Traitement des infections à Pseudomonas aeruginosa

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1 Traitement des infections à Pseudomonas aeruginosa
RICAI 7 Décembre 2007 Karine Faure SGRIVi, Unité des Maladies Infectieuses, CHU Lille EA2689, Université de Lille 2

2 Pseudomonas aeruginosa Caractéristiques
Bacille à Gram négatif, non sporulé, très mobile grâce à un cil polaire (le flagelle) Culture non exigeante sur milieux ordinaires en aérobiose stricte Facteurs cellulaires Adhésion et croissance Pili LPS Lectines Adhésines Alginate Flagelle Expression variable selon l’environnement ADAPTABILITE Facteurs extracellulaires: enzymes, toxines Lésions cellulaires Lésions tissulaires

3 Bactérie environnementale
Habitat Bactérie environnementale Sols humides Bactérie aquaphile eaux de rivière, d'égouts, de piscine, de mer eau potable, minérales ou thermales, eaux déminéralisées Environnement hospitalier Matériel: hôtelier (robinetterie) médical (sondes, trocarts, cathéters) chirurgical (instruments, prothèses) Solutions: antiseptiques, injectables végétaux, fleurs légumes, fruits Répandu dans le monde entier Hôtes: humain, animaux, végétaux RÉSERVOIR : existe à l'état saprophyte dans le sol, dans l'eau et dans la matière en décomposition; animaux et humains infectés; solutions infectées - solutions IV, savons, gouttes ophtalmiques, humidificateurs; l'organisme prolifère dans les milieux humides flore intestinale transitoire de l'homme ou de l'animal

4 Chaine épidémiologique
3ème rang des infections nosocomiales Hôte susceptible - Immunodéprimé: neutropénie - Malnutrition - Lésions des barrières muqueuses ou épithéliales . Procédures invasives: réanimation . Maladies sous-jacentes: mucoviscidose Réservoir - Endogène - Exogène . Vecteurs inertes . Mains souillées Sites : Infections urinaires Infections cutanées et suppurations Pneumonies

5 Interactions hôte - pathogène
P. aeruginosa Défense Voies aériennes indemne de P. aeruginosa P. aeruginosa Défense Colonisation des voies aériennes Défense P. aeruginosa Pneumonie à P. aeruginosa Notion de Pouvoir pathogène – Facteurs de risque de l’hôte Notion de Virulence du pathogène – Défenses de l’hôte

6 Résistance aux antibiotiques
Nombreuses résistances naturelles Nombreux mécanismes de résistance acquise Association des mécanismes très fréquente Amoxicilline C1g, c2g Céfotaxime... Kanamycine Néomycine Spectinomycine Chloramphénicol Tétracyclines Triméthoprime Sulfamides Nitrofuranes Anciennes quinolones Péfloxacine... Macrolides Lincosamides Synergistines Nitroimidazoles Glycopeptides Imperméabilité Membrane externe Porine Antibiotique PLP Modification de la cible Inactivation antibiotique Enzyme Pompe Efflux

7 Antibiotiques anti-pyocyanique
ß-lactamines - ticarcilline ± clavu - pipéracilline ± tazo - aztréonam - cefsulodine - céfopérazone - ceftazidime - cefpirome - céfépime - imipénème - méropénème Aminosides - gentamicine - nétilmicine - tobramycine - amikacine - isépamicine Fluoroquinolones - ofloxacine - ciprofloxacine - lévofloxacine - sitafloxacine Autres - colistine - polymyxine B - rifampicine - fosfomycine

8 Épidémiologie de la résistance en France
10 20 30 40 50 60 70 80 90 100 Ticarcilline Claventin Pipéracilline Tazocilline Céfépime Ceftazidime Aztréonam Imipénème Ciprofloxacine Tobramycine Amikacine Colistine * Le graphique en question est la synthse de plus d'une dizaine d'Žtudes multicentriques franaises sur la sensibilitŽ de P. aeruginsoa aux antibiotiques (GERPB, GERPA...).  Les deux colonnes reprŽsentent les extrmes (hauts et bas) des taux de sensibilitŽ pour chaque antibiotique dŽterminŽs dans ces Žtudes.  En gros, on obtient une fourchette qui permet de voir quelles sont les variations d'une Žtude ˆ l'autre sachant que certaines Žtudes incluaient des CHG et d'autres pas.  J'ai positionnŽ par des flches les dernires donnŽes recueillies en 2004 par le groupe GERPA uniquement composŽ de CHUs. En conclusion, la rŽsistance ne semble pas progresser de faon significative. Plésiat 2004

9 Rapport EARSS 2005 Pourcentage de souches invasives de P. aeruginosa résistantes à la pipéracilline

10 Rapport EARSS 2005 Pourcentage de souches invasives de P. aeruginosa résistantes à la ceftazidime REA-RAISIN 2005: Résistance à la ceftazidime 22,6% (26,2% en 2004)

11 Rapport EARSS 2005 10 pays / 23 > 25% Pourcentage de souches invasives de P. aeruginosa résistantes aux fluoroquinolones

12 Rapport EARSS 2005 Pourcentage de souches invasives de P. aeruginosa résistantes aux aminoglycosides

13 Combinaison des résistances

14

15 National surveillance of antimicrobial resistance
in Pseudomonas aeruginosa isolates obtained from intensive care unit patients from 1993 to 2002 14% ceftazidime, ciprofloxacin, tobramycin, and imipenem Antimicrob Agents Chemother Dec;48(12): Related Articles, Links   National surveillance of antimicrobial resistance in Pseudomonas aeruginosa isolates obtained from intensive care unit patients from 1993 to Obritsch MD, Fish DN, MacLaren R, Jung R. Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Nosocomial infections caused by Pseudomonas aeruginosa in critically ill patients are often difficult to treat due to resistance to multiple antimicrobials. The purpose of this study was to evaluate antimicrobial resistance among P. aeruginosa isolates from intensive care unit patients in the United States from 1993 to 2002 by using the Intensive Care Unit Surveillance Study database. Over the 10-year period, susceptibility of 13,999 nonduplicate isolates of P. aeruginosa was analyzed. From 1993 to 2002, nationwide increases in antimicrobial resistance were greatest for ciprofloxacin, imipenem, tobramycin, and aztreonam. Rates of multidrug resistance (resistance to > or =3 of the following drugs: ceftazidime, ciprofloxacin, tobramycin, and imipenem) increased from 4% in 1993 to 14% in The lowest dual resistance rates were observed between aminoglycosides or fluoroquinolones with piperacillin-tazobactam while the highest were for those that included beta-lactams and ciprofloxacin. Ongoing surveillance studies are crucial in monitoring antimicrobial susceptibility patterns and selecting empirical treatment regimens 4% 13999 souches Obritsch et al, AAC 2004

16 Hôte Bactérie Antibiotique

17 Hôte Bactérie Antibiotique

18 Émergence de résistants
Étude rétrospective , patients Émergence : 4% des pathogènes, 5.6% des infections Plus fréquent avec certains pathogènes P. aeruginosa 15.4% Serratia sp 7.8% Enterobacter sp 6.8% Moins fréquent avec d’autres S. aureus 2.2% S. pneumoniae 0.5% Autres strepto 0.3% Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies. Fish DN, Piscitelli SC, Danziger LH. Pharmacotherapy May-Jun;15(3):279-91 University of Colorado Health Sciences Center, Department of Pharmacy Practice, School of Pharmacy, Denver 80262, USA. The incidence of emergent resistance and clinical factors affecting its development were evaluated by retrospective review of 173 studies encompassing over 14,000 patients. Eight antibiotic classes and 225 individual treatment regimens were evaluated. Emergent resistance occurred among 4.0% of all organisms and 5.6% of all infections treated. It appeared to be significantly more frequent with penicillin and aminoglycoside monotherapy, with significantly lower rates associated with imipenem-cilastatin, aztreonam, and combination therapy. Clinical failure also appeared to be significantly more likely to occur after emergence of resistance among organisms treated with fluoroquinolones or aminoglycosides. Infections associated with higher resistance rates were cystic fibrosis, osteomyelitis, and lower respiratory tract infections. Resistance was most common in patients in intensive care units or receiving mechanical ventilation. It was also significantly frequent among studies performed in university or teaching hospitals. Organisms associated with high resistance rates were Pseudomonas aeruginosa, Serratia, Enterobacter, and Acinetobacter sp. Factors such as infection type, underlying diseases, type of institution, and specific pathogens warrant consideration when examining emergent resistance. (Fish et al, Pharmacotherapy 1995)

19 Hôte Bactérie Antibiotique

20 Émergence de résistants
Modèle de péritonite expérimentale à P. aeruginosa (108 CFU) Molécule % d’émergence Ceftazidime 25 Céfépime <10 Imipénème <5 Ciprofloxacine >60 Amikacine <5 A murine model of peritonitis allowing detection and quantification of in-vivo acquired resistance during short term therapy has been used in order to evaluate the capacity of antimicrobial combinations to limit emergence of resistance, as compared to individual components of the regimens. Mice were challenged intraperitoneally with 10(8) cfu of bacteria. Two hours later, a single antibiotic dose was injected subcutaneously: amikacin (15 mg/kg), ceftriaxone (50 mg/kg), pefloxacin (25 mg/kg), amikacin + ceftriaxone, amikacin + pefloxacin or ceftriaxone + pefloxacin. Escherichia coli and Staphylococcus aureus never became resistant. Single drug therapy yielded resistant mutants in Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae and Pseudomonas aeruginosa as follows: 74% of ceftriaxone-treated animals, 57% of pefloxacin treated animals and 27% of amikacin treated animals. All the tested combinations reduced the frequency of in-vivo acquired resistance produced by single drugs, and no combination selected resistance when the separate agents of the combination did not. Combining antimicrobial agents limits the risk of emergence of resistance during antibiotic therapy. (Pechere et al, JAC 1986)

21 271 patients/émergence de résistance chez 28 (10,2%)
Pseudomonas aeruginosa is a leading cause of nosocomial infections. The risk of emergence of antibiotic resistance may vary with different antibiotic treatments. To compare the risks of emergence of resistance associated with four antipseudomonal agents, ciprofloxacin, ceftazidime, imipenem, and piperacillin, we conducted a cohort study, assessing relative risks for emergence of resistant P. aeruginosa in patients treated with any of these drugs. A total of 271 patients (followed for 3,810 days) with infections due to P. aeruginosa were treated with the study agents. Resistance emerged in 28 patients (10.2%). Adjusted hazard ratios for the emergence of resistance were as follows: ceftazidime, 0.7 (P = 0.4); ciprofloxacin, 0.8 (P = 0.6); imipenem, 2.8 (P = 0.02); and piperacillin, 1.7 (P = 0.3). Hazard ratios for emergence of resistance to each individual agent associated with treatment with the same agent were as follows: ceftazidime, 0.8 (P = 0.7); ciprofloxacin, 9.2 (P = 0.04); imipenem, 44 (P = 0.001); and piperacillin, 5.2 (P = 0.01). We concluded that there were evident differences among antibiotics in the likelihood that their use would allow emergence of resistance in P. aeruginosa. Ceftazidime was associated with the lowest risk, and imipenem had the highest risk. (Carmeli et al AAC 1999)

22 Résistance à l’imipénème
Etude cas-contrôle 120 patients P. aeruginosa R 662 patients P. aeruginosa S Monovariée IRPA : IMP, OR: 4,96 PipTZ, OR: 2,39 Vanco, OR: 1,80 AG, OR: 2,19 ISPA: Vanco, OR: 1,64 Ampi-sulb, OR: 2 CSP2G, OR: 2 Le FDR de R à l’imipénème est IMP! Risk factors for the nosocomial recovery of imipenem-resistant Pseudomonas aeruginosa (IRPA) were determined. A case-control study design was used for the comparison of 2 groups of case patients with control patients. The first group of case patients had nosocomial isolation of IRPA, and the second group had imipenem-susceptible P. aeruginosa (ISPA). Control patients were selected from the same medical or surgical services from which case patients were receiving care when isolation of IRPA occurred. Risk factors analyzed included antimicrobials used, comorbid conditions, and demographic variables. IRPA was recovered from 120 patients, and ISPA from 662 patients. Imipenem (odds ratio [OR], 4.96), piperacillin-tazobactam (OR, 2.39), vancomycin (OR, 1.80), and aminoglycosides (OR, 2.19) were associated with isolation of IRPA. Vancomycin (OR, 1.64), ampicillin-sulbactam (OR, 2.00), and second-generation cephalosporins (OR, 2.00) were associated with isolation of ISPA. Antibiotics associated with ISPA are different from antibiotics associated with IRPA. The OR for imipenem as a risk factor for IRPA is less than that reported from studies in which control group selection was suboptimal. (Harris et al, CID 2002)

23 Antibiotiques utilisés Comorbidités Variables démographiques
Multivariée Antibiotiques utilisés Comorbidités Variables démographiques IMP-R Pas IMP-R 1a : ctr : patients avec un Pa IMP-S 1b : patients qui n’ont jamais developpe de Pa IMP-R durant leur séjour (Harris et al, CID 2002)

24 Antimicrob Agents Chemother. 2004 Dec;48(12):4606-10
Antimicrob Agents Chemother Dec;48(12): Related Articles, Links   National surveillance of antimicrobial resistance in Pseudomonas aeruginosa isolates obtained from intensive care unit patients from 1993 to Obritsch MD, Fish DN, MacLaren R, Jung R. Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Nosocomial infections caused by Pseudomonas aeruginosa in critically ill patients are often difficult to treat due to resistance to multiple antimicrobials. The purpose of this study was to evaluate antimicrobial resistance among P. aeruginosa isolates from intensive care unit patients in the United States from 1993 to 2002 by using the Intensive Care Unit Surveillance Study database. Over the 10-year period, susceptibility of 13,999 nonduplicate isolates of P. aeruginosa was analyzed. From 1993 to 2002, nationwide increases in antimicrobial resistance were greatest for ciprofloxacin, imipenem, tobramycin, and aztreonam. Rates of multidrug resistance (resistance to > or =3 of the following drugs: ceftazidime, ciprofloxacin, tobramycin, and imipenem) increased from 4% in 1993 to 14% in The lowest dual resistance rates were observed between aminoglycosides or fluoroquinolones with piperacillin-tazobactam while the highest were for those that included beta-lactams and ciprofloxacin. Ongoing surveillance studies are crucial in monitoring antimicrobial susceptibility patterns and selecting empirical treatment regimens Obritsch et al, AAC 2004

25 Hôte PK/PD Bactérie Antibiotique

26 Concentration-dépendants
Cmax/CMI AUIC: ASC 24h/CMI C max ASC CMI 24 h

27 Aminosides relation Cmax/CMI - guérison clinique
% Taux de guérison clinique In an examination of the relationships among plasma aminoglycoside concentrations, the minimal inhibitory concentration (MIC) for the infecting organism, and therapeutic outcome, data were analyzed from 236 patients with gram-negative bacterial infections who were participants in four clinical trials of gentamicin, tobramycin, and amikacin. Clinical response to therapy occurred in 188 (80%) patients. Elevated maximal and mean peak aminoglycoside concentration/MIC ratios were strongly associated with clinical response (P less than and P less than .0001, respectively). A graded dose-response effect was found between an increasing maximal peak concentration/MIC ratio and clinical response. By logistic regression the peak concentration/MIC ratios were associated significantly with clinical response after adjustment for underlying severity of illness and other factors correlated with response. These results demonstrate that a high peak concentration relative to the MIC for the infecting organism is a major determinant of the clinical response to aminoglycoside therapy. Cmax/CMI (Moore, JID 1987)

28 Résistance adaptative CMI; modèle statique in vitro
tobramycine P. aeruginosa The effect of single and multiple 2-h aminoglycoside exposures on the duration of the postantibiotic effect (PAE) and bacterial killing were investigated using a reference strain (ATCC 27853) and four clinical isolates of Pseudomonas aeruginosa. Concentration-dependent PAE and bacterial killing were demonstrated following single exposures to amikacin, gentamicin or tobramycin. Cultures were also repeatedly exposed to peak aminoglycoside concentration simulating traditional (three times a day) and once daily dosing regimens. Aminoglycoside re- exposures every 8 h at the original culture MIC produced significant, successive reductions in PAE (P < 0.05) and bacterial killing (P < 0.01) coincident with increases in culture MICs. Identical experiments re-exposing cultures to their predetermined, induced MICs demonstrated similar to significantly longer PAEs (P < 0.05) than those observed following first exposure. Multiple gentamicin or tobramycin exposures at 8 mg/L (traditional peak) every 8 h or 24 mg/L (once daily peak) once every 24 h both showed significant reductions in PAE (P < 0.05) and bacterial killing (P < 0.05) on repeated dosing. However, the once- daily high peak concentration exposure demonstrated significantly longer PAEs and greater bacterial killing both initially and upon re- exposure compared with the 8-hourly exposure. In addition, the once daily dosing regimen maintained substantially larger aminoglycoside concentration/MIC ratios. We conclude that multiple exposure of P. aeruginosa in-vitro, to aminoglycosides at the intervals tested, reduces the PAE and bacterial killing and increases the MICs. (Karlowsky et al, JAC 1994)

29 Résistance adaptative Bactéricidie; modèle statique in vitro
Killing log10 CFU/ml tobramycine P. aeruginosa contact = 2h The effect of single and multiple 2-h aminoglycoside exposures on the duration of the postantibiotic effect (PAE) and bacterial killing were investigated using a reference strain (ATCC 27853) and four clinical isolates of Pseudomonas aeruginosa. Concentration-dependent PAE and bacterial killing were demonstrated following single exposures to amikacin, gentamicin or tobramycin. Cultures were also repeatedly exposed to peak aminoglycoside concentration simulating traditional (three times a day) and once daily dosing regimens. Aminoglycoside re- exposures every 8 h at the original culture MIC produced significant, successive reductions in PAE (P < 0.05) and bacterial killing (P < 0.01) coincident with increases in culture MICs. Identical experiments re-exposing cultures to their predetermined, induced MICs demonstrated similar to significantly longer PAEs (P < 0.05) than those observed following first exposure. Multiple gentamicin or tobramycin exposures at 8 mg/L (traditional peak) every 8 h or 24 mg/L (once daily peak) once every 24 h both showed significant reductions in PAE (P < 0.05) and bacterial killing (P < 0.05) on repeated dosing. However, the once- daily high peak concentration exposure demonstrated significantly longer PAEs and greater bacterial killing both initially and upon re- exposure compared with the 8-hourly exposure. In addition, the once daily dosing regimen maintained substantially larger aminoglycoside concentration/MIC ratios. We conclude that multiple exposure of P. aeruginosa in-vitro, to aminoglycosides at the intervals tested, reduces the PAE and bacterial killing and increases the MICs. (Karlowsky et al, JAC 1994)

30 Fluoroquinolones Relation ASC 24h/CMI et efficacité
(%) 100 Modèles expérimentaux infection de la cuisse autres modèles 80 60 Mortalité 40 20 3 10 30 300 1000 100 ASC 24h / CMI (Craig, CID 1998)

31 Fluoroquinolones Relation ASC 24h/CMI et efficacité
(%) 64 patients ciprofloxacine patients cured Data obtained from 74 acutely ill patients treated in two clinical efficacy trials were used to develop a population model of the pharmacokinetics of intravenous (i.v.) ciprofloxacin. Dosage regimens ranged between 200 mg every 12 h and 400 mg every 8 h. Plasma samples (2 to 19 per patient; mean +/- standard deviation = 7 +/- 5) were obtained and assayed (by high-performance liquid chromatography) for ciprofloxacin. These data and patient covariates were modelled by iterative two-stage analysis, an approach which generates pharmacokinetic parameter values for both the population and each individual patient. The final model was used to implement a maximum a posteriori-Bayesian pharmacokinetic parameter value estimator. Optimal sampling theory was used to determine the best (maximally informative) two-, three-, four-, five-, and six-sample study designs (e.g., optimal sampling strategy 2 [OSS2] was the two-sample strategy) for identifying a patient's pharmacokinetic parameter values. These OSSs and the population model were evaluated by selecting the relatively rich data sets, those with 7 to 10 samples obtained in a single dose interval (n = 29), and comparing the parameter estimates (obtained by the maximum a posteriori-Bayesian estimator) based on each of the OSSs with those obtained by fitting all of the available data from each patient. Distributional clearance and apparent volumes were significantly related to body size (e.g., weight in kilograms or body surface area in meters squared); plasma clearance (CLT in liters per hour) was related to body size and renal function (creatinine clearance [CLCR] in milliliters per minute per 1.73 m2) by the equation CLT = ( CLCR ).weight. However, only 30% of the variance in CLT was explained by this relationship, and no other patient covariates were significant. Compared with previously published data, this target population had smaller distribution volumes (by 30%; P < 0.01) and CLT (by 44%; P < 0.001) than weight- and CLCR- matched stable volunteers. OSSs provided parameter estimates that showed good to excellent estimates of CLT (or area under the concentrations-time curve [AUC]) were unbiased and precise (e.g., r2 for AUC for all data versus AUC for OSS2 was > 0.99) and concentration-time profiles were accurately reconstructed. These results will be used to model the pharmacodynamic relationships between ciprofloxacin exposure and response and to aid in developing algorithms for individual optimization of ciprofloxacin dosage regimens. AUC/MIC à 24h Forrest, AAC 1993

32 Ratio AUC/CMI des valeurs >250 sont associées à une élimination rapide des BGN des patients porteurs de pnp nosoc Craig et al CID 2001

33 Craig et al CID 2001

34 Fish et al, JAC 2002 Ciprofloxacine Levofloxacine Gatifloxacine
Ctr Cefep Cefta Cefep-Cipro Cefta-Cipro Cefta-Levo Gatifloxacine Moxifloxacine J Antimicrob Chemother Dec;50(6): Related Articles, Links   Synergic activity of cephalosporins plus fluoroquinolones against Pseudomonas aeruginosa with resistance to one or both drugs. Fish DN, Choi MK, Jung R. University of Colorado Health Sciences Center, Antimicrobial Research Laboratory, Department of Pharmacy Practice, 4200 E. 9th Ave, Box C238, Denver, CO 80262, USA. Owing to increasing resistance in Pseudomonas aeruginosa, empirical drug regimens may include agents to which some strains may be resistant. The purpose of this study was to evaluate the in vitro activities of different combinations of cephalosporin plus fluoroquinolone against P. aeruginosa isolates with varying susceptibility to the study drugs. Broth microdilution susceptibility testing was performed with 10 clinical isolates of P. aeruginosa. The bactericidal activity of cefepime or ceftazidime alone and in combination with ciprofloxacin, levofloxacin, gatifloxacin or moxifloxacin was evaluated using time-kill methods. Colony counts were determined at 0, 4, 8 and 24 h, using antimicrobial concentrations of 0.5 x MIC. All procedures were performed in duplicate. Synergy was defined as a >2-log decrease in cfu/mL at 24 h compared with the single most active agent. The MICs for tested strains were: ceftazidime , cefepime , ciprofloxacin , levofloxacin , gatifloxacin and moxifloxacin mg/L. Four strains were susceptible to all drugs, two strains were cephalosporin susceptible and fluoroquinolone resistant, and two strains were cephalosporin resistant and fluoroquinolone susceptible. Two strains were resistant or intermediately susceptible to all drugs. Various cephalosporin and fluoroquinolone combinations were synergic against P. aeruginosa, including strains resistant to one or both agents in combination. No synergy was observed in two strains susceptible to all drugs. There were no differences noted between different cephalosporin and fluoroquinolone combinations. Concentrations used in this study are clinically achievable with recommended regimens in most cases. Cefta-Gati Cefta-Moxi Fish et al, JAC 2002

35 Temps-dépendants concentrations CMI temps 24 h
temps de contact à C > CMI T= t1 + t2 + t3 (%24h) > CMI CMI temps 24 h t1>CMI t2>CMI t3>CMI

36 Bêtalactamines Paramètre d’efficacité antibactérienne
Pneumonie K. pneumoniae Souris neutropénique Cefotaxime 10 9 8 Log 10 cfu per lung at 24 hours 7 6 5 20 40 60 80 100 (%) Time above MIC (Craig, CID 1998)

37 Serum of tissue drug concentration
MPC Serum of tissue drug concentration Mutant Selection Window MIC Time post-administration Concentration de prévention de mutation : concentration la plus basse de drogue qui dans l’agar permet de prévenir la croissance de tout type de mutant à partir de larges inocula Variable pour les pathogènes et les dorgues PneumoC : 4-7 x la CMI Idealized sketch of serum or tissue drug concentration after administration of a single dose of antibiotic to a patient. MIC and mutant prevention concentration (MPC), determined in laboratory studies, are indicated. The area between MPC and MIC (shaded) represents the mutant selection window

38 Emergence de mutants In vitro : analyse de l’émergence de mutants après exposition à des doses sub-inhibitrices de céfépime, cefpirome, ceftazidime, céfotaxime, pipéracilline, imipénème Fréquence la plus basse : céfépime, imipénème Les souches CSP-R restaient sensibles à imipénème et ciprofloxacine OBJECTIVE: To investigate whether stepwise selection of resistance mutations may mirror the continued bacterial exposure to antibiotics that occurs in the clinical setting. METHODS: We examined the in vitro development of resistance to a number of commonly used antibiotics (cefepime, cefpirome, ceftazidime, cefotaxime, piperacillin and imipenem) in Pseudomonas aeruginosa, a significant nosocomial pathogen. Stepwise resistance was assessed by serial passage of colonies located nearest to the inhibition zone on antibiotic-containing gradient plates. RESULTS: The lowest frequencies of spontaneous resistance mutations were found with cefepime and imipenem; these drugs also resulted in the slowest appearance of resistance of spontaneous resistance mutations. In five wild-type P. aeruginosa strains, cefepime-selected isolates required a mean of 30 passages to reach resistance; resistance occurred more rapidly in strains selected with other cephalosporins. P. aeruginosa strains that produced beta-lactamase or non-enzymatic resistance generally developed resistance more rapidly than wild-type strains. For most strains, resistance to all antibiotics except imipenem correlated with increased levels of beta-lactamase activity. Cross-resistance of cephalosporin-selected resistant mutants to other cephalosporins was common. Cephalosporin-resistant strains retained susceptibility to imipenem and ciprofloxacin. CONCLUSIONS: From our in vitro study, we can conclude that the rate of development of resistance of P. aeruginosa is lower with cefepime compared with other cephalosporines. (Carsenti-Etesse et al, Clin Microbiol Infect 2001)

39 Pneumonie à Klebsiella chez le rat Ceftazidime continue vs par 8h
Evaluation : dose totale journalière protégeant 50% des animaux (PD50) Résultats : Administration continue : 0,36 mg/kg/j Administration discontinue : 1,42 mg/kg/j Administration continue : 1,08 mg/kg/j Administration discontinue : 13,06 mg/kg/j 5h An experimental Klebsiella pneumoniae pneumonia in rats was used to study the influence of continuous or of intermittent (8-hr intervals) administration of ceftazidime on therapeutic efficacy. Antimicrobial response was evaluated with respect to the calculated total daily dose that protected 50% of the animals from death (PD50) until 16 days after termination of a four-day treatment. When antibiotic treatment was started 5 hr after bacterial inoculation, the PD50 values after continuous and after intermittent administration of ceftazidime were 0.36 and 1.42 mg/kg per day, respectively (P less than .001). With a delay in the administration of the antibiotic to 34 hr after inoculation, the respective PD50 values were 1.08 and mg of ceftazidime/kg per day (P less than .001). These studies show an improved therapeutic efficacy that increased with a delay in treatment when ceftazidime was administered by continuous infusion as compared with administration at 8-hr intervals. Continuous administration of PD50 doses of ceftazidime resulted in serum levels that were constantly below the MIC of the infecting Klebsiella strain. PMID: [PubMed - indexed for MEDLINE] 34h (Roosendal et al, 1985)

40 18 patients de réanimation
Dose de charge 12mg/kg, suivie de 6 g/24 h de ceftazidime soit en continu (n=8) soit en 3 bolus de 2g/8h (n = 10) Durant les 8 premières heures, concentrations sériques < 40 mg/L (5 fois la conc. crit. inf): groupe perfusion continue: 1 patient / 8 (38 mg/L) groupe bolus: 8 patients / 10 ( mg/L) Durant les 40 heures suivantes, temps avec des concentrations sériques > 40 mg/L: groupe perfusion continue: 100% groupe bolus: % We randomized 18 critically ill patients to receive ceftazidime 6 g/day by continuous infusion or bolus dosing (2 g 8 hourly), each with a loading dose of 12 mg/kg ceftazidime. During the first 8 h, plasma ceftazidime concentration fell below 40 mg/L in only one patient (trough 38 mg/L) from the infusion group, compared with eight from the bolus group (2-33 mg/L) for periods ranging from 73 to 369 min. Thereafter all infusion patients remained above 40 mg/L for 40 h of study versus 20-30% of bolus patients. The pharmacokinetic and pharmacodynamic characteristics of ceftazidime suggest that continuous infusions should be clinically investigated in outcome studies. PMID: [PubMed - indexed for MEDLINE] Lipman, JAC 1999; 43:

41 Etude prospective randomisée, USI Pneumonie nosocomiale
Ceftazidime 2gx3/j vs 3g/j en continu +tobra Résultats : Continue Discontinue Efficacité clinique 94% % Efficacité microbio 76% % (Nicolau et al, 2001)

42

43 AAC 2006

44 Mortalité à J 28 en fonction de la durée de traitement
.2 .4 .6 .8 1 5 10 15 20 25 30 jours 8 jours 15 jours p=0.65 18,8% 17,2% Chastre et al, JAMA 2003

45 Taux de récidive de l'infection pulmonaire
% 50 40 40.6% 30 20 25.4% 10 “8 jours” (n=64) “15 jours” (n=63) Chastre et al, JAMA 2003

46 Conclusion Résistance naturelle aux antibiotiques
Sélection de mutants résistants Nécessité d’avoir un traitement parfaitement adapté PK/PD Associations Durée