Resistant gram positives and use of newer antimicrobials
Resistant Gram Positivesand Use of NewerAntimicrobials in SOT Dr. Dino Sgarabotto Transplant ID Unit Padova General Hospital Padova - Italy
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
%• 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
Resistant Gram Positive Bacteria• Resistance to Penicillin• Resistance to Methicillin• Resistance (or tolerance) to Vancomycin/Teicoplanin• Resistance to new antibiotic (occasionally)
Resistant Gram Positive 1 • CNS & MRSA 2 • VISA & hVISA 3 • VRE and Enterococcus 4 ● Pen R Strept pneum
Nosocomial infections in medical intensive care units in the United States Others CNS Fungi Staph aureus EnterococcusCrit Care Med. 1999 May;27(5):853-4.
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.
Increasing Frequency of Resistance MRSA = methicillin-resistant Staphylococcus aureus; VRE = Vancomycin-resistant enteroccoci FQRP = Fluoroquinolone-resistant Pseudomonas aeruginosa
Introduction of New Antibacterial Classes • New drug development: $800,000,000 and 8 yrs • Other markets are better • Agency is indecisive • Expectations are unclear • Changes are common • Delays have become norm
Declining New Antibacterial Drug ApprovalsApprovals Spellberg, CID 2004, Modified
New drugs• Synercid (Quinupristin/dalfopristin)• Linezolid• Tigecycline• Daptomycin• Lipoglycopeptides Telavancin approved for cSSSI (phase III clinical trial for nosocomial pneumonia) Dalbavancin for cSSSI in phase III clinical trial (MRSA and MRSE, VISA and VRE)• Fifth generation cephalosporins Ceftobiprole approved for cSSSI in Canada and Swissland, more studies needed for USA and EU Ceftaroline approved for cSSSI and CAP• Iclaprim in phase III clinical trial for cSSSI and nosocomial pneumonia
Acquisition costs Drug Dosage Regimen a,b Cost/Day/patient ($) 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/dayQuinupristin- 3 (500 mg) vials = 7.5 mg/kg IV q 12 hours $3751.86dalfopristin $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
MRSA: Linezolid vs VancomycinIn the last ten years – despite being a bacteriostatic for the good penetration in softtissues, lungs, and CSF- several studies have considered non inferiority of linezolid inthe following settings:• cSSSI• nosocomial pneumonia• neurosurgical meningitisHowever, 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)
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
Animal Model of Implant-Associated Infection: Killing of planktonic MRSA in cage fluid 5 days after the completion of therapy 2 1ΔLog10 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
Animal Model of Implant-Associated Infection: cure rate of adherent MRSA in explanted cages Cure rate (%) 70 60 50 40 30 20 10 0Modified from Antimicrobial Agents and Chemiotherapy 2009, 53: 2719-2724
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?