Management of Nosocomial Infections in the Era of Increased Bacterial Resistance

Transcription

1 Management of Nosocomial Infections in the Era of Increased Bacterial Resistance Matteo Bassetti, MD, PhD Infectious Diseases Division Santa Maria Misericordia University Hospital Udine, Italy

2 Disclosures h Research grants - Astellas, Pfizer, MSD, Gilead h Advisor/consultant - Astra Zeneca, Astellas, Bayer, Cubist, Pfizer, MSD, Gilead, Angelini, Vifor, Shionogi, Novartis, Trius h Speaker/chairman - Astra Zeneca, Astellas, Pfizer, MSD, Gilead, Angelini, Vifor, Shionogi, Novartis

3 Antibiotic resistance and emergence of superbugs

4 Will Penicillin Fail in Future Time?

5 The BUGS perfect storm h MRSA h VRE h MDR A. baumannii h MDR P. aeruginosa h ESBL(+) E. coli h ESBL(+) K. pneumoniae h Carbapenemase(+) K. pneumoniae h S. pneumoniae PR/MR h M. tuberculosis MDR IDSA Public Policy. Clin Infect Dis. 2011;52(Suppl 5):S397-S428. ESBL, Extended- Spectrum Beta- Lactamases; MDR, mul9drug resistant; MRSA, Methicillin- resistant Staphylococcus aureus; PR, penicillin resistant; VRE, Vancomycin- resistant Enterococcus.

6 Bugs globalization.

7 Susceptibilities of Selected Antibiotics Against Selected Gram-Negative Bacilli 100 Percent (%) susceptible CTR CTZ CFP P/T I/C CIP 0 Acinetobacter spp. E. coli Klebsiella spp. P. aeruginosa n=4686 n=17,035 n=9774 n=9130 CTR, ceftriaxone; CTZ, ceftazidime; CFP, cefepime; P/T, piperacillin/tazobactam; I/C, imipenem/cilastatin; CIP, ciprofloxacin. Gales AC, et al. J Antimicrob Chemother. 2011;66:

8 Emerging Carbapenemases in Gram-negatives h KPC in Klebsiella and other enterics h MBLs (IMP and VIM) in P. aeruginosa h MBLs (VIM and NDM) in enterics h OXA-23/24/58 in Acinetobacter h OXA-48 in K. pneumoniae and E. coli

9 Antibiotic Options Decline Total no. of new antimicrobials New Antibacterial Agents Approved by the FDA the resistance situation worsens IDSA Public Policy. Clin Infect Dis. 2011;52(Suppl 5):S397-S428.

10 Bad bugs, no drugs: No ESCAPE h Bad Bugs, No Drugs: No ESCAPE 1 Enterococcus faecium (E), Staphylococcus aureus (S), Clostridium difficile (C), Acinetobacter baumannii (A), Pseudomonas aeruginosa (P), and Enterobacterobcteriaceae (E) h The late-stage clinical development pipeline remains unacceptably lean Some important molecules for problematic pathogens such as MRSA Few novel molecules for other ESCAPE pathogens No new drugs for infection due to MDR Gram-negative bacilli Rice LB. J Infect Dis. 2008;197: ; Boucher HW, et al. Clin Infect Dis. 2009;48:1-12; Peterson LR. Clin Infect Dis. 2009;49:992.

11 Epidemiology of severe sepsis Top 3 etiology % % % 10% pulmonary intraabdominal SSTI Engel C et al. Intensive Care Med 2007

12 Overview h Clinical challenges of ESCAPE-pathogens h Tigecycline pharmacological profile h Tigecycline clinical trials h Tigecycline issues - Opportunities of use in approved indications - Mortality in RCTs - Use in not approved indications - Higher dose?

