Terapia delle infezioni da Pseudomonas aeruginosa MDR

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1 Verona 23 ottobre 2010 Terapia delle infezioni da Pseudomonas aeruginosa MDR Pierluigi Viale Clinica di Malattie Infettive Policlinico S. Orsola Malpighi

2 Global resistance surveillance of Pseudomonas aeruginosa isolated in the Mystic programme Genta Tobra Pip/tazo Cefta Cefe Imi Mer Cipro Nort Eur South Eur East Eur

3 Imipenem resistance of Pseudomonas in pneumonia: a systematic literature review Zilberberg et al. BMC Pulmonary Medicine 2010, 10:45 Of the 46 studies identified, 20 included patients with pneumonia (imipenem 1,667, comparator 1,661). Pooled clinical success rates for PA were 45.2% (range %) for imipenem and 74.9% (range %) for comparator regimens. Microbiologic eradication was achieved in 47.6% (range 0.0% %) of isolates in the imipenem and 52.8% (range 0.0%-100.0%) in the comparator groups

4 COLISTINA

5 COLISTIN PRATICAL USE Predictions from modelling indicate that without a loading dose, it takes 2 3 days before the steady-state concentration of colistin is obtained. A loading dose of 9 million IU CMS and a maintenance dose of 4.5 million IU CMS every 12 hours would result in a right steady-state concentration of colistin but would achieve the target faster. The intrathecal and intraventricular doses of CMS are equal to IU/day. By the inhalation route, the recommended dosage ranges from IU every 12 hours to 2 million IU every 8 hours In renal dysfunction, the CMS dosage adjustment recommended by the manufacturers is as follows: for serum creatinine levels of mg/dl, 2 million IU every 12 h for serum creatinine levels of mg/dl, 2 million IU every 24 h for serum creatinine levels > 2.6 mg/dl, 2 million IU every 36 h During hemodialysis the recommended dose is 2 million IU after each session During CVVH the same dosage schedule as for normal renal function

6 COLISTIN PRATICAL USE In contrast to older information, recent data indicate that nephrotoxicity in ICU patients after CMS administration ranges from 0% to 36%. Safety data from 19 courses of prolonged intravenous CMS administration (mean duration 43.4 days and mean daily dose 4.4 million IU) showed that the median creatinine value increased only by 0.25 mg/dl, which returned to close to baseline at the end of therapy. The reported discrepancies could be attributed to the improvement in supportive care offered to seriously ill patients, the possible avoidance of coadministering other nephrotoxic drugs, different formulations of colistin lacking sulfate impurities and the different definitions of nephrotoxicity. On the other hand nephrotoxicity in the recently reported studies ranged from 0% to 14%. The incidence of neurotoxicity in earlier studies of colistin reached approximately 7%.

7 COLISTIN CLINICAL EXPERIENCE In total, from 1999 until August 2005, in 7 retrospective studies involving almost 300 patients without CF, among whom most represented ICU patients with VAP, intravenous CMS was given at a dose of 1 3 million IU every 8 hours for days. In almost all patients, at a rate close to 50%, either MDR P. aeruginosa or MDR A. baumannii were isolated in relevant cultures. Irrespective of the susceptibility patterns of the isolated pathogens, as a rule, CMS was given in combination with other antibacterials (mostly with a carbapenem). Clinical cure rates ranged between 57% and 73%, with mortality rates of %.

