus,epidermidis, H pylori, M avium,
Corynebacterium spp., M. pneumoniae, C trachomatis and
pneumoniae, Borrelia burgdorferi, H. influenzae, M. catarrhalis, and
Toxoplasma gondii
• Phase 2 trial for mild to moderate CAP
• Trimethoprim: Iclaprim:
• MRSA, VISA, MDR S pneumonia
• GNB: Enterobacter, Salmonella, L. pneumophila, H. influenzae, C.
pneumoniae
• Phase 3 trial for cSSSI

33. Other classes
• NXL103:
• mixture of modified quinupristin/dalfopristin
&streptogramin
• More effective against gram positive than other antibiotics
(MRSA, VRSA, VRE, S pnuemonia, H influenza
• Oral formulation
• Nitazoxanide : (Nidazode®)
• broad spectrum activity against anaerobic bacteria and
against anaerobic intestinal parasites
• FDA approved for Giardia intestinalis and Cryptosporidium
parvum in adults and children
• off-label use for Clostridium difficile (equivalent to
vancomycin and metronidazole)

34. Conclusions
Only 7 new antibiotics has been
approved by US FDA

35. Bassetti, M. Springer 2015

36. Bassetti, M. Springer 2015

37. Take home message
• Still limited therapeutic options for
• Carbapenemase producing Enterobacteriaceae,
• XDR A. baumannii, and P. aeruginosa
• No good evidence but may be
• ceftozolane/tazobactam,
• new carbapenems,
• combination of avibactam with B-lactam
• New tetracylines
• plazomicin in combination
• Most of newly developed antibiotic target gram positive
which glycopeptides and oxazolidinones are highly efficient
against MRSA

38. Proper usage of antibiotics

39. Phases of antibiotic development

40. Antibiotic Abuse in Our units 2013
57.0%
43.0%
Antibiotic Abuse in ICU1
No
Yes 60.7
%
39.3
%
Antibiotic Abuse in ICU3
Alexandria Critical Care Department

41. Types of antibiotic abuse 2013
27.5%
4.5%
11.4%
0.6%
3.9%
2.2%
5.1%
70%
11.40%
30%
1.40%
10%
5.70%
12.90%
0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0%
No clear indication
Early change
Usage of same class
Usage of 2 b-lactam
Prolonged duration
Redundant
Unlikely coverage…
ICU1
ICU3
Alexandria Critical Care Department

43. Thank you