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Nice buiatric 2006-1,Antibiotic dosage regimen based on PK-PD concepts and the possible minimization of resistance,PL Toutain UMR 181 Physiopathologie et Toxicologie Exprimentales INRA/ENVT,ECOLE NATIONALE VETERINAIRE T O U L O U S E,24th World Buiatric Congress. France. 15. October 2006,Nice buiatric 2006-2,Why to optimize dosage regimen for antibiotics,To optimize efficacy Reduce the emergence and selection of resistance,Nice buiatric 2006-3,Dosage regimen and antibioresistance,The design of appropriate dosage regimens may be the single most important contribution of clinical pharmacology to the resistance problem Schentag, Annal. Pharm. 1996 Little attention has been focused on delineating the correct drug dose to suppress the amplification of less susceptible mutant bacterial sub-populations Drusano et al (2005),Nice buiatric 2006-4,Selecting a dosage regimen for a particular animal or group of animals,Individual animal (or herd) issues Probability of “cure” without side effects,Public health issues Probability for avoiding enriching a resistant bacterial subpopulation,The prescribing veterinarian is the steward of a valuable resource and must consider both individual health issues as well as public health ones Possible conflict of interest between the two goals,Nice buiatric 2006-5,Why to optimize dosage regimen for antibiotics,To optimize efficacy Reduce the emergence and selection of resistance Target pathogen: efficacy issue Non target pathogen: human safety issue Zoonotic bacteria (food borne pathogens) Commensal flora (resistance gene reservoir),Nice buiatric 2006-6,Biophases & antibiorsistance,G.I.T,Proximal,Distal,1-F%,Rsistance = lack of efficacy,Rsistance = public health concern,Target biophase Bug of vet interest,Blood,Food chain,Environmental exposure,Man,Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus),F%,Nice buiatric 2006-7,Biophases & antibiorsistance,G.I.T,Proximal,Distal,Intestinal secretion Bile,Rsistance = lack of efficacy,Rsistance = public health concern,Biophase Bug of vet interest,Blood,Food chain,Environmental exposure,Man,Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus),Systemic administration,Quinolones Macrolides Ttracyclines,Nice buiatric 2006-8,Public Health Concerns : Human pathogenic bacteria spreading from animal reservoirs,Current main concerns: Resistance emerging to commonly used empiric therapies for acute GI tract infections Salmonella Fluoroquinolone-resistance 3rd gen. Cephalosporin-resistance Campylobacter Fluoroquinolone-resistance Macrolide-resistance,Nice buiatric 2006-9,Emergence of quinolone resistance in Salmonella typhimurium DT104 in UK following licensing of fluoroquinolones for use in food animals,Sthr & Wegener, Drug resistance Updates, 2000, 3:207-209,Nice buiatric 2006-10,Dosage regimen and resistance: Epidemiological evidences,Nice buiatric 2006-11,Dosage regimen and prevention of resistance,Many factors (e.g.; broad vs. narrow spectrum) can contribute to the development of bacteria resistance the most important risk factor is repeated exposure to inappropriate antibiotic concentrations (exposure) dosage regimen should minimize the likelihood of exposing pathogens to sublethal drug levels,Nice buiatric 2006-12,Drug factors influencing resistance,Regimen Route of administration, dose, interval of administration, duration of treatment,Nice buiatric 2006-13,Effect on Penicillin resistance in pneumococcus isolates (n=465) of duration of b-lactam use, 6 months before swab collection,Nb of days of b-lactam use 1-7 8-14 14,Odd ratios 0.86 1.5 2.5,95% CI 0.37- 2.02 0.73- 3.06 1.3 - 4.82,Nasrin et al. BMJ, 2002,Nice buiatric 2006-14,Dosage regimen and antibiotic resistance,Treatments were initiated 7 days post challenge (E. coli) and continued for 14 days,Treatment Control Label use Gradient Pulse Rotation with dissimilar antimicrobials Rotation with similar antimicrobials,Dosing scheme No antibiotics Apramycin, 150g/ton of feed for 14 days Apramycin, 50g/ton of feed for 5 days, then 100g/ton for 5 days then 150g/ton for 4 days Apramycin, 150g/ton of feed for 3 days, then 3 days without antibiotics, sequence repeated throughout the 14-day period Apramycin, 150g/ton of feed for 5 days, then