8 COLISTIN CLINICAL EXPERIENCE In 2007, two retrospective monotherapy studies with CMS were published. In the first study, no difference in mortality rates (51.6% vs 45.1%) was observed between 31 patients with VAP caused by isolates susceptible only to colistin who were treated with CMS monotherapy and 30 patients with VAP caused by carbapenem-susceptible strains who were treated with imipenem/ cilastatin or meropenem as monotherapy. Patients who received appropriate empirical therapy had significantly better outcome compared to those who received inappropriate empirical therapy (mortality 36.6% vs 70%, respectively; p = 0.014). Rios FG et al. VAP due to susceptible only to colistin microorganisms. Eur Respir 2007; 30: In the largest retrospective matched case-control study thus far to assess the efficacy of monotherapy with CMS, the latter was compared with imipenem in VAP caused by isolates susceptible only to colistin (n = 60) and carbapenem susceptible A. baumannii or P. aeruginosa. A favourable clinical response was observed in 75% of patients without difference in the time to resolution of infectious parameters between the two groups. Kallel H, et al. Safety and efficacy of colistin compared with imipenem in the treatment of VAP: a matched case-control study. Intensive Care Med 2007; 33 :

9 Colistin therapy for microbiologically documented multidrug-resistant Gramnegative bacterial infections: a retrospective cohort study of 258 patients Falagas ME et al, Intern J Antimicrob Ag 2010; 35: Over a 7-year period (October 2000 to October 2007), 258 patients received intravenous colistin for at least 72 h for microbiologically documented multidrug-resistant Gramnegative bacterial infections, comprising 170 (65.9%) Acinetobacter baumannii, 68 (26.4%) Pseudomonas aeruginosa, 18 (7.0%) Klebsiella pneumoniae, 1 (0.4%) Stenotrophomonas maltophilia and 1 (0.4%) Enterobacter cloacae. Cure of infection occurred in 79.1% of patients, nephrotoxicity in 10% and hospital survival in 65.1%.

10 Colistin therapy for microbiologically documented multidrug-resistant Gramnegative bacterial infections: a retrospective cohort study of 258 patients Falagas ME et al, Intern J Antimicrob Ag 2010; 35:

11 Colistin therapy for microbiologically documented multidrug-resistant Gramnegative bacterial infections: a retrospective cohort study of 258 patients Falagas ME et al, Intern J Antimicrob Ag 2010; 35:

12 Polymyxin B versus other antimicrobials for the treatment of P. aeruginosa bacteraemia Kvitko CH et al J Antimicrob Chemoter Advance Access published October 20, 2010 Retrospective cohort study. Patients 18 years of age and who received appropriate therapy for 48 h for P. aeruginosa bacteraemia were analysed. Clinical covariates were assessed and compared between patients treated with polymyxin B and other drugs (comparators). Data were retrieved from medical records. A total of 133 patients were included: 45 (33.8%) treated with polymyxin B and 88 (66.2%) with comparators.

13 Nebulized and intravenous colistin in experimental pneumonia caused by P. aeruginosa Lu Q et al Intensive Care Med (2010) 36: Lung bacterial burden after 24 h of colistin administration In the aerosol group, median peak lung tissue concentration of colistin was 2.8 mcg g-1 (25 75% IQR: ) In the intravenous group, colistin could not be detected in any of the analyzed lung segments.

14 Nebulized and intravenous colistin in experimental pneumonia caused by P. aeruginosa Lu Q et al Intensive Care Med (2010) 36: Colistin peak lung tissue concentrations according to histological severity of pneumonia following 24-h treatment by nebulized colistin.

15 Nebulized and intravenous colistin in experimental pneumonia caused by P. aeruginosa Lu Q et al Intensive Care Med (2010) 36: Regional distribution of colistin peak lung tissue concentrations measured 1 h after the third aerosol of colistin on lung specimens obtained in different lung segments representative of each lobe S2 S3 S6 S8 S10 upper lobe middle lobe lower lobe

16 Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonian caused by Gram-negative bacteria. Rattanaumpawan P et al, J Antimicrob ChemotherAdvance Access published September 28, 2010 One hundred adult patients who developed Gram-negative VAP received systemic antibiotics according to the decisions of their responsible physicians. The patients were randomized to receive an additional 4 ml of nebulized sterile normal saline (NSS) (n¼49) or nebulized CMS equivalent to 75 mg of colistin base in 4 ml of NSS every 12 h until systemic antibiotic therapy of VAP was ended.

