Beta‐lactams for MDR GPC?
Javier Garau Hospital Universitario Mutua de Terrassa Barcelona Spain • MRSA
• Enterococcus faecalis and Enterococcus faecium • MDR Streptococcus pneumoniae
MRSA New Beta‐lactams and
combinations active against MRSA Antibiotic Range MIC50 MIC90 Ceftobiprole (511)* 0.25‐2 0.5 2 Ceftaroline (661)** 0.12‐2 0.5 1 ¶ Tomopenem (52) 0.12‐32 4 8 § ME1636 (100) 0.063‐4 1 2
Fosfomycin + imipenem
Vancomycin 0.5‐2 1 1 Imipenem 0.063‐128 32 64
* Olivier D et al, AAC 2006 ** Ge Y et al, 42th ICAAC, Chicago 2007 ¶ Koga T et al, AAC 2005 § Kurazono M et al, AAC 2004
CEFTOBIPROLE • Ceftobiprole medocaril is an extended‐spectrum cephalosporin with activity against MRSA, other MDR GPC, Enterobacteriaceae, and Pseudomonas aeruginosa . • Inactivity includes extended‐spectrum beta‐lactamase (ESBL)‐ producing Enterobacteriaceae and Enterococcus faecium. • Ceftobiprole was bactericidal (99.9% killing) against 9 of 10 MRSA strains tested at 4x MIC after 24 h. Ceftobiprole also yielded significant activity at earlier periods, with 90% killing of all strains at 2x MIC at 6 and 12 h (Lin G et al, Diagn Microbiol Infect Dis 2008) • Two clinical trials support its efficacy for cSSSIs. Ceftobiprole was noninferior to vancomycin in suspected gram ‐positive cSSSIs, with cure rates of 93.3% and 93.5%, respectively.
Antistaphylococcal Activity of Ceftobiprole
Bogdanovich T et al, AAC 2005
Cumulative proportions of MRSA isolates (n 511) inhibited by increasing concentrations of antimicrobial agentsa
Olivier D et al, AAC 2006 Cumulative proportions of MRSA isolates (n 511) inhibited by increasing concentrations of antimicrobial agentsa
Olivier D et al, AAC 2006 A Randomized, Double-Blind Trial Comparing Ceftobiprole Medocaril with Vancomycin plus Ceftazidime for the Treatment of Patients with Complicated Skin and Skin-Structure Infections
Noel G J et al, CID 2008 Ceftobiprole in the rabbit model of osteomyelitis
The efficacies of 4 weeks of treatment with ceftobiprole (40 mg/kg/s.c./q6h), vancomycin (30 mg/kg/s.c./q12h), or linezolid (60 mg/kg/po/q8h) were compared, in the rabbit model of MRSA tibial osteomyelitis. After treatment with ceftobiprole, the bacterial titers in all infected left tibiae from evaluable rabbits were below the level of detection, whereas only 73% of infected left tibiae from VAN or linezolid‐treated animals had bacterial titers below the level of detection Yin L‐Y et al, AAC 2008 CEFTAROLINA (PPI‐0903M, T‐91825)
•A novel semi-synthetic cephalosporin with broad-spectrum activity, currently undergoing phase III clinical trials. Administered IV as a prodrug (ceftaroline fosamil), rapidly converted in plasma into active ceftaroline. . •Based on MC simulations in subjects with normal renal function, 600 mg CPT q12h administered as either a 1-h or 3-h infusion will achieve a high PTA to be able to eradicate target pathogens at an MIC of 2 µg/mL. A 3-h infusion provides a modest increase in the %T>MIC and allows good coverage for the target of 4 µg/ml (Ge Y et al, 18th ECCMID, Barcelona 2008)
•Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections. the clinical cure rate: 96.7% (59/61) for ceftaroline versus 88.9% (24/27) for vancomycin. The microbiological success rate was 95.2% (40/42) for ceftaroline versus 85.7% (18/21) for standard therapy (Talbot G H et al, AAC 2007) Ge Y et al, Abstract C2-863, 42th ICAAC, Chicago, 2007
Ge Y et al, Abstract C2-863, 42th ICAAC, Chicago, 2007
Real‐Time Evaluation of Ceftaroline vs. Vancomycin & Daptomycin in a Rat S. aureus Endocarditis Model Using In Vivo Bioluminescent Imaging
• S. aureus Xen29 derived from MSSA ATCC12600 (Xenogen Corp.). It contains a complete lux operon (luxA to luxE) and is capable of producing both the Luciferase enzyme and its substrate, thereby constitutively emitting a bioluminescent signal when the organism is metabolically active Additionally, this strain forms biofilms on catheters. • A well‐characterized experimental rat endocarditis model (female Sprague ‐Dawley rats). An indwelling polyethylene catheter was positioned in the left ventricle of each animal, with the tip passing across the aortic valve,to induced sterile vegetations. • At 7 days post‐catheterization, the animals were infected intravenously with ~105 CFU S. aureus Xen29
Xiong Y Q, et al, Abstract B-819, 42TH icaac, Chicago 2007
CPT treatment resulted in more significant reduction of bacterial loads in vegetations than either VAN or DAP.
