Indications of CAZ-AVI and CTL-TAZ. The clinical need, beyond the approved indications

Transcription

1 XXXIV Congreso Chileno de Infectología SOCHINF2017 The Old and the New for the Treatment of Multi-drug resistant Gram-Negative Bacilli The New: Ceftazidime-Avibactam and Ceftolazone-Tazobactam Indications of CAZ-AVI and CTL-TAZ. The clinical need, beyond the approved indications Ana Cristina Gales, MD, PhD Infectious Diseases Division Escola Paulista de Medicina UNIFESP São Paulo - Brazil

2 Disclosures Consultant, Scientific Advisor and Speaker s Bureau, Consulting fee and Speaker honorarium Bayer BD MSD Pfizer General Coordinator, Brazilian Committtee on Antimicrobial Susceptibility (BrCAST ) Consultant WHO National Health Surveillance Agency, Brazil (ANVISA) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

3 Outline Ceftolozane/tazobactam & Ceftazidime/Avibactam Chemical structure Mechanism of action Antimicrobial activity Approved therapeutic indications Clinical experience with off-label use (Real Life)

4 Ceftolozane/Tazobactam (CEF/TAZ) Ceftazidime Zhanel et al. Drugs 2014;74:31 51.

5 Ceftolozane/Tazobactam (CEF/TAZ) Mechanism of Action Specific channel protein Gram-Negative Bacteria Porin channel ZX O Polysaccharide lipid A Outer membrane Lipopolysaccharide (LPS) Ceftolozane is a potent penicillin-binding protein (PBP) inhibitor and has a high affinity for all Pseudomonas aeruginosa PBPs (1b, 1c and 3) essential for cell wall synthesis 1,2 Lipoprotein Peptidoglycan layer β-lactamase Periplasmic space Plasma membrane Cell wall Tazobactam is a well established β-lactamase inhibitor that protects ceftolozane from hydrolysis by select extended-spectrum β-lactamase-producing Enterobacteriaceae 2,3 Penicillin-binding protein Proteins 1. Moyá B et al. Antimicrob Agents Chemother 2010;54: Zhanel GG et al. Drugs 2014;74:1. 3. Sader HS et al. Antimicrob Agents Chemother 2014;58: LPS = lipopolysaccharide; PBP = penicillin-binding protein.

6 Ceftolozane/Tazobactam (CEF/TAZ) Spectrum of Activity of Activity Enterobacteriaceae (including some ESBL-producing isolates - EC EC >> >> KPN) P. aeruginosa (AmpC) Limited activity against anerobes anaerobes (Prevotella spp.) IT DOES NOT HAVE ACTIVE AGAINST CARBAPENEMASE- PRODUCING GRAM-NEGATIVE ISOLATES (Classes A, B, or D); Acinetobacter; Staphylococci; or Enterococci.

7 Ceftolozane/Tazobactam: Antimicrobial Activity against P. aeruginosa Resistance Mechanism β-lactams Porin β-lactamase Hyperexpression of Efflux Systems OprD alteration AmpC Hiperproduction MexAB-OprD MexXY-OprD Ceftolozane Ceftazidime Cefepime Pip/Taz. Imipenem Meropenem No activity against carbapenemase-producing P. aeruginosa isolates Castanheira M, et al. Antimicrob Agents Chemother. 2014;58:

8 Ceftolozane/Tazobactam (CEF/TAZ) pk/pd Index pk/pd index of CEF that best correlates with in vivo efficacy is the percentage of the dosing interval that free concentration of CEF in plasma exceeds the MICs (% f T > MIC) Mouse thigh infection model Bacteriostasis: 24.8% T > MIC 1-Log kill: 32.2% T > MIC Chandorkar et al J Antimicrob Chemother 2012;67(10): P. aeruginosa Bacteriostasis: 31% T > MIC 1-Log kill: 39% T > MIC 2-Log kill: 42% T > MIC Lepak et al. Antimicrob Agents Chemother 58: In vitro and animal models indicate that the percent time above the MIC associated with ceftolozane/taz efficacy is lower ( 30%) than with other cephalosporins ( %) Craig & Andes Antimicrob Agents Chemother. 2013;57:

9 Ceftolozane/Tazobactam (CEF/TAZ) Clinical Indications FDA (22.Dec.2014) ASPECT-cUTI (Levofloxacin) + ASPECT-cIAI (Meropenem) Complicated Intra-abdominal Infections (ciai), used in combination with metronidazole Complicated Urinary Tract Infections (cuti), including pyelonephritis EMA (18.Sep.2015) 29. Mar.2017 Abdominal and gastrointestinal infections; cuti including acute pyelonephritis Modification of an agreed pediatric investigation plan (cuti) The most common adverse reactions ( 3% in pooled Phase 3 trials) occurring in patients receiving CEF/TAZ were nausea, headache, constipation, diarrhea, and pyrexia and were generally mild or moderate in severity.

10 Ceftolozane/Tazobactam (CEF/TAZ) Dosage of CEFTOLOZANE/TAZOBACTAM by Infection in Healthy Adults Older Than 18 Years Infection Dose Frequency cuti (Acute pyelonephritis) ciai (+ metronidazole) Infusion Time (hours) Duration of Treatment CEF/TAZ 1.5 g q8h 1 7 days CEF/TAZ 1.5 g q8h days Dosage of CEFTOLOZANE/TAZOBACTAM has to be Adjusted in Patients With Renal Impairment Estimated CrCl (ml/min) Recommended Dosing Regimen for CEF/TAZ 1.5 g 30 to mg ceftolozane/250 mg tazobactam IV q8h 750 mg q8h 15 to mg ceftolozane/125 mg tazobactam IV q8h 375 mg q8h End-stage renal disease on hemodialysis A single loading dose of 500 mg ceftolozane / 250 mg tazobactam followed after 8 hours by a 100 mg ceftolozane/50 mg tazobactam maintenance dose administered q8h 750 mg 150 mg q8h

11 Ceftolozane/Tazobactam (CEF/TAZ) Data Limitation of Clinical Trials Critically ill patients Cystic fibrosis or COPD patients with acute pulmonary exacerbations Patients with pneumonia as well as other body sites of infections Pediatric population Patients with renal impairment, including those on continuous renal replacement therapy XDR Pseudomonas aeruginosa

12 Ceftolozane/Tazobactam Therapy of Respiratory Infections due to Multidrug-Resistant Pseudomonas aeruginosa Cef/Taz at 3 g intravenously every 8 hours Gelfand & Cleveland. Clin Infect Dis Sep 1;61(5):853-5.

13 Higher dose for VAP Lung epithelial lining fluid concentrations of ceftolozane are approximately 48 % of serum concentrations Chandokar et al. J Antimicrob Chemother.2012;67: Higher dose increases the probability of target attainment in the lungs Xiao et al. J Clin Pharmacol 016 Jan;56(1): Doses of 3 g (2 g ceftolozane/1 g tazobactam) IV have been safety administered in healthy volunteers Miller et al. Antimicrob Agents Chemother.2012;56:

14 MIC distribution of Enterobacteriaceae and P. aeruginosa isolates from hospitalized patients with pneumonia from 2012 US/European Union surveillance data and simulated PTA of ceftolozane in ELF (B) in patients with normal renal function 3g CFT/TAZ 60-min IV q8 h. 1.5g CFT/TAZ 60-min IV q8 h. >90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of 8 mg/l in ELF High PTA ( 90%) in ELF for patients with: - Moderate renal impairment (CrCL of ml/min): 1.5-g CFT/TAZ - Severe renal impairment (CrCL of ml/min): 750 mg CFT/TAZ Xiao et al. J Clin Pharmacol 2016 Jan;56(1):56-66.

15 Cystic Fibrosis/COPD exacerbation Monogue et al. Antimicrob Agents Chemother 2016 Oct 21;60(11): g q8h 60 infusion 3g q8h 60 infusion Multicenter, open-label study Population pk and safety of CFT/TAZ 3 g q8h 20 adult CF patients with acute pulmonary exharcebation

16 1. Vickery et al. Pharmacotherapy Oct;36(10):e154-e Stokem et al. Respiratory Medicine Case Reports. DOI: /j.rmcr Soliman et al. JMM Case Reports, , doi: /jmmcr Acute Pulmonary Exacerbation in Cystic Fibrosis/COPD Case Age y-o Comorbidities Pathogen Cef/Taz Regimen Combo RX Clinical Outcome 1 25 CF XDR PSA (MIC, 1.5 ug/ml) 3g q8h - 1h 12 days IV cipro + inhaled Tobra 2 35 CF, Lung TX, DM, hypertension XDR PSA (2) (MICs, 0.5 and 2.0 ug/ml) 2g q12h - 1h 14 days CrCL= ml/min None 2 59 COPD XDR PSA (MIC, 8 ug/ml) 3g q8h - 1h 14 days None 1. Patient received CEF/TAZ 1.5g q8h 1h - MIC, ug/ml (Mar-Jun) 2. Patient later received a 2 nd course of CEF/TAZ

17 14- y-o pt with pulmonary exacerbation due to two MDR-P. aeruginosa Cef/Taz MICs = 0.5 μg/ml (mucoid), and 1 μg/ml (non mucoid) Beta-lactam allergy D1 Cipro + Amikacin D14 Cipro + Pip/Taz 2,400 mg over 3h q 6h D6 Cipro + Pip/Taz Desensitization 2,400 mg over 1h q6h D20 Cipro 30 mg/kg/day + Cef/Taz Desensitization Cef 93 mg/kg/day 1.5g over 1h q8h D26 Cef/Taz 750mg over 1h q8h ( transaminases 14 days Ang et al. Antimicrob Agents Chemother 2016 Sep 23;60(10):

18 Blood samples (n =4) were collected after administration of the fourth dose of C/T 1.5 g q8h over 1h Higher peak plasma: 94.1 vs 74.4 ug/ml Shorter half-life: 1.1 vs 3.1h Smaller volume of distribution: 7.9 vs 13.5L Ang et al. Antimicrob Agents Chemother 2016 Sep 23;60(10):

19 Pediatric Population 9 y-o with refractory acute myeloid leukemia R Blood samples at Day 3 C/T 1.5, 3, and 5h MIC, 6 ug/ml Half-life = 1.3h Cmin = 5.7 μg/ml Estimated [Plateau] = 74.1 μg/ml 91% T > MIC Last 4 months, many hospitalizations due to febrile neutropenia MDR P. aeruginosa treated with cefepime, tobramycin + ciprofloxacin Cellulitis + Pansinusitis by XDR P. aeruginosa CEF 50mg/kg q8h over 3h + Cipro + tobramycin for 3 weeks Good clinical response Hospital discharge Aitken et al. Pediatr Infect Dis J Sep;35(9):

20 Pediatric Population 2-weeks later: New episode of febrile neutropenia XDR P. aeruginosa MIC, 8 ug/ml CEF 40mg/kg q6h over 3h 1333 mg/670 mg 9 y-o with refractory acute myeloid leukemia Cellulitis + Pansinusitis by XDR P. aeruginosa Blood samples at Day 3 C/T 1.5, 3, and 5h Half-life = 1.4h C min = 18.1 ug/ml Estimated [Plateau] = 54.3 μg/ml Good clinical response Hospital discharge Free Trough [15 μg/ml] 2 x MIC 100% T>MIC Aitken et al. Pediatr Infect Dis J Sep;35(9):

21 Case Reports J Antimicrob Chemother Jun 1. doi: /jac/dkx172. J Antimicrob Chemother Apr 1;72(4): Infection Feb;45(1):

22 Retrospective Studies Study Patients Pathogen Source Dosing Mono therapy Munita (N=35) Multicentric Dihn (N=15) France Cáston (N=12) Spain Haidar (N=21) Pittsburg Sacha (N=60) Cancer (5), TX (6), CF (6), RRT (10) TX (6), Immuno (4) Immuno (4), TX (1) TX (9), 3 ihd 2 CRRT 49 pt TX (17), CA (7), CRRT (14) CR-PAE Baseline R Pneumonia (18), osteo/abscess (5), bacteremia (6) XDR-PAE Pneumonia (5 VAP), septic shock (10) MDR-PAE (emergen ce of R in 2 pt) MDR-PAE (emergen ce of R in 3 pt) Most PAE Pneumonia (6), septic shock (10) Resp tract inf (18), ciai (1), cuti (1), BSI (1) Pneumonia (34), ciai (11 ), SSTI (3) Outcomes 3g q8h 27 (77%) Clinical success: 74% In-hospital mortality: 25% 3g q8h (only 4) 3g q8h (only 4) FDA (11); 3g q8h (5), 5 (33%) Clinical success: 67% All-cause mortality: 27% Not reported 5 (23.8%) 52 SD 29 (48.3%) Clinical success: 75% In hospital mortality: 25% Clinical success: 71% 30-day all-cause mortality:10% (Attributable:5%) Clinical success: 64% In-hospital mortality: 40%

23 Patients with Renal Impairment 66-year-old man with a history of chronic kidney disease SerCr = 3 4 mg/dl) and recurrent nephrolithiasis with bilateral stents Positive urine and blood cultures for MDR PSA (Cef/Taz MIC = 2 μg/ml) 375 mg (250 mg/125 mg) dose of Cef/Taz q8h (Mono) for 25 days Drug measurement at end of infusion in1 h, 3, 5 and 8 h - HLPC Concentration of CEF at 8 h = μg/ml Patel et al. Infect Dis Ther (2016) 5: year- old female with cystic fibrosis (CF), malnutrition, chronic kidney disease, DM, post lung transplant and acute pulmonary exacerbation Positive cultures for two MDR PSA (Cef/Taz MIC = 0.5 and 2 ug/ml) 3g (2 g/1g) dose of Cef/Taz q12h (Mono) for 14 days C/T measurement during treatment Estimated CEF peak = μg/ml; trough = 9.2 μg/ml. Serum half-life shorter (2.3 h vs. 2.6 h) Stokem et al. Resp Med Case Rep DOI: /j.rmcr

24 Continuous Renal Replacement Therapy Study Age Source of Infection Cef/Taz Dosage Kuti et al. 75 y-o Shock septic (CAP) - VAP by PSA (Cef/Taz MIC =0.75 μg/ml) 3g q8h 1h 10 days Observation Cmax = μg/ml, Cmin = 43.3 μg/ml, t ½ = 4.7h Oliver et al. 61 y-o Septic shock prosthetic hip joint infection PSA (Cef/Taz MIC =1.5 μg/ml) Bremmer et al. 47 y-o Endocarditis - Pneumonia, Bacteremia, Osteomyelitis (PSA (Cef/Taz MIC = 2 μg/ml ) 1.5 g q8h over 4 h (adjusted dose) 3g q8h 1h 6 wk All patients were on continuous venovenous hemodiafiltration (CVVHDF) Cmax = μg/ml, Cmin = μg/ml, t ½ =31.1h Cmax= μg/ml; t ½ = 13.3h; Reduced drug clearance (1.5g q8h) Oliver eta al. Antimicrob Agents Chemother 2016; 60: Bremmer et al. Pharmacotherapy 2016;36(5):e30 e33)

25 On Going Clinical Trials Identification Title Intervention NCT NCT Pharmacokinetics of Ceftolozane/Tazobactam in Patients With Burns Safety and Efficacy Study of Ceftolozane/Tazobactam to Treat Ventilated Nosocomial Pneumonia (MK-7625A-008) (ASPECT-NP) Ceftolozane/tazobactam 3g single-dose Ceftolozane/tazobactam 3g q8h versus Meropenem 1g q8h 8-14 days NCT Tissue Penetration of Ceftolozane/Tazobactam in Diabetic Patients With Lower Limb Infections 3 or more doses of ceftolozane/tazobactam IV administered over 1h q8h

26 Not yet recruiting Ceftolozane Tazobactam Pharmacokinetics in Infected Critically Ill Patients With an Indwelling External Ventricular Drain An Observational Pharmacokinetic Sudy of Ceftolozane- Tazobactam in Intensive Care Unit in Patients With and Without CRRT MK-7625A Plus Metronidazole Versus Meropenem in Pediatric Participants With Complicated Intra-Abdominal Infection (ciai) (MK-7625A-035) MK-7625A Versus Meropenem in Pediatric Participants With Complicated Urinary Tract Infection (cuti) (MK-7625A-034)

27 Ceftazidime/Avibactam (CAZ/AVI) inhibition of PBPs, which are important for the cross-linking of peptidoglycan in the bacterial cell wall. Avibactam covalently and reversibly binds the catalytic serine at position 70 of classes A, C, and D (OXA-48) beta-lactamases Krishnan et al. PLoS ONE10(9): e

28 Ceftazidime/Avibactam (CAZ/AVI) Spectrum of Activity Enterobacteriaceae (including KPC, OXA-48) P. aeruginosa IT DOES NOT HAVE ACTIVE AGAINST METALLO-BETA- LACTAMASE-PRODUCING GRAM-NEGATIVE ISOLATES (ClASS B); Acinetobacter; Staphylococci; or Enterococci. Van Duin & Bonomo. Clin Infect Dis Jul 15;63(2): Castanheira et al. Antimicrob Agents Chemother Jul 22;60(8):

29 Activity of Ceftazidime-Avibactam Tested against β- Lactamase-Producing Isolates from 63 US Hospitals ( ) KPC-producing isolates (N=304) CRE (N=326) MIC90 0,5 0,5 MIC % Susceptible % Susceptible 2 CTX-M-producing isolates (N=1,120) ESBL (N=2,129) 0,12 0,12 MIC (μg/ml) 0,5 100% Susceptible % Susceptible 15,588 Enterobacteriaceae All isolates inhibited at MIC, 4 μg/ml, except for 5 MβL producers. Castanheira et al. Antimicrob Agents Chemother Jul 22;60(8):

30 Ceftazidime/avibactam pk Ceftazidime, 2 g every 8 h Avibactam, 500 mg every 8 h Cmax, mg/l t 1/2, h V, L AUC 0 tau, mg.h/l fauc 0 tau, mg.h/l Protein binding, % 21 8 Elimination (urine), % >97 Falcone & Paterson. J Antimicrob Chemother 2016 Oct;71(10): Zasowski et al. Pharmacotherapy.2015 Aug;35(8):

31 Ceftazidime/avibactam Pharmacodynamic targets for ceftazidime (50%fT>MIC) and avibactam (50%fT>CT, CT = 0.5 μg/ml) MacVane et al. AAC 2014:58(3): Coleman et al AAC Jun;58(6): No pk/pd data on prolonged infusion of Caz/Avi Cerexa, I. a subsidiary of Actavis plc. Ceftazidime-Avibactam for Injection Anti-Infective Drugs Advisory Committee. Administration USFaD, ed. InfectiveDrugsAdvisoryCommittee/UCM pdf2014

32 Mazuski et al. Clin Infect Dis Jun 1;62(11): Wagenlehner et al Clin Infect Dis Sep 15;63(6): Carmeli et al. Lancet Infect Dis Jun;16(6):

33 CE, clinically evaluable; CI, confidence interval; cmitt, clinically modified intent-to-treat; TOC, test-of-cure ECCMID, Vienna, 2017.

34 Ceftazidime/avibactam Clinical Indications FDA (FEBRUARY, 2015) Complicated intra-abdominal infections (ciai), used in combination with metronidazole Complicated urinary tract infections (cuti), including pyelonephritis EMA (JUNE, 2016) Complicated intra-abdominal infection used, in combination with metronidazole Complicated urinary tract infection, including pyelonephritis Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP)

35 Ceftazidime/avibactam

36 Ceftazidime/Avibactam (CAZ/AVI) Data Limitation of Clinical Trials Critically ill patients Patients with bloodstream infections as well as other body sites of infections Pediatric population Patients with renal impairment Carbapenemase producers Mono or Combination Therapy

37 Bloodstream Infections (BSI) Study Diagnosis Pathogen CAZ/AVI Susceptibility Camargo (AAC 2015) Jacobs (IJAA 2016) Wu (CID 2016) Wu (CID 2016) Therapy Bowel TX + BSI KPC-KPN 26 mm 1,250 g q8h 2h + ertapenem 1g qd for 14 days Pancreas TX + kidney TX (2015) Hematoma BSI due to ciai (abscess) Endocarditis? UTI, chronic respiratory failure, aortic valve replacement, mitral valve repair, DM, CKD Septic Shock (UTI), DM, CAD, CHF,CKD, Dementia KPC-KPN 0.5 μg/ml 2.5 mg q8h 4h + tigecycline+ colistin for 32/23/28 days CRE-KPN 1.5 μg/ml Monotherapy - 42 days (?) Dose adjusted to CrC CRE-E. aerogenes 1.5 μg/ml Monotherapy 15 days Outcome Discharge d from ICU Died on Day 37 (desaturation cardiac arrest) Discharge d to nursing facility Cure

38 Ceftazidime/avibactam 64 years (range, 26 78); Median Charlson Score: 4 SAPS II: 34; SOFA: 5 University of Pittsburgh Medical Center April, Feb, patients with CRE infections treated with CAZ/AVI ( 3 days) Most frequent agent KPC-producing K. pneumoniae Monotherapy (26) Combination Therapy (11) Clinical Success 15 of 26 (58%) 7 of 11 (64%) Microbiological failure: 27% (10/37) CAZ/AVI Resistance (3/10) Survival rates at 30-day (76% ); 90-day (62%) Shields RK et al. Clinical Infectious Diseases Advance Access published September 13, 2016

39 Mortality of CRE infections treated with CAZ/AVI Study Patients Body Source Monotherapy 30-day Mortality Observation Shields (AAC 2017) Jan/09-Feb/17 N= % ICU IAI (46%), BSI (26%), Resp (13%) 33% 28% Primary BSI & CAZ/AVI predictors of clinical success VanDuin (CID 2017) Colistin (N=99) vs CAZ/AVI (N=38) BSI (46%), Resp (22%) Most patients received CAZ/AVI or COL combined to other agents CAZ/AVI: 9% vs COL 32% p= Probability of a better outcome w/ CAZ/AVI Caston (IJAA 2017) June/12- Mar16 N=31 Patients with hematologic malignancies or aplastic anemia Primary Bacteremia (45%), CVC (19%), Resp (19%) % Combo therapy 45.2% CAZ/AVI (25%) vs others (52.5% - NS) septic shock and higher Pitt score associated with higher mortality

40 Shields et al. Antimicrob Agents Chemother 2017

41 69y-o, brain abscess due to an E. coli BSI secondary to CVC infection by XDR PSA Computed tomography revealed seven necrotic lesions in both lungs highly suggestive of septic embolisms CAZ/AVI 2.5 g q8h over 2-h infusion, colistin 2 MU q8h + 1 MU q8h inhaled for 18 days. 56 y-o, DM, pan sinusitis with bone necrosis BSI secondary to CVC infection by XDR PSA Meropenem 2 g q8h and colistin 2MU q8h without clinical improvement Meningitis CAZ/AVI 2.5 g q8h over 2-h infusion, colistin 2 MU q8h for 30 days. Susceptible to CAZ/AVI by EUCAST disk-diffusion: 21mm and 23 mm Xipell et al. Int J Antimicrob Agents 2017 Feb;49(2):

42 Ceftazidime/Avibactam (CAZ/AVI) Post-Neurosurgical Meningitis 27-year old man w/ traumatic brain injury undergoing left-sided hemicraniectomy developed 14 days later a meningitis caused by KPC-2 producing K. pneumoniae ST 307 Susceptible only to COL (MIC, 0.25 μg/ml) and CAZ/AVI (MIC, 1 μg/ml) Treated with CAZ/AVI monotherapy (2.5g q6h over 2h for 14 days) Samuel et al. Open Forum Infect Dis 2016; 3 Suppl 1: Elderly patient with diffuse subarachnoid hemorrhage and intraventricular hemorrhage with early obstructive hydrocephalus. An external ventricular drain was placed but later the patient underwent a suboccipital craniectomy due to artery aneurysm. - Patient developed a pneumonia by CR-K. pneumoniae on Day 23, and later a meningitis by CR-KPN - Susceptible to CAZ/AVI by disk-diffusion, susceptibility to colistin also determined by disk-diffusion (?) Treated with CAZ/AVI (2.5g q8h over 2h for 21 days) + 10 mg intra-ventricular gentamicin for 15 days Holik et al. J Antimicrob Chemother 2017 Oct 10. doi: /jac/dkx358.

43 Cottagnoud P et al. ICAAC, 2007 Abstract F1-321 Ceftazidime penetration in the CSF Ceftazidime 2-3g CSF (μg/ml) Serum:CSF at 2 to 3 h postinfusion Noninflamed meninges (N=6) (media, 0.8) 101.5/0.8 (±82.5/± 0.8) Asseptic meningitis (N=5) (media, 16) 50.1/12.6 (± 15.0/± 13.6) Bacterial/Fungal meningitis (N=7) (media, 22.6) 57.6/22.6 (± 30.0/± 16.2) Experimental models of meningitis in rabbits after infection with an AmpCproducing K. pneumoniae (CAZ MIC, 128 mg/l) The mean CSF penetration of avibactam was 38%. Modai et al. Antimicrob Agents Chemother Jul;24(1): Fong & Tomkins. Antimicrob Agents Chemother Jul;26(1): Ceftazidime/avibactam in the CSF Ceftazidime monotherapy was unable to reduce the CSF bacterial load, while > 5 log reduction at 8h after initiation of CAZ/AVI therapy was observed.

44 Pharmacokinetic data from two patients with KPC producing K. pneumoniae bloodstream infections, both of whom had renal impairment, and one of whom was morbidly obese. Prolonged half-lives Larger Vss Considering the larger volumes of distribution and levels observed in our patients, recommended doses and intervals may not be sufficient for obese patients with renal failure, especially for those infected with KPC-producing organisms. Veillette et al Pharmacotherapy (11):e172-e177.

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46 On going Clinical Trials (recruiting) Study of Ceftazidime-Avibactam Blood Concentrations in Intensive Care Unit Patients With Renal Failure Requiring Continuous Dialysis - NCT

47 Conclusions Moderate evidence for pneumonia and bloodstream infections. Very scarce data for children. Few evidence for correct dosage in patients on continuous venovenous hemodiafiltration (CVVHDF). Data comparison is difficult few studies using distinct regimens and measuring at different moments Room for therapeutic drug monitoring? Dilemma Patients enrolled on clinical trials usually do not represent the real life. They do not represent the scenario, where new antibiotics will be prescribed.