17 Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonian caused by Gram-negative bacteria. Rattanaumpawan P et al, J Antimicrob ChemotherAdvance Access published September 28, 2010

18 COLISTIN PRATICAL USE future studies with colistin necessitate large prospective, possibly comparative, trials in MDRinfections of ICU patients under well-designed protocols and reliable susceptibility testing; further pharmacokinetic/ pharmacodynamic exploitation; Clarification in vivo of the possible benefits of coadministering colistin with other antimicrobials, such as the carbapenems and rifampicin; evaluation of nebulized colistin as single VAP therapy versus combination with parenteral colistin; better monitoring and elucidation of resistance mechanisms; larger experience in specific populations, for example the febrile neutropenic host.

19 DORIPENEM

20 DORIPENEM Doripenem, the most recently FDA-approved carbapenem, possesses an antimicrobial spectrum similar to meropenem against Gram-negative pathogens and similar to imipenem against Gram-positive pathogens, while retaining 2- to 4-fold lower MICs against P. aeruginosa compared with meropenem A potential advantage of this new carbapenem over the existing members of the class is its lower potential for the selection of resistance in vitro Fluoroquinolone Enhances the Mutation Frequency for Meropenem-Selected Carbapenem Resistance in P.aeruginosa, but Use of the High-Potency Drug Doripenem Inhibits Mutant Formation Tanimoto K et al, Antimicrob Ag Chemother 2009; 52: Preliminary data indicate that PK/PD applications, by means of prolonged infusion and supported by the relative stability of the infusate in ambient conditions, may help in the treatment of strains with borderline MICs, thus overcoming low-level resistance

21 Susceptibility of Pseudomonas aeruginosa clinical isolates in Japan to doripenem and other antipseudomonal agents Fujimura T Intern J Antimicrob Ag 2009; 34: the susceptibility of 694 Pseudomonas aeruginosa clinical isolates to nine antipseudomonal agents including doripenem was investigated The MIC90 of doripenem was 2-fold lower than that of meropenem, imipenem and amikacin and was 4-fold lower than that of piperacillin, ceftazidime, cefepime, ciprofloxacin and tobramycin

22 EFFICACY AND SAFETY OF INTRAVENOUS INFUSION OF DORIPENEM VERSUS IMIPENEM IN VAP: A MULTICENTER,RANDOMIZED STUDY Chastre J et al. Crit Care Med 2008; 67: PER-PATHOGEN CLINICAL AND MICROBIOLOGICAL CURE RATES

23 EFFICACY AND SAFETY OF INTRAVENOUS INFUSION OF DORIPENEM VERSUS IMIPENEM IN VAP: A MULTICENTER,RANDOMIZED STUDY Chastre J et al. Crit Care Med 2008; 67: PER-PATHOGEN CLINICAL AND MICROBIOLOGICAL CURE RATES

24 Lucasti C et al. Clin Ther 2008;30:

25 FOSFOMICINA

26 FOSFOMYCIN Since penetration of fosfomycin is reported to be sufficient in various body compartments, particularly during inflammation, peak plasma concentrations are anticipated to exceed the MICs of the tested MDR pathogens after a maximum dosage of 8 g intravenously every 8 hours. Clinical data with fosfomycin for MDR infections are very scarce.

27 Fosfomycin for the treatment of infections caused by multidrug-resistant nonfermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies Falagas ME et al. Int J Antimicr Agents 2009; 34: Microbiological studies 23 microbiological studies 1859 MDR non-fermenting Gram neg isolates Susceptibility rate to fosfomycin of MDR P aeruginosa isolates was >=90%, and 50-90% in 7/19 and 4/19 relevant studies, respectively. Only 3/85 (3.5%) MDR A baumannii and 0/31 MDR Burkholderia spp isolates were susceptible to fosfomycin. Fosfomycin was synergistic in combination with a beta-lactam, aminoglycoside or ciprofloxacin in 46/86 (53.5%) MDR P aeruginosa isolates

28 Fosfomycin for the treatment of infections caused by multidrug-resistant nonfermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies Falagas ME et al. Int J Antimicr Agents 2009; 34: One animal study found a good therapeutic effect of the combination fosfomycin/gentamicin against MDR P. aeruginosa endocarditis. In six clinical studies, 33 patients with MDR P. aeruginosa infections (mainly pulmonary exacerbations of cystic fibrosis) received fosfomycin (25/33 in combination with other antibiotics); 91% of the patients clinically improved.

29 COMBINAZIONI

30 In Vitro Double and Triple Bactericidal Activities of Doripenem, Polymyxin B, and Rifampin against MDR A. baumannii, P. aeruginosa, K. pneumoniae, and E. coli Urban C et al, Antimicrob Ag Chemother 2010;54:

31 Colistin-Tobramycin Combinations Are Superior to Monotherapy Concerning the Killing of Biofilm P. aeruginosa Herrmann G et al, J Infect Dis 2010; 202: Colistin Tobramycin Combo

32 Colistin-Tobramycin Combinations Are Superior to Monotherapy Concerning the Killing of Biofilm P. aeruginosa Herrmann G et al, J Infect Dis 2010; 202: Five CF patients consecutively inhaled 1 million IU (3 ml) of colistin and 300 mg (5 ml) of tobramycin twice daily for 28 days. The change in the number of P. aeruginosa colony-forming units in sputum at day 30, compared with day 1, was used as the primary end point inhaled colistin-tobramycin resulted in a mean decrease in P. aeruginosa of log cfu/ml of sputum (P=.027)

33 The Combination of Meropenem and Levofloxacin Is Synergistic with Respect to both Pseudomonas aeruginosa Kill Rate and Resistance Suppression Louie A et al, Antimicrob Agents Chemother Jun;54(6): Effect of combination therapy versus that of monotherapy on WT P. aeruginosa PAO1 Monotherapy Combo

34 The Combination of Meropenem and Levofloxacin Is Synergistic with Respect to both Pseudomonas aeruginosa Kill Rate and Resistance Suppression Louie A et al, Antimicrob Agents Chemother Jun;54(6):

35 The Combination of Meropenem and Levofloxacin Is Synergistic with Respect to both Pseudomonas aeruginosa Kill Rate and Resistance Suppression Louie A et al, Antimicrob Agents Chemother Jun;54(6):

36 OTTIMIZZAZIONE DELL USO DEI FARMACI DISPONIBILI

37 Suboptimal Aminoglycoside Dosing in Critically Ill Patients Rea RS et al, Ther Drug Monit 2008;30: probability (%) of simulated patients with optimal PD target (C MAX /MIC > 10) with gentamicin N = 102 TDM = JAN 2004 DEC

38 Suboptimal Aminoglycoside Dosing in Critically Ill Patients Rea RS et al, Ther Drug Monit 2008;30: Probability (%) of Cmax >10³ MIC by Different MIC and AG Dose

39

40 Ceftazidime plasma concentration (mg/l) Intravenous continuous infusion of ceftazidime in febrile neutropenic patients with acute myeloid leukemia: a helpful tool for maximizing drug exposure Pea F, Viale P et al., Antimicrob Agents Chemother, 2005; 49: N = 20 CL CR = 1.64 ± 0.35 ml/min/kg CEFTAZIDIME: LD 1G 6G/24h CI Time after stopping continuous infusion (h)

41 High-Dose Continuous Infusion b-lactam Antibiotics for the Treatment of Resistant Pseudomonas aeruginosa Infections in Immunocompromised Patients Moriyama B et al, Ann Pharmacother 2010;44:929-35

42 REASSESSMENT OF RECOMMENDED IMIPENEM DOSES IN FEBRILE NEUTROPENIC PATIENTS WITH HAEMATOLOGICAL MALIGNANCIES Lamoth F et al. Antimicrob Agents Chemother 2009 Feb, 59: CHARACTERISTICS OF PATIENTS

43 REASSESSMENT OF RECOMMENDED IMIPENEM DOSES IN FEBRILE NEUTROPENIC PATIENTS WITH HAEMATOLOGICAL MALIGNANCIES Lamoth F et al. Antimicrob Agents Chemother 2009 Feb, 59: CHARACTERISTICS OF PATIENTS

44 REASSESSMENT OF RECOMMENDED IMIPENEM DOSES IN FEBRILE NEUTROPENIC PATIENTS WITH HAEMATOLOGICAL MALIGNANCIES Lamoth F et al. Antimicrob Agents Chemother 2009 Feb, 59: PERCENTAGE OF SIMULATED PATIENTS WITH C MIN > 1 MG/L 500 Q4H over 30 min 1000 Q8H over 30 min

45 MEROPENEM DOSING IN CRITICALLY ILL PATIENTS WITH SEPSIS AND WITHOUT RENAL DYSFUNCTION: INTERMITTENT BOLUS vs CONTINUOUS ADMINISTRATION? Roberts JA et al. J Antimicrob Chemother 2009 July; 64: PROBABILITY OF PD TARGET ATTAINMENT (50% free T>MIC) Alma Mater Studiorum Università di Bologna

46 Meropenem by continuous versus intermittent infusion in VAP due to gramnegative bacilli Lorente L et al. Ann Pharmacother 2006;40: Alma Mater Studiorum Università di Bologna

47 Outcomes of Bacteremia due to Pseudomonas aeruginosa with Reduced Susceptibility to Piperacillin-Tazobactam: Implications on the Appropriateness of the Resistance Breakpoint Tam VH et al Clin Infect Dis 2008; 46:862 7 Thirty-day mortality rate according to piperacillin-tazobactam MIC.

48 Piperacillin-Tazobactam for P. aeruginosa Infection: Clinical Implications of an Extended- Infusion Dosing Strategy Lodise TP et al, Clin Infect Dis 2007; 44: Results of the probability of target attainment analysis for pip-taz therapy Monte Carlo simulation study

49 Piperacillin-Tazobactam for P. aeruginosa Infection: Clinical Implications of an Extended- Infusion Dosing Strategy Lodise TP et al, Clin Infect Dis 2007; 44:357 63

50 Alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to patients with VAP. Boselli E et al, Crit Care Med 2008; 36: Relationship between serum piperacillin concentrations and creatinine clearance.

51 WHAT DOES IT MEAN CORRECT ANTIBIOTIC THERAPY? The microorganism point of view - A GOOD MICROBIOLOGICAL / EPIDEMIOLOGICAL CHOICE The drug point of view - A CORRECT PHARMACOKINETICAL CHOICE and ADMINISTRATION liphophilic vs hydrophilic drugs Viale P & Pea F Crit Care Med 2006 time dependent vs concentration dependent drugs MIC value DRUG CHOICE DAILY SCHEDULA The patient point of view - A TARGETED PHYSIOPHATOLOGICAL DAILY SCHEDULA illness severity grading physio-pathological conditions affecting distribution Clinical condition

52 Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department Gaieski DF et al, Crit Care Med 2010; 38: Design: Single-center cohort study. Setting: The emergency department of an academic tertiary care center from 2005 through Patients: Two hundred sixty-one patients undergoing early goal-directed therapy. Interventions: None. Measurements: Effects of different time cutoffs from triage to antibiotic administration, qualification for early goal-directed therapy to antibiotic administration, triage to appropriate antibiotic administration, and qualification for early goal-directed therapy to appropriate antibiotic administration on inhospital mortality were examined. The mean age of the 261 patients was yrs; 41% were female. In-hospital mortality was 31% for the cohort as a whole; it was 35.1% for culture-positive patients vs. 25.7% (p.11) for culture-negative patients.

53 Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department Gaieski DF et al, Crit Care Med 2010; 38:

54 Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department Gaieski DF et al, Crit Care Med 2010; 38: