1. Resistant Gram Positives
and Use of Newer
Antimicrobials in SOT
Dr. Dino Sgarabotto
Transplant ID Unit
Padova General Hospital
Padova - Italy

2. Short Case: MRSE vascular graft-related septic shock
• 52 yr old male patient was diagnosed an ascending aortic pseudoanerysm at the
level of the end to end anastomosis between donor and recipient aorta and an
aortic arch aneurysm, three years after a HTx
• A conventional repair was inappropriate because of significant comorbidities.
Therefore, the patient underwent a debranching of the aneurysmatic neck
vessels associated with vascular graft anastomosis between the left and right
common carotid artery and the left subclavian artery and an aortic arch stent
insertion for aneurysm exclusion, via transapical access in mini-thoracotomy
• Two months after surgery, after a few days of low grade fever, the patient
developed hypotension and he was admitted to ICU with a clinical diagnosis of
septic shock
• 6 blood cultures grew Methicillin-Resistant Staphylococcus epidermidis
(MRSE) with a Vancomycin/Teicoplanin MIC of 4, Daptomycin MIC of 1 and
Doxycycline MIC of 1 ug/ml
1/2

3. %
• Empiric antibiotic therapy was Meropenem/Ciprofloxacin/Teicoplanin
• Therapy was then switched to Daptomycin 8 mg/kg/24h associated with
Doxycycline 100 mg/12h, with steady clinical improvement
• Four weeks later, the patient was transferred from ICU to a heart rehabilitation
center, where the antibiotic treatment was continued over the next 4 weeks
• In conclusion, the patient received 8 weeks of Daptomycin/Doxycycline without
any further maintenance antibiotic therapy. At 11 month follow-up, the clinical
course has been uneventful
• This case report suggests that MRSE was deeply embedded in the stent biofilm,
posing a serious limitation to antibiotic efficacy
• Our long term follow-up may suggest that Daptomycin/ Doxycycline
association might not only have achieved suppression but perhaps even MRSE
eradication from the biofilm
2/2

4. Resistant Gram Positive Bacteria
• Resistance to Penicillin
• Resistance to Methicillin
• Resistance (or tolerance) to
Vancomycin/Teicoplanin
• Resistance to new antibiotic
(occasionally)

5. Resistant Gram Positive
1 • CNS & MRSA
2 • VISA & hVISA
3 • VRE and Enterococcus
4 ● Pen R Strept pneum

6. Nosocomial infections in medical intensive care units
in the United States
Others
CNS
Fungi
Staph aureus Enterococcus
Crit Care Med. 1999 May;27(5):853-4.

7. Epidemiology of Microorganisms Causing CVC-
Related BI in Patients Receiving TPN, 1997–2008
YEAR
1997-1999 2002-2002 2003-2005 2006-2008 Overall (%)
No of CVC 653 619 620 684 2,576
CVC days 3675 3608 3844 4334 15,461
Organism
CoNS 49 36 43 26 154 (69.4)
MSSA 20 7 5 0 32 (14.4)
Candida 3 2 4 2 11 (5.0)
GNB 3 3 2 3 11 (5.0)
MRSA 1 2 4 0 7 (3.2)
NFGNB 0 1 2 2 5 (2.3)
Enterococci 1 0 0 1 2 (0.9)
TOTAL 77 51 60 34 222 (100.2)
Infection Ratea 21.7 13.7 15.6 7.7 14.4
Data are no of cases, unless otherwise indicated. GNB,
Enterobacteriaceae; NFGNB, non-fermenting Gram-negative bacilli.
Collins C J et al. Clin Infect Dis. 2009;49:1769-1770 a No of cases per 1000 CVC days.

8. Increasing Frequency of Resistance
MRSA = methicillin-resistant Staphylococcus aureus; VRE = Vancomycin-resistant enteroccoci
FQRP = Fluoroquinolone-resistant Pseudomonas aeruginosa

9. Introduction of New Antibacterial Classes
• New drug development: $800,000,000 and 8 yrs
• Other markets are better
• Agency is indecisive
• Expectations are unclear
• Changes are common
• Delays have become norm

10. Declining New Antibacterial Drug
Approvals
Approvals
Spellberg, CID 2004, Modified

11. New drugs
• Synercid (Quinupristin/dalfopristin)
• Linezolid
• Tigecycline
• Daptomycin
• Lipoglycopeptides
Telavancin approved for cSSSI (phase III clinical trial for nosocomial pneumonia)
Dalbavancin for cSSSI in phase III clinical trial (MRSA and MRSE, VISA and
VRE)
• Fifth generation cephalosporins
Ceftobiprole approved for cSSSI in Canada and Swissland, more studies
needed for USA and EU
Ceftaroline approved for cSSSI and CAP
• Iclaprim in phase III clinical trial for cSSSI and nosocomial pneumonia

12. Bacteria (no. of isolates) MIC90 (µg/mL)
Quinupristin-
Telavancin Vancomycin Linezolid Daptomycin
dalfopristin
MSSA (n=1217)
0.5 1 2 0.5 0.5
MRSA (n=1082)
0.25 1 2 0.5 0.5
MSSE (n=100)
0.5 2 1 1 0.25
MRSE (n=272)
0.5 2 1 1 0.25
E. faecalis vancomycin
susceptible (n=429)
1 2 0.25 1 1
E. faecalis
harboring VanA gene (n=22)
16 >512 2 1 N/A
E. faecium
vancomycin susceptible (n=92)
0.25 1 2 4 2
E. faecium
harboring VanA gene (n=223)
8 512 2 4 1
E. faecium
harboring VanB gene (n=17)
2 0.5 1 4 4
S. Pneumoniae penicillin
susceptible (n=204)
0.03 0.5 1 N/A N/A
S. Pneumoniae penicillin
nonsusceptible (n=72)
0.015 0.5 1 N/A N/A

13. Acquisition costs
Drug Dosage Regimen a,b Cost/Day/patient ($) Cost/14 day therapy ($)
1 (750 mg) + 1
Telavancin 10 mg/kg IV q 24 hours (250mg) vial = $1842.40
$131.60/day
3 (1000 mg) vials =
Vancomycin 15 mg/kg IV q 12 hours $170.10
$12.15/day
1 (500 mg) vial =
Daptomycin 4mg/kg IV q 24 hours $1817.48
$129.82/day
2 (600 mg) vials =
Linezolid 600 mg IV q 12 hours $1620.64
$115.76/day
Quinupristin- 3 (500 mg) vials =
7.5 mg/kg IV q 12 hours $3751.86
dalfopristin $267.99/day
Loading dose of 100 mg x
2 (50 mg) vials =
Tigecycline 1 then 50 mg IV q 12 $1090.40
$75.20/day
hours
2 (600 mg) vials =
Ceftaroline 600 mg IV q 12 hours $1148
$ 82/day

14. MRSA: Linezolid vs Vancomycin
In the last ten years – despite being a bacteriostatic for the good penetration in soft
tissues, lungs, and CSF- several studies have considered non inferiority of linezolid in
the following settings:
• cSSSI
• nosocomial pneumonia
• neurosurgical meningitis
However,
good tissue penetration
does not mean
clinical superiority
not even in nosocomial pneumonia (see: “Linezolid versus vancomycin or
teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis” by
Kalil AC, Murthy MH, Hermsen ED, Neto FK, Sun J, Rupp ME in Crit Care Med.
2010 Sep;38(9):1802-8)

15. Left sided endocarditis
• If MRSA is the cause:
none of the new drugs is non-inferior to vancomycin
• If VRE is the cause:
still missing a replacement for vancomycin

16. 10 novel antibacterial drugs by 2020

17. Animal Model of Implant-Associated Infection:
Killing of planktonic MRSA in cage fluid 5 days after
the completion of therapy
2
1
ΔLog10 CFU/ml
0
-1
-2
-3
-4
-5
-6
-7
-8
Modified from John AK, Baldoni D, Haschke M, Rentsch K, Schaerli P, Zimmerli W, and Trampuz A: AAC 2009, 53: 2719-2724

18. Animal Model of Implant-Associated Infection:
cure rate of adherent MRSA in explanted cages
Cure rate (%)
70
60
50
40
30
20
10
0
Modified from Antimicrobial Agents and Chemiotherapy 2009, 53: 2719-2724

19. Summary
• New antimicrobials against Gram positive bacteria are available and some other
are on the way: the future looks better compared with what we have against
MRD Gram negative
• VRE still is the most difficult to be treated in particular settings
• Device-related infections are highly challenging once the device cannot be
removed
• For the time being there is still the need of using antibiotic associations for
exploiting the synergistic effects
• Animal data suggest all rifampin associations have not the same potency: some
are better than others
• Still a lot has to be done:
Doxycycline or tigecycline can substitute Rifampin?
3 antibiotics instead of 2 against a biofilm can be better like in TB and in
HIV therapy?