Xiong Y Q, et al, Abstract B-819, 47th ICAAC, Chicago 2007
In Vivo Efficacy of Ceftaroline (PPI-0903), a New Broad-Spectrum Cephalosporin, Compared with Linezolid and Vancomycin against Methicillin-Resistant and Vancomycin-
Intermediate Staphylococcus aureus in a Rabbit Endocarditis Model
Jacqueline C et al, AAC 2007 Tomopenem
• Tomopenem,(CS‐023, RO4908463) is a novel 1ß‐ methylcarbapenem with 5‐substituted pyrrolidin ‐3‐ ylthio groups, including an amidine moiety at the C‐2 position • It is more stable to hydrolysis by human renal DHPI than meropenem or imipenem, and is bactericidal against P. aeruginosa and methicillin‐resistant Staphylococcus aureus • The pharmacodynamics of tomopenem against S. aureus is similar to those of other members of the carbapenem class, with the exception that MRSA is included (MacGowan AP et al, AAC 2008)
In vitro activity of Tomopenem against MRSA
Antibiotic
CS‐023 (52) 0.12‐32 4 8 Imipenem 0.03‐> 32 32 >32 Ampicillin 16‐> 32 32 > 32 Levofloxacin 0.12‐> 32 4 > 32
Koga T et al, AAC 2005
ME1036 (formerly CP5609) is a novel parenteral carbapenem with a 7- acylated imidazo[5,1-b]thiazole-2-yl group attached directly to the carbapenem moiety of the C-2 position
Antibacterial activities of ME1036 and reference compounds for clinical isolates of bacteria
Range MIC50 MIC90
Kurazono M et al, AAC 2004
Efficacies of ME1036 and vancomycin in the successive 1- ,3-, and 5-day treatments of endocarditis caused by S. aureus CR1434 in rabbits. Values in parentheses indicate the number of sterile vegetations/number of animals treated. , P 0.05 versus the results for the controls; , P 0.01 versus the results for the controls (Steel’s test).
Nagura J et al, AAC 2005
COMBINATION OF FOSFOMYCIN
WITH BETA‐LACTAMS Grif K et al, JAC 2001
Fosfomycin in combination with antistaphylococcal agents
In vitro effect of fosfomycin (40 mg/L) alone and in combination with meropenem Against the MRSA DSM 46320. Data are mean + SEM Without antimicrobial agents, meropenem, 16 mg/L, fosfomycin, 40 mg/L X fosfomycin + meropenem
Grif K et al, JAC 2001
Efficacy of the Fosfomycin (Fos) plus Imipenem (I) Combination in the Treatment of Experimental Endocarditis (EE) Caused by (MRSA)
Infusion pump which simulates the human serum kinetics of either Fos (2 gr iv q6h), Imi (1 gr iv q6h) or Van (1 gr iv bid). Peak and trough serum levels were: 40 and 9 mg/L for Fos, 50 and 2 mg/L for Imi and 46 and 6 mg/L for Van
Miró JM et al, Abstract 1015m 39th ICAAC, 1999
Enterococcus faecalis
New Beta‐lactams and combinations active against E. faecalis
Antibiotic Range MIC50 MIC90 Ceftobiprole (511)* 0.125‐0.5 0.125 0.5 Ceftaroline (182)** 0.5‐8 2 4 ¶ Tomopenem (52) 0.12‐32 4 8 § ME1036 (53) 0.063‐4 0.5
B‐lactam + B‐lactam
Vancomycin 0.5‐2 1 2 Imipenem 0.5‐8 2 4
* Pankush G A et al, AAC 2006 ** Ge Y et al, 42th ICAAC, Chicago 2007 ¶ Koga T et al, AAC 2005 § Kurazono M et al, AAC 2004
Time-Kill and Synergism Studies of Ceftobiprole against Enterococcus faecalis, Including -Lactamase-Producing and Vancomycin-Resistant Isolates
Time-kill and synergism studies of BPR and streptomycin against two Bla isolates of E. faecalis. Panel A, TX0630; panel B, TX5070. Detection limit, 10 CFU/ml.
Sm, streptomycin
Arias C A et al, AAC 2007 Evaluation of ceftobiprole medocaril against Enterococcus faecalis in a mouse peritonitis model
• Mice infected intraperitoneally with strains of E. faecalis: (i) the Bla+ strain HH22; (ii) two vancomycin‐resistant strains (TX2484 and V583); and (iii) OG1RF (a laboratory strain), using 10 x the LD50 for each strain. Ceftobiprole doses of 25, 12.5 and 6.25 mg/kg (single doses) and ampicillin 50, 25, 12.5 and 6.25 mg/kg (single and double doses) were administered subcutaneously immediately after bacterial challenge and mice were monitored for 96 h. • RESULTS: All four E. faecalis had ceftobiprole MICs
ME1036: in vitro potency and spectrum of activity
MIC90 (µg/ml) ME1036 Ceftriaxone Levofloxacin Imipenem All streptococci (203) 0.06 2 4 1 S. aureus MS (29) ≤0.015 4 8 0.03 S. aureus MR (55) 1 >32 >32 32 S. aureus VANCO-I or -R (27) 2 >32 32 >32 CoNS MS (35) ≤0.015 8 16 0.03 CoNS MR (68) 1 >32 >32 32 E. faecalis (53) 0.25 >32 >32 2 E. faecium (52) >32 >32 >32 >32 M. catarrhalis (101) 0.03 1 0.03 0.06 L. monocytogenes (21) ≤0.015 >32 1 0.06 C. jeikeium (22) >32 >32 >32 >32 H. influenzae (105) 0.06 0.12 0.06 0.5 Enterobacteriaceae (368; 69 ESBL) 0.5 >32 2 2 No Enterobacteriaceae (108) >32 >32 32 >32 S.D. Brown et al, Abstract F1-342,47th ICAAC, Chicago 2007
B‐lactam +B‐lactam synergy
• 73 year old man with type II DM, CRF and mild dementia • Two days history of malaise, fever and mild diarrhea. • On admission: obtunded, not following orders. T 38.2 ºC, BP 150/90, RR 24/min; III/IV Systolic murmur in axilla. EKG, old MI. Hb 9,5 g, WBC 14.000/mm3 platelets 90.000/mm 3: BUN 90, creatinine, 2,6 mg/dl • Two sets of blood cultures grew E faecalis. Ampicillin IV given. • Fever persisted and patient’s condition unchanged. A sputum culture grew Stapylococcus aureus and cloxacillin IV was added • 48h later fever was gone, patient was lucid and able to follow orders.Died suddenly on day 30 of hospital stay • At autopsy, massive AMI, healing mitral valve SBE. Gram stain and cultures of valve were negative
Enhanced activity of ampicillin by oxacillin against enterococci
Garau J et al, JAC 1979;5: 31‐36 Enhanced activity of ampicillin by oxacillin against enterococci
Garau J et al, JAC 1979;5: 31-36 Enhanced activity of ampicillin by oxacillin against enterococci
Garau J et al, JAC 1979;5: 31-36 Enhanced activity of ampicillin by oxacillin against enterococci
Garau J et al, JAC 1979;5: 31-36 Synergistic Effect of Amoxicillin and Cefotaxime against Enterococcus faecalis
Mainardi JL et al, AAC 1995;39: 1984-1987
Synergistic Effect of Amoxicillin and Cefotaxime against Enterococcus faecalis
With cefotaxime, 50% saturation of PBPs 2 and 3 obtained at very low concentrations (< 1µg/ml), while 50% saturation of PBPs 1, 4 and 5 was obtained with > 128 µg/ml With amoxicillin, 50% saturation of PBPs 4 and 5 at 0.12 and 0.5 µg/ml, respectively
Mainardi JL et al, AAC 1995;39: 1984-1987
Efficacy of ampicillin plus ceftriaxone in treatment of experimental endocarditis due to Enterococcus faecalis strains highly resistant to aminoglycosides
Gavaldá J et al, AAC 1999;43: 639-646
Treatment of Enterococcus faecalis Endocarditis with Ampicillin plus Ceftriaxone
The clinical cure rate at 3 months was 67.4% (29 of 43 patients) among all episodes.The rate of clinical and microbiological cure in patients who completed the protocol was 100% in the HLAR E. faecalis endocarditis group. No episodes of breakthrough bacteremia occurred. There were 2 relapses in the non-HLAR E. faecalis endocarditis group. Gavaldá J et al, Ann Int Med 2007
Enterococcus faecium
• No synergy Beta‐lactam Beta‐lactam
• Ceftobiprole, MIC90 >32 mg/L
• Ceftaroline, MIC90 > 16 mg/L
• Tomopenem, MIC90 >32 mg/L
• ME1036, MIC90 >32 mg/L
MDR Streptococcus pneumoniae
New Beta‐lactams active against
MDR Streptococcus pneumoniae
ANTIBIOTIC Range MIC50 MIC90 Ceftobiprole (298)* < 0.016‐4 0.5 1 Ceftaroline (296)** < 0.008‐0.5 0.12 0.12 § Faropenem (120) 0.5‐1 1 ¶ Tomopenem (CS‐023) (47) 0,06‐0.5 0.12 0.25 ¥ ME1036 (129) 0.03‐0.25 0.06 0.25
Amoxicillin 0.5‐8 2 4‐8 Ceftriaxone 0.5‐8 0.5‐1 0.5‐8
* Kosowska K et al, AAC 2005 **Ge Y et al, 42th ICAAC, Chicago, 2007 ¶ Koga T et al, AAC 2005 ¥ McGee L et al, 42th ICAAC, Chicago 2007 § Critchley IA et al, AAC 2008 (against 19A strains R to Amox-MIC, 8)
PENICILLIN G FDA new susceptibility breakpoints for pneumonia caused by Streptococcus pneumoniae
The susceptible breakpoint for meningitis caused by S. pneumoniae remains unchanged (0.06 mcg/mL). Emergent Streptococcus pneumoniae serotype 19A in the United States, 2005
• The incidence of IPD due to serotype 19A increased from 0.8 to 2.5 cases per 100,000 population between 1998 and 2005 (P < .05), whereas the overall incidence of IPD decreased from 24.4 to 13.8 cases per 100,000 population (P < .05). • Simultaneously, the incidence of IPD due to penicillin‐resistant 19A isolates increased from 6.7% to 35% (P < .0001). • Of 151 penicillin‐resistant 19A isolates, 111 (73.5%) belonged to the rapidly emerging clonal complex 320, which is related to multidrug‐ resistant Taiwan(19F)‐14. The remaining penicillin‐resistant strains were highly related to other clones of PCV7 serotypes or to isolates within major 19A clonal complex 199 (CC199). In 1999, only CC199 and 3 minor clones were apparent among serotype 19A isolates. During 2005, 11 multiple‐isolate clonal sets were detected, including capsular switch variants of a serotype 4 clone Moore M R et al, JID 2008 Prevalence of Serotype 19A Streptococcus pneumoniae among Isolates from U.S. Children in 2005‐2006 and Activity of Faropenem • Of 393 isolates of Streptococcus pneumoniae from U.S. children in 2005 ‐2006, non ‐vaccine serotypes accounted for 89.1% of isolates, with serotype 19A the most prevalent, representing 30.5% of all isolates.
• MIC90 of faropenem against serotype 19A isolates was 1 microg/ml, compared to >/=8 microg/ml against amoxicillin/clavulanate, cefdinir, cefuroxime axetil and azithromycin
Critchley I A et al, AAC 2008
Ceftobiprole and comparator -lactam MICs for S. pneumoniae clinical isolates with specific PBP genotypes
Davies T A et al, AAC 2006 Ge Y et al, Abstract C2-863, 42th ICAAC, Chicago, 2007
Ceftaroline and ME1036 tested against 120 isolates of S. pneumoniae from CDC (2001-2006), and against R6 laboratory mutants of different PBPs
120 clinical isolates 18 R6 mutants β-lactam Range MIC50 MIC90 Range MIC50 MIC90 Cefotaxime 4-≥16 8 8 0.03-16 2 16 Penicillin 0.5-16 8 8 0.03-16 2 8 Ceftriaxone 2-≥16 8 8 0.06-16 2 4 Ceftaroline 0.125-2 0.5 0.5 ≤0.01-0.25 0.03 0.03 ME1036 0.03-0.25 0.06 0.12 ≤0.01-0.03 0.03 0.03
L. McGee et al, Abstract C2-215, 47th ICAAC, Chicago 2007
Faropenem
• Faropenem, a penem, is a new oral ‐lactam antibiotic that will be administered as the prodrug ester, faropenem daxolate. Penems are characterized by a broad antibacterial spectrum with good ‐lactamase stability, but they exhibit a short plasma elimination half‐lifeThe • Iin vitro activity of faropenem has been evaluated extensively against respiratory pathogens and less extensively against aerobic gram‐positive, gram‐negative, and anaerobic organisms. • Prospective, randomized, multicenter clinical trials have demonstrated noninferiority of faropenem to comparators for the treatment of acute bacterial sinusitis, community ‐acquired pneumonia, acute exacerbation of chronic bronchitis, and uncomplicated skin and skin structure infections. • Adverse events associated with faropenem appear to be minimal and include nausea, vomiting, and diarrhea Summary
• Two new cephalosporins, ceftobiprole and ceftaroline active against MRSA and MDRSP. Ceftobiprole with good activity against E. faecalis • Two new carbapenems, tomopenem and ME1036,active against MRSA and MDRSP. ME1036, active against E. faecalis • Old B‐lactams, alone or in combination, are still useful agents in MRSA, MDRSP and E. faecalis infections • E. faecium is resistant to all new B‐lactams and there is no synergy of B‐ lactams in combination against this species