13 Overview h Clinical challenges of ESCAPE-pathogens h Tigecycline pharmacological profile h Tigecycline clinical trials h Tigecycline issues - Opportunities of use in approved indications - Use in other indications

14 ESCAPE pathogens (Bad Bugs) Enterococcus faecium Staphylococcus aureus Clostridium difficile Acinetobacter baumannii Pseudomonas aeruginosa Enterobacteriaceae 1 tigecycline spectrum 1 included ESBL and carbapenemases producing Rice LB. J Infect Dis. 2008;197:1079 Boucher HW, et al. Clin Infect Dis. 2009;48:1 Peterson, LR. Clin Infect Dis. 2009;49(6):992-3

15 Tigecycline: an extended broad-spectrum Staphylococci (incl. MRSA, VISA, VRSA) Enterococci (incl. VRE, LRE) Streptococci (incl. PRP) Listeria Corynebacterium Enterobacteriaceae (incl. ESBL, AmpC, MBL) Acinetobacter (incl. MDR) S. maltophilia H. influenzae Moraxella Pasteurella Anaerobes Atypicals - Legionella - Mycoplasma - Chlamidia - M. fortuitum Neisseria Campylobacter NOT Active Proteus spp. P.aeruginosa

16 Broad/Extended spectrum antimicrobials available for monotherapy Antibiotic Gramnegative Grampositive Resistant Gramnegative Resistant Grampositive Anaerobe Pseudo β-lactam/ β-lactamase Inhibitor 3 rd - Gen. Cephs Tigecycline no proteus Glycopeptides Carbapenems Quinolones Varies by product within class In Vitro Activity No In Vitro Activity

17 ESCAPE pathogens (Bad Bugs) Enterococcus faecium Staphylococcus aureus Clostridium difficile Acinetobacter baumannii Pseudomonas aeruginosa Enterobacteriaceae 1 tigecycline spectrum 1 included ESBL and carbapenemases producing Rice LB. J Infect Dis. 2008;197:1079 Boucher HW, et al. Clin Infect Dis. 2009;48:1 Peterson, LR. Clin Infect Dis. 2009;49(6):992-3

18 Carb-R EB*: In vitro susceptibility Susceptibility Colistin 92,60% Fosfomycin 60,50% Tigecycline 80,20% 1 Chloramphenicol <25% Ciprofloxacin <25% Nitrofurantoin <25% Temocillin 4,90% *Enterobacteriaceae 1=FDA breakpoints 2 mg/l 2=EUCAST brealpoints 1 mg/l Livermore et al. Int J Antimicrob Agents. 2011;37:415-9

19 Overview h Clinical challenges of ESCAPE-pathogens h Tigecycline pharmacological profile h Tigecycline clinical trials h Tigecycline issues - Opportunities of use in approved indications - Use in other indications

20 Tigecycline and Pharmacokintics and Pharmacodynamics Serum concentration (µg/ml) h Linear PK h C max = µg/ml µg/ml 2 h C min = 0.13 µg/ml h AUC 0-24h = 4.7 µg h/ml h t ½ = 42 hours h V ss = 639 L Time after- dose(hr) 1 After100mg 2 After 10 days of 50 mg BID Rello J. J Chemother. 2005;17(suppl 1): Pfizer Pharma

21 Intrapulmonary Pharmacokinetics Tigecycline 50 mg q12h of Tigecycline Conc (ug/ml) ,1 0, Time (hours) AUCELF/AUCserum = 1.32 AUCAC/AUCserum = 77.5 Alveolar Cells ELF Serum infected patients? higher doses? Conte et al. Int J Antimicrob Agents. 2005;25:523-9

22 Overview h Clinical challenges of ESCAPE-pathogens h Tigecycline pharmacological profile h Tigecycline clinical trials h Tigecycline issues - Opportunities of use in approved indications - Use in other approved indications

23 h Approved for: - cssti - ciai

24 Tigecycline in critical-ill patients : Experience in the RCTs n APACHE II (mean) Subrrogate marker csssi 422 (CE) no Surgery/drainage 109 (25,8%) Bacteremia 23 (5,4%) ciai 631 (m-itt) 6,3 Peritonitis 21 (3,3%) 40 (6,3%) CABP 424 (m-itt) no Fine IV-V 84 (19,8%) 22 (5,1%) HAP 467 (m-itt) 12,3 -- NA MRSA 117 (m-itt) 7, (9,4%) MDR-GN 112 (m-itt) 10, (2,8%) csssi=complicated skin and skin structure infection; ciai=complicated intra-abdominal infections CAP=community-acquired bacterial pneumonia HAP=hospital acquired pneumonia MRSA=methicillin-resistant S.aureus MDR-GN=multidrug-resistant Gram-negatives Babinchak T et al. Clin Inf Dis 2005; 41: S354-S367 Ellis-Grosse et al. Clin Inf Dis 2005; 41: S341-S353 Tanaseanu, et al. Diagn Microbiol Infect Dis. 2008;61: Florescu et al. J Antimicrob Chemother. 2008;62 Suppl 1:i17-28 Vasilev et al. J Antimicrob Chemother. 2008;62 Suppl 1:i29-40

25 ciai Randomized Clinical Trials (RCT): where are the critical-ill patients? RCT 1 RCT 2 RCT 3 Drug n APACHE II Ertapenem =9% Pip/Tazo =6.7% Meropenem 71 Mean 5.8 Imipenem 64 Mean 6.4 Doripenem =88% Meropenem =91.5% RTC=randomized clinical trial RCT 1=Solomkin et al. Annals Surg 2003;237: RCT 2=Zanetti et al. Int J Antimicrob Agents 1999;11: RCT 3=Lucasti et al. Clin Ther. 2008;30:868-83

26 Complicated intra-abdominal infection (ciai): Tigecycline Experience Clinical Trials ciai study -301ww- 1 Treatment Clinical success Tigecycline 86.1% Imipenem 86.2% a ciai study -400ww- 2 Treatment Clinical success Tigecyline 70.4% CRO+MZD 74.3% a Case series n APACHE II Swoboda et al Curcio et al Eckmann et al Bassetti et al Outcome Mortality 30% Success 78% Success 75% Success 73% a p<.0001 for noninferiority b p=.009 for noninferiority 1 Babinchak T et al. Clin Inf Dis 2005;41:S354-S367 2 Towfigh et al Clin Microbiol Infect Swoboda et al. J Antimicrob Chemother. 2008;61: Curcio et al. J Antimicrob Chemother. 2009;64: Eckmann C, et al. Chemotherapy 2011;57:275 6 Bassetti M et al. BMC Infect Dis 2010 Sep 29;10:287

27 2010 IDSA Guidelines on Anti-infective Agents for Complicated IAIs Type of Therapy Single Agent Class β-lactam/ β-lactamase inhibitor Carbapenem Complicated Community-Acquired Infections Mild-tomoderate Ampicillin/ Sulbactam Ticarcillin/Clav. Ertapenem High risk * Why not? Piperacillin/Tazobactam Imipenem, Meropenem, doripenem Glycycycline Tigecycline Tigecycline Combo Regimen Cephalosporinbased Fluoroquinolone -based Cephalosporins + Metronidazole Fluoroquinolone + Metronidazole 3 rd /4 th Gen. Cephalosporin + Metronidazole Ciprofloxacin/levo + Metronidazole * Severe physiologic disturbance, advanced age, immunocompromized Solomkin JS et al Clin Infect Dis 2010;50:133-64

28 Paul-Ehrlich-Society (Germany) 2010 recommendation diffuse secondary peritonitis Diagnosis Antibiotic agent duration Level of Recom. Level of evidence Community acqui. Acylaminopenicillin/BLI 3-5 days A I diffuse Cephalosporin Gr. 3a/4 A/B I ± Risk factors Fluorquinolon Gr. 2/3 o. A/B I + Metronidazol Carbapenem group 1 A I Carbapenem group 2 A I Tigecycline B I Nosocomial Carbapenem group 1 7 days A I postoperative Carbapenem group 2 A I (change of Acylaminopenicillin/BLI A I antibiotic class!) Tigecycline A II Fluorquinolon group 4 B I Eckmann C et al. Chemother J 2010

29 Real-life experiences

30 Results: Study design and prescription of tigecycline Country Germany Italy Spain-1 France Spain-2 Total Study design Prospective, multicentre Prospective, monocentre Prospective, multicentre Prospective, multicentre Retrospective, multicentre Period Sept 06 Mar 10 Jan 07 Apr 11 Aug 08 Dec 10 Sept 08 May 10 July 06 Oct 11 Centres, n Inclusion criteria Any ward Any ward Surgical ICU ICU Any indication Any indication cssti and ciai only Prescription of tigecycline Any indication Any indication Total patients, N ciai, n (%) 418 (40.8) 162 (51.1) 94 (81.7) 78 (50.0) 33 (19.5) 785 (44.1) cssti, n (%) 163 (15.9) 41 (12.9) 18 (15.7) 17 (10.9) 15 (8.9) 254 (14.3) Other, n (%) a 444 (43.3) 114 (36.0) 3 (2.6) 61 (39.1) 121 (71.6) 743 (41.7) a Other includes other non-cssti and non-ciai infections, such as bacteraemia and pneumonia. cssti and ciai represented 58.3% of the total number of patients treated with tigecycline Bassetti M, et al. J Antimicrob Chemother. 2013; 68 Suppl 2: ii5 ii14.

31 Bassetti M, et al. J Antimicrob Chemother. 2013; 68 Suppl 2: ii5 ii14. Results: Clinical characteristics Germany Italy Spain-1 France Spain-2 Total Total patients, N ICU admission, n (%) 545 (53.2) 135 (42.6) 2 (1.7) 156 (100) 165 (100) 1003 (56.4) ICU missing/ Unknown, n History of prior AB, n (%) 864 (84.5) 240 (75.7) 21 (18.3) 145 (92.9) 158 (93.5) 1428 (80.2) History of prior AB missing/unknown, n Percentages were calculated for patients with non-missing data only. Heterogeneity in the percentage of patients enrolled from the ICU i.e., 100% ICU in France and Spain-2 versus 1.7% in Spain-1

32 Results: Disease severity scores at baseline 100 Patients With APACHE II Score >15 or SOFA Score 7 (%) Overall mean APACHE II score = 17.7 ± 7.9; 61.6% >15 Overall mean SOFA score = 7.0 ± 4.0; 54.4% Germany (n =935) Italy (n = 317) 2.6 Spain-1 (n = 38) France (n = 150) Spain-2 (n = 165) APACHE II scores were collected in Germany, Italy, Spain-1 and Spain-2. SOFA scores were collected in France and Spain-2. Percentages were calculated for patients with non-missing data only. Bassetti M, et al. J Antimicrob Chemother. 2013; 68 Suppl 2:ii5 ii14. APACHE, Acute Physiology and Chronic Health Evalua9on; SOFA, Sequen9al Organ Failure Assessment.

33 Clinical response in cssti by APACHE II score at EOT 100 APACHE II 15 APACHE II > Clinical Response (%) Germany (n =127) Italy (n = 41) Spain-1 a (n = 3) Spain-2 (n = 14) Total (n = 185) Patients who received the standard dose of tigecycline alone or in combination; percentages were calculated for patients with non-missing data only; no data on APACHE II score were available in the study from France. A response was defined as clinical cure or improvement without additional antibiotic. Montravers P, et al. J Antimicrob Chemother. 2013; 68 Suppl 2: ii15 ii24.

34 Clinical outcome at EOT in patients with ciai treated with tigecycline* 77.4% of ciai patients who received treatment with tigecycline alone or in combination had a clinical response Clinical Outcome (%) ,311,7 Germany (n = 375) 81,5 18,7 0 Italy (n = 162) 91,3 3,3 Spain-1 (n = 92) 5,4 61,6 21,9 16,4 France (n = 73) 67,7 29 Spain-2 (n = 31) 3,2 77,4 14,2 8,5 Total (n = 733) Response Non-response Indeterminate *Tigecycline was given at standard dose, alone or in combination. Percentages were calculated for patients with non-missing data only. Response was defined as clinical cure or improvement without additional antibiotic. Non-response was defined as failure or improvement with additional antibiotic. Patients whose response could not be ascertained were assigned an indeterminate outcome. Eckmann C, et al. J Antimicrob Chemother. 2013; 68 Suppl 2: ii25 ii35.

35 Rational to use tigecycline in ciai ciai Communityacquired Health care associated Risk factors for ESBL-GN No Yes ESBL-GN Yes ESBL-GN MDR-non fermenters E.faecium/E.faecalis MRSA

36 Tigecycline in Abdominal Infections Monotherapy Combination Treatment CA and HA sec peritonitis Tertiary peritonitis

37 Tigecycline FDA drug safety communication (Sep 2010) Infection Type Tigecycline Deaths/Total Pts Comparator Antibiotics Deaths/Total Pts Risk Difference a (95% CI) cssti 12/834 (1.4%) 6/813 (0.7%) 0.7 ( 0.3, 1.7) ciai 42/1382 (3.0%) 31/1393 (2.2%) 0.8 ( 0.4, 2.0) CAP 12/424 (2.8%) 11/422 (2.6%) 0.2 ( 2.0, 2.4) HAP 66/467 (14.1%) 57/467 (12.2%) 1.9 ( 2.4, 6.3) Non-VAP b 41/336 (12.2%) 42/345 (12.2%) 0.0 ( 4.9, 4.9) VAP b 25/131 (19.1%) 15/122 (12.3%) 6.8 ( 2.1, 15.7) RP 11/128 (8.6%) 2/43 (4.7%) 3.9 ( 4.0, 11.9) DFI 7/553 (1.3%) 3/508 (0.6%) 0.7 ( 0.5, 1.8) Overall adjusted 150/3788 (4.0%) 110/3646 (3.0%) 0.6 (0.1, 1.2) c a Risk difference is the difference between the percentage of patients who died in the tigecycline and comparator antibiotic groups. 95% CI for each infection type was calculated using the normal approximation method without continuity correction; b Subgroups of the HAP population; c Overall adjusted (random effects model by trial weight) risk difference estimate. Tigecycline is approved in Europe for treatment of ciai and cssti, excluding diabetic foot infections, where it is known or suspected that other alternatives are not suitable Available at: Accessed October CAP, community- acquired pneumonia; CI, confidence interval; DFI, diabe9c foot infec9on; VAP, ven9lator- associated pneumonia; RP, resistant pathogens.

38 Clinical response and mortality modeling in tigecycline complicated intra-abdominal infection trials through post hoc analyses METHODS h 5 trials were included in the analyses: Two phase 3, randomized, double-blind trials with imipenem as the comparator One phase 3, randomized, non-powered trial with imipenem as the comparator Two phase 4 randomized, open-label trials comparing tigecycline with ceftriaxone and metronidazole h Clinical response definitions Cure: study drug and initial intervention resolved the IAI Failure: additional surgical or radiological intervention and/or additional antibiotic treatment were received to cure the infection, death after day 2 due to the infection or a treatment-related AE; or discontinuation of study drug due to treatment-related AE h Final multivariate logistic regression model was used to identify factors significantly related to clinical failure in the CE population and mortality in the mitt population (received 1 dose of test article) Bassetti M, et al. Poster p2106 presented at ECCMID 2012.

39 Mortality modelling (mitt population) Variable Odds Ratio (95% CI) P-value Age (1.46, 2.11) < Decreased total protein (1.14, 1.82) Source of infection (vs appendix) Stomach/duodenum (1.14, 9.63) Small bowel (2.22, 17.71) Large bowel (1.79, 11.83) Intra-abdominal abscess (0.95, 8.39) Gall bladder (0.15, 2.49) Decreased probability of (1.12, 1.89) controlling source infection a Size of abscess b (1.01, 1.59) ICU in 24 hours after surgery (1.02, 3.37) Baseline pressor use (1.23, 5.37) a 1 = <25%, 2 = 25 49%, 3 = 50 74%, 4 = 75 95%, 5 = >95%; b 0 = no abscess, 1 = <10 ml, 2 = ml, 3 = >100 ml. Bassetti M, et al. Poster p2106 presented at ECCMID 2012.

40 Conclusion of the post-hoc analyses h Treatment assignment interaction with organ dysfunction was identified in the multivariate clinical response modelling; tigecycline clinical response as higher in subjects with organ dysfunction and lower in subjects without organ dysfunction h Tigecycline was not associated with mortality in the multivariate mortality modelling in ciai Bassetti M, et al. Poster p2106 presented at ECCMID 2012.

41 Overview h Clinical challenges of ESCAPE-pathogens h Tigecycline pharmacological profile h Tigecycline clinical trials h Tigecycline issues - Opportunities of use in approved indications - Mortality in RCTs - Use in not approved indications - Higher dose?

42 Tigecycline in the treatment of infections from multi-drug resistant Gram-negative pathogens h h TIG for >5 days either as monotherapy (M group) or as presumed active monotherapy (PAM group). In the PAM group, all co-administered antimicrobial(s) were resistant in vitro against the targeted pathogen(s) or had been clinically and microbiologically failing after 5 days of therapy despite in vitro susceptibility. 45 pts (35 in ICU) - 28 Acinetobacter baumannii - 23 Klebsiella pneumoniae infections - 21 VAP/HCAP, 10 BSI, 14 surgical infections (SI) - Successful overall clinical outcome was 80% h 81.8% in M group, h 78.3% in PAM group, h 90.5% in VAP/ HCAP, 80% in BSI, 64.3% in SI Tigecycline is not currently approved for the treatment of HAP and bacteremia Poulakou et al. J Infection 2009;58:

43 Ventilator-associated pneumonia (VAP): Tigecycline experience Poulakou et al. 1 Anthony et al. 2 Schafer et al. 3 Curcio et al. 4 Curcio et al. 5 n VAP n VAP + BSI a 11% NA 14% 8% 19.5% APACHE II (mean) 18 NA NA NA e 18 A.baumannii 83% 83% 100% 100% 48% Monotherapy 50% 16% 22% 63% 37% Combination 50% 84% 78% c 27% 63% Colistin 77% 40% b 35% d 30% NA Clinical success Total 88% 50% 81% 69,9% 63% a bloodstream infections, b 1 pt. nebulized, c 9 pts. with imipenem, d nebulized, e median MPM II=58 1 Poulakou et al. Journal of Infection. 2009;58: Anthony et al. Clin. Infect. Dis.2008;46: Schafer et al. Pharmacotherapy. 2007;27: Curcio et al. J Chemother. 2009;21: Curcio et al. Infez Med. 2010;18:27-34.

44 Tumbarello M, Viale PL, Viscoli C, Bassetti M et al. Clin Infect Dis, Italian experience on KPC Kaplan-Meier survival estimates of 125 patients who received adequate therapy Survival, % Days Combination therapy Monotherapy

45 Multivariate analysis of factors associated with death among patients with bloodstream infection due to KPC producing Klebsiella Pneumoniae. Shock ( ) Inadequate initial treatment ( ) APACHE III score (mean ± SD) - - < ( ) Tigecycline & Colistin & Meropenem ( ) Tumbarello M, Viale PL, Viscoli C, Bassetti M et al. Clin Infect Dis,

46 Overview h Clinical challenges of ESCAPE-pathogens h Tigecycline pharmacological profile h Tigecycline clinical trials h Tigecycline issues - Opportunities of use in approved indications - Mortality in RCTs - Use in not approved indications - Higher dose?

47 Tigecycline in HAP: pkpd considerations h The PD target most closely associated with tigecycline efficacy is the AUC/MIC ratio. h AUC/MIC of 8.78 were required to produce 2 log kill, in a pneumonia murine model by A. baumannii (MIC 1.0 mg/l) respectively. h 50mg tigecycline twice daily is probably underdosed for the treatment of pneumonia caused by typical, extracellularacting bacteria (low ELF concentrations). h Tigecycline doses of up to 200 mg/day may be required to provide adequate exposure for microorganisms with MIC 1.0 mg/l Ambrose et al. Clin. Infect. Dis. 2007;44: Koomanachai et al. J Antimicrob Chemother. 2009;63: Burkhardt et al. Int J Antimicrob Agents. 2009;34:101-2.

48 2000 HAP - Test Article Administration Tigecycline IV* 150 mg load then 75 mg q12h LDOT Visit TOC Visit 1:1:1 Randomization Tigecycline IV* 200 mg load then 100 mg q12h Imipenem-cilastatin IV** 1 g q8h 7-14 days days after LDOT *Tigecycline Adjunctive Rx: ceftazidime 2 g IV q8h and aminoglycoside (tobramycin 7mg/ kg daily or amikacin 20 mg/kg daily) ** Imipenem-cilastatin Adjunctive Rx: vancomycin 15 mg/kg IV q12h and aminoglycoside (tobramycin 7mg/kg daily or amikacin 20 mg/kg daily)

49 Clinical response in phase 2 (study 2000) vs. phase 3 (study 311) HAP trials Clinical responses in phase 2 and phase 3 hospital-acquired pneumonia (HAP) trials, comparing different doses of tigecycline (TGC) and imipenem/ cilastatin (IMI/CIL; 70% confidence intervals). CE, clinically evaluable; c-mitt, clinical modified intention to treat.

50 2000 HAP- TGC Serum concentration Mean tigecycline (TGC) serum concentrations in subjects with hospital-acquired pneumonia after intravenous infusions.

51 2000 HAP Safety TGC 75 MG (N = 36 ) n (%) TGC 100MG (N=35) n (%) IMIPENEM (N=34) n (%) P TEAEs 31 (86.1) 27 (77.1) 28 (82.4) Nausea 2.8% 8.6% 0% Vomiting 2.8% 5.7% 0% Diarrhea 2.8% 14.3% 2.9% SAEs 12 (33.3) 9 (25.7) 10 (29.4) Deaths 7 (19.4) 3 (8.6) 7 (20.6) AE with outcome of death None of the deaths were related to study medication

52 Please Do Not Forget h Tigecyline as a tool to save carbapenems, either as a primary treatment or deescalation h Tigecycline to avoid «collateral damage»

53 Maximizing Antibiotic Heterogeneity Reduces Selective Pressure 1-4 Cephalosporins Penicillins MIXING* Tigecycline Carbapenems Quinolones The addition of novel agents may improve heterogeneity and preserve the activity of broad-spectrum antibiotics 5-7 *Mixing = balanced application of entire antibiotic portfolio, regarding the local situation of resistance and the individual patient, contributes to the minimization of selective pressure (eg, The Tarragona Strategy ) Sandiumenge A, et al. J Antimicrobial Chemother. 2006;57: Bonhoeffer S, et al. Proc Natl Acad Sci USA. 1997;94: Sandiumenge A, et al. Intensive Care Med. 2003;29: Rello J. Eur Resp Rev. 2007;16: Wilcox MH. Surg Infect. 2006;7: Paterson DL, et al. Clin Infect Dis. 2003;36: Wilcox MH. Hosp Med. 2005;66:

54 Selective Pressure from Broad-Spectrum Antibiotics Leads to Pathogen Resistance Broad-Spectrum Antibiotics High Selective Pressure Cephalosporins Enterococci/VRE 1,2 MRSA 2 Clostridium difficile 2 Acinetobacter baumannii 2 ESBL-producers 2-4 Quinolones MRSA 2,5 Escherichia coli 6,7 Pseudomonas aeruginosa 2,8 VRE 9 Clostridium difficile 2,10 Carbapenems VRE 11 Acinetobacter baumannii 12 Pseudomonas aeruginosa 12 Stenotrophomonas maltophilia 13 VRE=vancomycin-resistant Enterococci; MRSA=methicillin-resistant Staphylococcus aureus; ESBL=extended-spectrum β-lactamase. 1. Bradley SJ, et al. J Antimicrob Chemother 1999;43: Paterson DL. Clin Infect Dis. 2004;38(Suppl 4):S341-S Patterson JE, et al. Infect Control Hosp Epidemiol. 2000;21: Bantar C, et al. Antimicrobial Agents Chemother. 2004;48: Weber SG, et al. Emerg Infect Dis. 2003;9: Yagci D, et al. Antimicrobial Agents Chemother. 2009;53: Jones GL, et al. J Antimicrobial Chemother. 2008;62: Neuhauser MM, et al. JAMA. 2003;289: Sakka V, et al. Clin Microbial Infect.2008;14: Hookman P, et al. Dig Dis Sci. 2007;52: Padiglione AA, et al. Antimicrobial Agents Chemother. 2008;47: Falagas ME, et al. J Hospital Infect. 2006;64: Meyer E, et al. J Hosp Infect. 2006;64:

55 Tigecycline Its Role in the Hospital 1-Surgical site infection 2-cSSSI in patients with MDR-pathogens risk factors 3-cIAI in high risk patients (ie. nosocomial peritonitis) 4. Other uses (HAP, bacteremia) : better in combination and with higher doses 5. Part of mixing strategy: carbapenems-sparing regimens

56 Register at: