Bad Bugs, Which Drugs? Superior Potency for Better Outcomes In

Infectious & Tropical Diseases Unit Department of Transplantation Ospedale di Circolo e Fondazione Macchi – University of Insubria, Varese,Italy

Remaining treatment options for extensively resistant Gram-positive cocci

Paolo Grossi © by author

nd ESCMID Online22 ECCMID Lecture Library London 31.03.2012 - 03.04.2012 New therapeutic options for treatment of MDR Gram-positives

• Despite concerns about vancomycin use in the treatment of multidrug-resistant Gram-positives, evidence for better therapeutic outcomes with alternative antibiotics is lacking. • Daptomycin, Ceftaroline and Telavancin were associated with comparable clinical cure rates compared with vancomycin in the treatment of complicated MRSA skin and soft tissue infections. • In the treatment of hospital-acquired pneumonia, both telavancin and linezolid resulted in significantly greater clinical cure rates compared with vancomycin.© by author • Despite greater clinical cure rates, no difference in overall or infection-related mortality was detected. • Of concern is the appearance of daptomycin and linezolid resistanceESCMID following increased Online use. Lecture Library Treatment of MRSA Bacteremia

Uncomplicated Treatment Complicated Treatment duration duration Daptomycin 6 Daptomycin 8- mg/kg iv once At least 2 10 mg/kg iv 4-6 weeks daily AI weeks once daily BIII Vancomycin AII

• Addition of gentamycin to vancomycin is not recommeded for bacteremia or native© valveby author endocarditis • Addition of rifampin to vancomycin is not recommeded for bacteremia or native valve endocarditis ESCMID Online Lecture Library Liu C, et al. CID 2011:52:285–292 Treatment of MRSA Pneumonia Treatment Adult dose Class Treatment duration

15-20 mg/kg q8- IV vancomycin A-II 12 h 7-21 days or linezolid 600 mg PO/IV bid A-II depending on the extent of or clindamycin 600 mg PO/IV q8 infection h, if the strain is (B-III) susceptible

• In patients with MRSA pneumonia© bycomplicated author by empyema, antimicrobial therapy should be used in conjunction with drainage procedures (A-III). • For serious infections, vancomycin trough concentrations of 15–20 lg/mL are recommended (B-II). In seriously ill patients a loading dose of 25–30 mg/kg (actualESCMID body weight) Online may be considered Lecture. Library Liu C, et al. CID 2011:52:285–292 Linezolid in Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Randomized,Controlled Study Clinical Success Rates 100 Linezolid Vancomycin

80 83.3 80.1

69.9 67.8 60 57.6 54.8

40 46.6 44.9 Clinical success rate success Clinical

20 © by author

P = 0.042 P = 0.045 P = 0.002 P = 0.004 0 ESCMIDPP at EOS OnlineMITT at EOS Lecture PP at EOT Library MITT at EOT Wunderink RG, et al. Clin Infect Dis. 2012 Mar 1;54(5):621-9 Mortality: Kaplan-Meier Plot – 60 Days: mITT

.80

.60

.40

.20 Linezolid Vancomycin Survival Distribution Function Distribution Survival * * * Linezolid Censor© by ●author ● ● Vancomycin Censor 0 0 10 20 30 40 50 60 Time (Days) 94 subject deaths ( 15.7%) in linezolid arm 100ESCMID subject deaths (17.0%)Online in vancomycin Lecture arm Library Wunderink RG, et al. Clin Infect Dis. 2012 Mar 1;54(5):621-9 6 Treatment options for extensively resistant Gram-positive cocci

Drug Approved indications Daptomycin SSTI Bacteremia/Endocarditis Tygecycline SSTI IAI CAP (US) Telavancin © bycSSTI author (US) HAP Ceftaroline SSTI ESCMID Online LectureCAP Library Daptomycin indications in Europe

Indication Dose Administration cSSTI 4 mg/kg

Once daily by RIE due to S. aureus 6 mg/kg 30-minute i.v. infusion or 2-minute i.v. injection SAB when associated with 6 mg/kg RIE or with cSSTI © by author

ESCMID Online Lecture Library 8 Novartis Europharm Ltd. Cubicin® (daptomycin) Summary of Product Characteristics. 2009 Factors associated with loss of daptomycin susceptibility in Staphylococcus aureus

ESCMID Online Lecture Library Moise PA, et al. Lancet Infect Dis 2009; 9: 617–24 Selection of Daptomycin resistant PVL+ MSSA during Daptomycin treatment (4 mg/kg)

Isolate Daptomycin MIC Identification Details (mg/L) Interpretation (CLSI & Etest) Isolate Cefoxitin disc Gram Final ID Etest Microbroth Reference 30µg/L

7695069 GPC 28mm (S) S. aureus 0,75 0,5 Susceptible (18/09/2008) © by author 7744632 Non- GPC 29mm (S) S. aureus 3 2 (2/10/2008) susceptible

P.Grossi ESCMID2008. Unpublished Online data Lecture Library How can we increase daptomycin efficacy when treating complicated SAB or IE?

. Increasing daptomycin dose . ↑↑ Cmax/MIC - ↑↑ AUC/MIC . 8-10 mg/kg/day . Higher doses (12 mg/kg/d)? . A high once-daily dose (≥ 8 mg/kg) of daptomycin is often considered for difficult- to-treat infections© (e.g.by author involving biofilms) and high bacterial burden, based on its dose-dependent anti-bacterial activity. ESCMID Online Lecture Library

Safety of High-Dose Daptomycin for Gram- Positive Infections Kullar R., et al. ICAAC 2009

. HD DAP (> 8 mg/kg/day) was well-tolerated in 153 patients with complicated Gram-positive infections. . Over 90% of patients had end-of therapy CPK levels < 150 IU/L. . No direct relationship was found between DAP dose and CPK levels. . Concomitant HMG-CoA reductase inhibitor therapy did not predict CPK elevations.© by author . HD DAP may prove to be a safe alternative for treatment of Gram-positive infections. ESCMID Online Lecture Library Clinical and microbiological outcomes of higher dose (HD) and standard dose (SD) Daptomycin

ESCMID Online Lecture Library Bassetti M, et al. International Journal of Antimicrobial Agents 36 (2010) 459–461 Use of Daptomycin on Gram-positive pathogens Personal experience in Varese (N of cases=67, 21% SOT)

* © by author • Execellent Outcome; 1 case of MSSA cSSTI failure (selection of Daptomycin non- susceptible strain after 10 days of 4 mg/kg/day • Excellent safety profile (1 patient developed reversible CPK elevation) * DocumentedESCMID at follow-up Online Lecture Library A. Tebini, et al. ICAAC Chicago 2011 – Poster # K1413 Dosage and duration of DAP H8 therapy

Patients, n (%) Most frequently used initial daptomycin dose ≥8 and ≤10 mg/kg/day 223 (95.3) >10 mg/kg/day 11 (4.7) Median duration of daptomycin therapy Days (min─max) Overall 25 (14─20) Inpatients 21 (1─110) Outpatients 21 (3─85) ICU © by author 7 (1─51)

. The frequency of DAP H8 use increased over the 4 consecutive years (3%, 8%, 12% and 18%, respectively) ESCMID Online Lecture Library Utili R, et al. ECCMID 2012, P1846 15 Clinical outcomes for DAP H8 for ≥14 days by infection type

Success Failure Non-evaluable 97.1 100 93.3 88 86.3 80 74.1

18.5 20 11.4 Patient population (%) 4.7 7.3 5.3© by author 7.4 1.3 2.3 0 2.9 0 Overall Endocarditis Osteomyelitis SSTI Bacteraemia (n=234) (n=75) (n=44) (n=34) (n=27) ESCMID Online Lecture Library Utili R, et al. ECCMID 2012, P1846 16 Clinical outcomes for DAP H8 for ≥14 days by pathogen

Success Failure Non-evaluable 100 92.4 88.9 88.1 88.3 89.3

20 10.7 Patient population (%) 6.7 4.4 7.1 4.8© by 7author 4.7 4.5 3 0 0 All S. aureus MSSA (n=42) MRSA (n=43) CoNS (n=66) Enterococci (n=90) (n=28)

CoNS: Staph.ESCMID epidermidis and other CoNS Online; Enterococci: E. Lecturefaecalis, E. faecium and Library Enterococcus spp.

Utili R, et al. ECCMID 2012, P1846 17 Adverse events

. The overall rates of AEs were independent of the duration of daptomycin ≥8 mg/kg/day treatment (16.6% for <14 days, 14.9% for ≥14 days and 18.2% for ≥30 days). . Adverse events (AEs), regardless of relationship to daptomycin, were reported in 15.8% of patients receiving daptomycin ≥8 mg/kg/day for ≥14 days, including 3.8% of patients with creatine phosphokinase (CPK) elevations and 0.4% of patients with musculoskeletal AEs, which is comparable to patients© receiving by author ≥8 mg/kg/day daptomycin for <14 days (16.6%) and patients on approved dose of daptomycin (4 to 6mg/kg/day; 13.2%). ESCMID Online Lecture Library Utili R, et al ECCMID 2012 Support for initial high dose daptomycin followed by dose de-escalation

Daptomycin11 activity against high inoculum clinical MRSA isolates in vitro1

Growth control 9 DAP 6 mg/kg DAP 610 mg/kg Time of escalation/de-escalation 7 DAP 10 mg/kg DAP 106 mg/kg

5 CFU/g of simulated of simulated CFU/g

endocardial vegetation endocardial 3 Log © by author

1 0 4 8 96 24 32 48 56 72 100 104 120 128 144 152 168 192 Time (hours) Refer to the daptomycin Summary of Product Characteristics for dosing recommendations2 1. Vidaillac CESCMID et al. Antimicrob Agents ChemotherOnline 2011;55:2160 Lecture–2165 Library 2. Novartis Europharm Ltd. Cubicin (daptomycin) Summary of Product Characteristics. 2011 How can we increase daptomycin efficacy when treating complicated SAB or IE?

. Daptomycin combinations . To look for synergy and greater bactericidal activity . To avoid development of resistance . To decrease individual doses © by author

ESCMID Online Lecture Library Daptomycin Plus Fosfomycin Is Synergistic Against MSSA and MRSA Strains: From Bench to Bedside

ESCMID Online Lecture Library Miro JM, et al. ICACC 2009 Daptomycin-Oxacillin Combinations in Treatment of Experimental Endocarditis Caused by Daptomycin Nonsusceptible Strains of MRSA

Collectively, these results suggest that combination therapy regimens of DAP and OX has enhanced in vivo efficacy relative to DAP monotherapy in DAPr strains which exhibit the DAP-OX seesaw phenomenon in vitro. This combination antibiotic approach may be relevant to salvaging DAP therapy in patients with evolving increases in DAP MICs during treatment, especially when OX MICs decrease in parallel. © by author

ESCMID Online Lecture Library Yang S-J. AAC 2010;54:3161–3169

• In conclusion, the novel combination of DAP plus TMP/SMX provided rapid bactericidal activity and provides a therapeutic option for treating DNS MRSA infections, especially when bactericidal activity is desired. © by author

ESCMID Online Lecture Library High Level Getamycin Resistant E. faecalis in Europe - 2010

ESCMID Online Lecture Library www.ecdc.europa.eu HLAR – Enterococcal IE

• HLAR is an acquired mechanism of resistance that impaires the synergism between ampicillin or glycopeptide and aminoglycoside • Some options are needed to treat this emerging resistant pathogens

• Ampicillin + Ceftriaxone© by forauthor E. faecalis • Ampicillin + Daptomycin for E. faecalis and E. faecium ESCMID OnlineGavalda J etLecture al. Ann Intern LibraryMed 2007; 146: 574-579 Kelesidis T et al. Clin Infect Dis 2011; 52: 228-234 Daptomycin MIC distribution against enterococci collected during 2006 in Europe

Daptomycin MIC, mg/L: no. isolates (%)

≤0.12 0.25 0.5 1 2 4 8

15 53 395 534 167 5 0

Enterococcus spp.* (n=1169) (1.3) (4.5) (33.8) (45.7) (14.3) (0.4) (0.0) 5 43 344 334 15 0 0

E. faecalis* (n=741) (0.7) (5.8) (46.4) (45.1) (2.0) (0.0) (0.0) 5 41 343 333 15 0 0

E. faecalis van-S (n=737) (0.7) (5.6) (46.5) (45.2) (2.0) (0.0) (0.0) 0 2 1 1 0 0 0 † E. faecalis van-NS (n=4) (0.0) (50.0) (25.0) (25.0) (0.0) (0.0) (0.0) 3 2 40 188 138 5 0

E. faecium* (n=376) (0.8) (0.5) (10.6) (50.0) (36.7) (1.3) (0.0) 2 1 27 128 116 5 0 E. faecium van-S (n=279) (0.8) ©(0.4) by author(9.7) (45.9) (41.6) (1.8) (0.0)

† 1 1 13 60 22 0 0 E. faecium van-NS (n=97) (1.0) (1.0) (13.4) (61.9) (22.7) (0.0) (0.0)

† The MIC90 is highlighted.ESCMID *All isolates regardless of susceptibility Online to vancomycin. Vancomycin Lecture non-susceptible, i.e. resistant Library(≥32 mg/l) and intermediate (8–16 mg/l) combined. JMI European Surveillance Report 2007 Ampicillin + Daptomycin

• This drug association seems promising according to some in vitro study, also to treat E. faecium VR – infections • Synergism between ampicillin and daptomycin • Ampicillin enhance daptomycin killing also against VRE modifying bacterial surface charge • Ampicillin seems to avoid selections of DNS-strains, expecially where the bacterial© by author inoculum was high

Entenza JM et al. Int. J. Antimicrob. Agents 2010; 35:451– 456 SakoulasESCMID G et al. AntimicrobOnline Agents Lecture Chemother Library. 2012 Feb;56(2):838 -44 Time kill curves against VRE with Daptomycin (D) and Ampicillin (A) at the specified concentrations in Mueller-Hinton Broth

Sakoulas G,ESCMID et al. AAC 2012;56:838 Online-44 Lecture Library Daptomycin – Ampicillin Combination in enterococcal infectious endocarditis

ID Age Strain HLAR Valve Surgery Outcome 1 61 E. faecalis / PROSTHETIC AORTA YES Cured 2 59 E. faecalis Yes NATIVE AORTIC YES Cured 3 49 E. faecium Yes NATIVE MITRAL NO Cured 4 49 E. faecalis Yes PROSTHETIC MITRAL NO Cured 5 76 E. faecalis / ©PROSTHETIC by author AORTA YES Cured

ESCMID Online Lecture Library Tebini A, et al. ECCMID 2012, O346

ESCMID Online Lecture Library Ceftaroline

. Ceftaroline is sometimes referred to as ‘a fifth generation’ cephalosporin because it is active (uniquely for licensed cephalosporins) against MRSA. . It has recently been approved for use in cSSSI (and community-acquired pneumonia) by the FDA, and is awaiting a decision from the EMA. . Ceftaroline binds to penicillin-binding protein (PBP) 2a, an MRSA-specific PBP that has low affinity for most other beta- lactam antibacterials, and© is byactive author in vitro against MRSA, MR Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococcus faecalis (not E. faecium), and many Gram- negativeESCMID pathogens. Online Lecture Library Ceftaroline: Administered as Prodrug

C H 3 N + O N O N N N S P N O S N O O N S S O O O Prodrug: Rapid Biotransformation in Plasma

C H 3 N + O N N H N 2 N S © by authorN S N O N O S S Bactericidal Activity O O Active Metabolite: Ceftaroline ESCMID Online Lecture Library

ESCMID Online Lecture Library Clinical response rates of selected baseline isolates at Day (E-MITT population)

ESCMID Online Lecture Library Friedland H.D., et al. AAC Accepts, published online ahead of print on 6.2.2012 Antibiotic Development: The 10 x '20 Initiative

ESCMID Online Lecture Library TELAVANCIN  Telavancin is a lipoglycopeptide antibiotic newly approved for the treatment of gram-positive infections.

 It has activity against vancomycin susceptible enterococcus, many streptococcus species, and S aureus including MRSA.

 Telavancin retains potent activity against MRSA isolates with MICs of 2 mg/ml to vancomycin.  It has recently gained FDA approval for complicated skin and skin structure infections caused by susceptible organisms.

 In the clinically evaluable population patients receiving telavancin with diminished renal function had a lower rate of clinical cure compared to patients with creatinine clearance estimates of >50 ml/min. The decrease was not© bysignificant author in the all-treated populations and was not seen in the vancomycin comparator group.  Additionally,ESCMID the drug Onlinehas been studied Lecture in hospital Library-acquired pneumonia and found to be non-inferior to vancomycin. Clinical cure rates and 95% confidence intervals at follow-up/test of cure by baseline pathogen for the pooled microbiologically evaluable population of the ATTAIN studies

ESCMID Online Lecture Library

. On 19 May 2011 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Vibativ, 250 mg, 750 mg powder for concentrate for solution for infusion for the treatment of adults with nosocomial pneumonia (NP) including ventilator associated pneumonia,© by knownauthor or suspected to be caused by methicillin-resistant Staphylococcus aureus (MRSA).

. Vibativ should be used only in situations where it is known or suspected that other alternatives are not suitable. ESCMID Online Lecture Library

Conclusions

• Pharmaceutical companies are withdrawing from antibiotic development due to antibiotic resistance and antibiotics’ low return on investment. • Few molecules are currently available for the treatment of severe infections due to MDR Gram-positives and some of them are already loosing their efficacy • The use of Daptomycin at high dose or in combination with beta- lactams or cotrimoxazole has been shown to prevent the development of non-susceptible strains and to treat severe infections. However, most of the currently available data come from small case series or in vitro studies • Data on the use of new molecules© by author like Ceftaroline and Telavancin are still lacking • An optimized use of the currently available drugs might help in preservingESCMID their acitivity Online Lecture Library