sulfamethazine formulated for 118g/kg BW in drinking water for 5 days then carbadox, 50g/ton of feed for 4 days Apramycin, 150g/ton of feed for 5 days, then gentamicin 6.6 mg/L of drinking water for 5 days then neomycin formulated for 22mg/kg BW in drinking water for 4 days,Mathew, 2003,Nice buiatric 2006-15,Effect of 14-day antibiotic dosing regimen on sensitivity (MIC, g/mL) to apramycin by E. coli recovered,AB dosing day post challenge regimen 3 6 10 13 17 31 Control (no AB) 4.3 3.9 3.5 3.1 2.3 2.6 Label 5.9 41.1 56 49 50 6.6 Rotation Similar AB 3.5 4.2 200 182 141 7.6 Rotation Dissimilar AB 2.6 38.8 44 14 14.0 3.8 Gradient 50, 100, 150 3.5 3.5 3.5 68.5 109.9 2.8 Pulse (3 days) 5.2 4.3 3.6 4.0 7.0 3.7,Mathew, 2003,Nice buiatric 2006-16,How to determine a dosage regimen that is both efficacious and that minimizes the risk to promote resistance,Nice buiatric 2006-17,How to find and confirm a dose (dosage regimen),Dose titration Animal infectious model Clinical trial PK/PD,Nice buiatric 2006-18,The dose-titration,Nice buiatric 2006-19,The dose-titration: experimental infectious model,Severe not representative of the real world Prophylaxis vs. metaphylaxis vs. curative power of the design generally low for large species influence of the endpoints,Nice buiatric 2006-20,How to find and confirm a dose (dosage regimen),Dose titration Animal infectious model Clinical trial PK/PD,Nice buiatric 2006-21,Bacteriological vs clinical success: the pollyanna phenomenon,Nice buiatric 2006-22,The Pollyanna phenomenon,If efficacy is measured by symptomatic response, drugs with excellent antibacterial activity will appear less efficacious than they really are and drugs with poor antibacterial activity will appear more efficacious than they really are. The clinical efficacy does not always indicate bacteriological efficacy making it difficult to distinguish between antimicrobials on clinical outcomes only,Nice buiatric 2006-23,The Pollyanna effect,Discrepency between clinical and bacteriological results,Efficacy (%),Merchant et al. Pediatrics 1992,Antibiotic effect,Placebo effect,Bacteriological cure,Clinical success,Otitis media,Nice buiatric 2006-24,The Pollyanna effect,0,30,60,90,0,0.5,2,16,64,Dose (mg/kg),Response %,Mortality,Bacterial,shedding,Ceftiofur oral,Yancey et al. 1990 Am. J. Vet.Res.,Nice buiatric 2006-25,EFFICACY OF ORAL PRADOFLOXACIN AND AMOXYCILLIN/CLAVULANATE IN CANINE CYSTITIS AND PROSTATITIS,Data from Bayer Animal Health (VERAFLOX SYMPOSIUM),Nice buiatric 2006-26,The Pollyanna phenomenon,The clinical efficacy does not always indicate bacteriological efficacy and a good clinical efficacy is not enough to validate an appropriate dosage regimen,Nice buiatric 2006-27,The role of antibiotics is to eradicate the causative organisms from the site of infection,Jacobs. Istambul, 2001,Nice buiatric 2006-28,How to find and confirm a dose (dosage regimen),Dose titration Animal infectious model Clinical trial PK/PD,Nice buiatric 2006-29,The main goal of a PK/PD trial in veterinary pharmacology,To be an alternative to dose-titration studies to discover an optimal dosage regimen,Nice buiatric 2006-30,What is PK/PD?,Nice buiatric 2006-31,Dose titration,Dose,Response clinical,Black box,PK/PD,Dose,Response,PK,PD,Plasma concentration,Body,pathogen,Nice buiatric 2006-32,Medium concentration,Test tube,Response MIC,In vitro,MIC is very variable from pathogen to pathogen and should be acknowledged The idea at the back of the PK/PD indices were to develop surrogates able to predict clinical success by scaling a PK variable by the MIC,PK/PD: in vitro,Nice buiatric 2006-33,Dose titration,Dose,Response clinical,Black box,PK/PD,Dose,Response,PK,PD,A plasma concentration variable scaled by MIC,Body,pathogen,Nice buiatric 2006-34,Dose titration vs. PK/PD : the explicative variable,Effect,Effect,Dose,DOSE (external dose),EXPOSURE (internal dose),effect,A PK/PD SURROGATE,AUC,AUC/MIC,Exposure scaled by MIC,Nice buiatric 2006-35,PK/PD indices as indicator of antibiotic efficacy,Nice buiatric 2006-36,The surrogates (predictors) of antibiotic efficacy,AUC/MIC, TMIC, Cmax/MIC,Nice buiatric 2006-37,PK/PD predictors of efficacy,MIC,Cmax,Concentrations,24h,Time,Cmax/MIC,Cmax/MIC : aminoglycosides,AUIC =,AUC MIC,AUC/MIC : quinolones, tetracyclines, azithromycins,TMIC : penicillins, cephalosporins, macrolides,TCMI,Nice buiatric 2006-38,Why these indices are termed PK/PD,AUIC # =,AUC CMI,Dose / Clearance CMI50(90),PK,PD, Dual dosage regimen adaptation,Nice buiatric 2006-39,Relationship between dose and PK/PD predictors of efficacy,Breakpoint value e.g. 125,PD,PK,Free fraction,Bioavailability,Nice buiatric 2006-40,Why plasma concentration The site of infection,Update : 22 mai 2019,Nice buiatric 2006-41,Only the free (non-bound) fraction (concentration) of the drug can interact with bacterial receptors Only the concentration of free drug that is of concern for its PK/PD relationship,Nice buiatric 2006-42,MIC is a reasonable approximate of the concentration of free drug needed at the site of infection,Nice buiatric 2006-43,Most infections of interest are located extra-cellularly and direct comparisons to total tissue concentration with PD parameters are meaningless,Cars, 1991,Nice buiatric 2006-44,Where are located the pathogens,ECF Most bacteria of clinical interest - respiratory infection - wound infection - digestive tract inf.,Cell (in phagocytic cell most often) Legionnella spp mycoplasma (some) chlamydiae Brucella Cryptosporidiosis Listeria monocytogene Salmonella Mycobacteria Meningococci Rhodococcus equi,Nice buiatric 2006-45,When there is no barrier to penetration, the level of free drug in serum is an adequate surrogate marker for biophase concentration,Cars, 1991,Nice buiatric 2006-46,Plasma,Interstitial fluid,Cell,Surrogate marker (TMIC, AUIC, Cmax/MIC),Biophase for most bacteria of veterinary therapeutical interest,Biophase for facultative and obligatory intracellular pathogens,Total concentration,Mannhemia, Pasteurella Haemophilus, Streptococcus, Staphylococcus, Coli, Klebsiella,Bound F,Bound F,Cytosol (Listeria, Shigella),Phagosome (Chlamydiae),Phagolysosome (S. aureus, Brucella, Salmonella),Obligatory or facultative bacteria,B,Brain, retina, prostate,Efflux pump,B,Cell membrane,Tissular barrier,B,B,Barrier, efflux pump,F,Bound,F,Porous capillaries,lipophilicity,Bound,B,B,F,Nice buiatric 2006-47,Tissue concentrations,According to EMEA “unreliable information is generated from assays of drug concentrations in whole tissues (e.g. homogenates)“,EMEA 2000,Nice buiatric 2006-48,Magnitude of PK/PD parameter required for efficacy,Istambul, 2001,Nice buiatric 2006-49,Relationship Between TMIC and Efficacy for Carbapenems (Red), Penicillins (Aqua) and Cephalosporins (Yellow),Nice buiatric 2006-50,Relationship between PK/PD parameters and efficacy for cefotaxime against Klebsiella pneumoniae in a pneumonia model,3,10,30,100,300,1000,3000,24 h AUC/MIC ratio,5,6,7,8,9,10,0,20,40,60,80,100,Time above MIC (%),5,6,7,8,9,10,R = 94%,Peak MIC ratio,01,1,10,100,1000,10000,Log10 CFU per lung at 24 h,Craig CID, 1998,5,6,7,8,9,10,Nice buiatric 2006-51,Efficacy index: clinical validation,Free serum concentration need to exceed the MIC of the pathogen for 40-50% of the dosing interval to obtain bacteriological cure in 80% of patients,Bacteriological cure versus time above MIC in otitis media (from Craig and Andes 1996),S. pneumoniae Penicillin cephalosporins,H. influenzae Penicillin cephalosporins,Time above MIC (%),Bacteriologic cure (%),100,50,0,0,50,100,Nice buiatric 2006-52,PK/PD parameters: -lactams,Time above MIC is the important parameter determining efficacy of the -lactams TMIC required for static dose vary from 25-40% of dosing interval for penicillins and cephalosporins. Free drug levels of penicillins and cephalosporins need to exceed the MIC for 40-50% of the dosing interval to produce maximum survival,Graig,Nice buiatric 2006-53,Betalactam,Goal: to maximize the duration of exposure over which free drug levels in biophase exceed the MIC no further significant reduction in bacteria count when concentration exceed 4 MIC,Nice buiatric 2006-54,Comparison of relationships between 24-hr AUC/MIC and efficacy against Pneumococci for fluoroquinolones in animals and patients,Patients with CAP and AECB 58 patients enrolled in a comparative trial of levofloxacin vs. gatifloxacin Free-drug 24-hr AUC/MIC 33.7, the probability of a microbiologic cure was 100%,Andes & Craig Int. J. Antimicrob. Agents, 2002, 19: 259,Nice buiatric 2006-55,AUIC = 125 h as a consensus descriptor of antibiotic action,Roughly speaking AUIC = 125 h is equivalent to say that the mean concentration should be 5 times the MIC over 80% of the dosage interval (24h),Schentag et al. 1990,Nice buiatric 2006-56,Efficacy index: clinical validation,2,4,6,8,10,12,60,80,100,Relationship between the maximal peak plasma level to MIC ratio and the rate of clinical response in 236 patients with Gram-negative bacterial infections treated with aminoglycosides (gentamicin, tobramycin, amikacin),Moor et al. 1984 J. Infect. Dis.,Maximum peak/MIC ratio,Response rate (%),Nice buiatric 2006-57,Modern interests in pharmacodynamics,Establish the PK/PD target required for effective antimicrobial therapy Identify which PK/PD parameter (TMIC, AUC/MIC, peak/MIC) best predicts in vivo antimicrobial activity Determine the magnitude of the PK/PD parameter required for in vivo efficacy (static effect, 1 or 2 log kill) Define resistance for those situations where one cannot attain the target required for efficacy,Nice buiatric 2006-58,Magnitude of PK/PD parameter required for efficacy: the case of quinolones for calf,Nice buiatric 2006-59,Bacterial growth in serum containing danofloxacin for incubation periods of 0.25 to 6h,Log cfu/ml,0,0.02,0.04,0.06,0.08,0.12,0.16,0.20,0.24,0.28,0.32,1.E+00,1.E+03,1.E+06,1.E+09,0,1,2,3,4,5,6,Incubation time (h),P. Lees,Conc.,Nice buiatric 2006-60,Sigmoidal Emax relationship for bacterial count vs ex vivo AUIC24h in goat 1 serum,P. Lees,-7,-6,-5,-4,-3,-2,-1,0,1,0,50,100,150,200,250,300,AUIC24h,Observed,Predicted,Bacteriostatic AUIC24h = 18 h,Bactericidal AUIC24h = 39 h,Elimination AUIC24h = 90 h,Log cfu/ml difference,Nice buiatric 2006-61,Ex vivo AUC24h/MIC (h) values for danofloxacin and marbofloxacin in calf serum,Parameter Danofloxacin Marbofloxacin Bacteriostatic 15.9 2.0 37.3 6.9 Bactericidal 18.1 1.9 46.5 6.8 Elimination 33.5 3.5 119.6 10.9 Slope 17.3 4.2 11.5 3.3 Values are mean sem (n=6),P. Lees,Nice buiatric 2006-62,PK/PD indices Determination of breakpoint values,To optimize efficacy To minimize resistance,Update: 17/05/2004,Nice buiatric 2006-63,Effectiveness of PK/PD indices as predictor for the development of antimicrobial resistance,Nice buiatric 2006-64,There is evidence that the likelihood for the selection of bacteria with mutation conferring resistance can be predicted on basis of PK/PD relationship,Nice buiatric 2006-65,Impact of dosage regimen on the emergence of resistance: Experimental evidences,Nice buiatric 2006-66,AUIC and bacterial eradication,Nosocomial pneumonia treated with IV ciprofloxacin AUIC was highly predictive of time to bacterial eradication If AUIC 250 h/day : eradication of organism on day 1 of therapy good target for nosocomial pneumonia and compromised host defense,100,50,0,4,8,12,Days after start of therapy,% patients remaining culture positive,Schentag Symposium, 1999,AUIC 125,AUIC 125-250,AUIC 250,Nice buiatric 2006-67,Suboptimal antibiotic dosage as a risk factor for selection of penicillin-resistant Streptococcus pneumoniae : in vitro kinetic model,Odenholt et al. (2003) Antimicrobial Agents and Chemotherapy, 47: 518-523,Nice buiatric 2006-68,Material and Methods,Mixed culture of Stretococcus pneumoniae containing ca. 90% susceptible, 9% intermediate and 1% resistant bacteria In vitro kinetic model Exposure to Penicillin : TMIC varied from S = 46 to 100 % I = 6 to 100 % R = 0 to 48 %,Odenholt, 2003,Nice buiatric 2006-69,Selection by penicillin of resistant bacteria in a mixed population of S.pneumoniae: control,A,Odenholt, 2003,Nice buiatric 2006-70,Selection by penicillin of resistant bacteria in a mixed population of S.pneumoniae,B,Odenholt, 2003,Nice buiatric 2006-71,Selection by penicillin of resistant bacteria in a mixed population of S.pneumoniae,C,Odenholt, 2003,Nice buiatric 2006-72,Selection by penicillin of resistant bacteria in a mixed population of S.pneumoniae,D,Odenholt, 2003,Nice buiatric 2006-73,Selection by penicillin of resistant bacteria in a mixed population of S.pneumoniae,E,Odenholt, 2003,Nice buiatric 2006-74,Selection by penicillin of resistant bacteria in a mixed population of S.pneumoniae,F,Odenholt, 2003,Nice buiatric 2006-75,Optimisation of Meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas a