Postgraduate Course 9 How to optimise antibiotic use in respiratory infections

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1 ERS Annual Congress Barcelona 7-11 September 2013 Postgraduate Course 9 How to optimise antibiotic use in respiratory infections Thank you for viewing this document. We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author by the author Saturday, 7 September :30-13:00 Room: 5.2 (CC5)

2 The EUROPEAN RESPIRATORY monograph A publication of the European Respiratory Society Editor in Chief: Tobias Welte The Spectrum of Bronchial Infection Edited by Francesco Blasi and Marc Miravitlles Monograph 60, Published June 2013 ISBN Each book-length issue of the European Respiratory Monograph covers a specific area of respiratory medicine, providing in-depth reviews that give clinicians at all levels a concise, comprehensive guide to symptoms, diagnosis and treatment. If you re an ERS member, you automatically have full online access to the Monographs. To join the ERS, visit Find out more at erm.ersjournals.com

3 Postgraduate Course 9 How to optimise antibiotic use in respiratory infections Aims: To train participants in the correct use of antibiotic therapy in patients with lower respiratory tract infections. HERMES LINKS ADULT: A.1 Structure and function of the respiratory system, B.3 Non-TB respiratory infections. Target audience: Pulmonologists, intensivists, emergency-medicine doctors, respiratory physicians, clinical researchers, thoracic surgeons, general practitioners. Chairs: H. Lode (Berlin, Germany), S. Aliberti (Milan, Italy) COURSE PROGRAMME PAGE 09:30 Pharmacokinetic and pharmacodynamic issues in respiratory infections 5 A. Dalhoff (Kiel, Germany) 10:15 Antibiotic use in special populations: renal failure and the obese patient 21 F. Scaglione (Milan, Italy) 11:00 Break 11:30 Antibiotics in the critically ill and septic patient 37 F. Pea (Udine, Italy) 12:15 Inhaled antibiotic therapy 61 M. Loebinger (London, United Kingdom) Faculty disclosures 87 Faculty contact information 89 Answers to evaluation questions 91

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5 Pharmacokinetic and pharmacodynamic issues in respiratory infections. Axel Dalhoff University Medical Center Schleswig-Holstein Institute for Infection Medicine Brunswiker Str. 4 D Kiel Germany adalhoff@t-online.de Aims The aim of this presentation is to provide basic knowledge about the basic principles of pharmacokinetics and pharmacodynamics of antibacterial agents and to use these principles to safeguard and to optimize therapy of respiratory tract infections. Summary Respiratory tract infections continue to be a major source of morbidity and mortality. Attainment of pharmacokinetic/pharmacodynamic (PK/PD) targets is one of the relevant factors determining therapeutic outcome of an infection. Furthermore, PK/PD calculations can be used to safeguard therapy. Typically, PK/PD assessments are based on the susceptibility, i.e. the minimal inhibitory concentration (MIC) of the agent for the pathogen, and preclinical infection models. In vitro-, ex vivoand in vivo infection models as well as in vitro pharmacokinetic models and in silico modelling have been developed to explore antibacterial pharmacodynamics. Any of the models used are indented simplifications of the clinical situation. This information is supplemented with pharmacokinetic data like the maximal serum concentration (Cmax) or area under the serum concentration versus time curve (AUC) of the free fraction of the drug in serum. Thus, PD-characteristics can be correlated with PKparameters. These models provide important information on the likelihood of clinical efficacy and risk for resistance-development. The relationships between pharmacodynamic (MIC) and PK-parameters are classified as being either time- or concentration dependent. PK/PD surrogates being predictive for the likelihood of clinical efficacy are either the period of time for which a drug exceeds the serum concentrations (T > MIC), or the ratios Cmax/MIC and AUC/MIC. Based on information derived from susceptibility distributions of the causative pathogens, and PK/PD targets derived from nonclinical models of infection and clinical data, PK/PD surrogates have been defined predicting the statistical likelihood of clinical outcome and/or emergence of resistance (see next two slides). These PK/PD surrogate indices should be attained with a probability of at least 90%, although an attainment rate of 95% would be ideal. Table 1: PK/PD surrogates and their magnitudes being predictive for efficacy (DI = dosing interval) penicillins Drug class cephalosporins carbapenems Macrolides + clindamycin PK/PD parameter T > MIC (% of DI) T > MIC (% of DI) T > MIC (% of DI) T > MIC (% of DI) Magnitude for efficacy 40%-50% for streptococci + Gram neg. 25%-30% for staphylococci 25%-30% 40%-50%

6 azithromycin 24h AUC/MIC 25-25h Aminoglycosides fluoroquinolones 24h AUC/MIC Peak/MIC 24h AUC/MIC Peak/MIC 100h h for Gram-neg. + staph/hap (CAVE!); 25-35h for pneumococci/cap; 8-10 for Gram-negatives and staphylococci (CAVE!) PK/PD assessments can be performed by using either deterministic- or probabilistic methods. Frequently, PK/PD calculations are based on the mean MICs, and mean PK-parameters. The PK/PD surrogates thus calculated generate single-point estimates; such deterministic calculations provide information on what is possible. However, the susceptibility pattern of a given pathogen as well as the PK-parameters of a given agent provide a Gaussian distribution, so that the possible combinations of kinetic and dynamic values are extremely complex. The use of probabilistic methods factors in the entire range of possible surrogate values and the probability of achieving them. Therefore, probabilistic methods should be used for PK/PD calculations to safeguard therapy of RTIs and to predict the likelihood of clinical efficacy of an antibacterial agent. As both, the susceptibility pattern of each and every species of pathogens causing a RTI, as well as PK in different patient populations differ, population-based approaches differentiating between the various bacterial species as well as defined groups of infected patients (e.g. CAP, HAP, VAP, etc.) should be used for PK/PD considerations. For example, the resistance rates (and thus the MICs inhibiting 90% of the isolates) P. aeruginosa strains isolated from cystic fibrosis patients are as high as 54%, strains isolated from VAP-patients having been treated previously with a quinolone were found to be 57% resistant, whereas those isolated from non-treated VAP-patients were 26% resistant, and the isolates from HAP-patients were 18% resistant. Consequently, it is important to base PK/PD calculations on strain populations only having been isolated from patients suffering from a specific infectious disease. Generalizing calculations based on a given species irrespective from the origin of the material (i.e. infectious site) from which the strain has been isolated, are misleading. By applying the differentiating approach it becomes evident that first, MICs of the pathogens change over time; emerging resistance passes unnoticed in routine susceptibility testing but puts the patient at risk. PK/PD calculations detect susceptibility shifts early on, thus safeguarding antibacterial therapy. Based on PK/PD calculations, either the dose should be adjusted, or the authorities should change the usage categorization precluding the empirical use of agents. Once granted marketing authorizations should be revisited every two to five years based on the actual MIC-distribution and probabilistic PK/PD calculations. Second, PK of an agent differ not only between healthy volunteers and patients, but also between different patient-populations. Third, PK (in particular their penetration into different infectious sites) of various agents even of one drug-class differ. Thus, PK/PD surrogates, too, differ indication-, species-, and drug- specifically. Consequently, PK/PD surrogates used to safeguard therapy should not be defined class-specifically but should be defined for a specific agent causing a specific disease. In conclusion, consideration of disease- and species-specific factors in PK/PD calculations will optimize the likelihood of therapeutic success. References 1. Ambrose P, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A, Drusano GL: Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it s not just for mice anymore. Clin Infect Dis 2007;44:79-86 Excellent review of pharmacodynamics of antibacterial agents 2. Craig WA: Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1-12

7 3. Dalhoff A, Ullmann U: Correlation between pharmacokinetics, pharmacodynamics and efficacy of antibacterial agents in animal models. Eur J Clin Microbiol Infect Dis 1990;9: Martinez MN, Papich MG, Drusano GL: Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother 2012; 56: Excellent review of the impact of appropriate dosing to reduce the risk of selecting resistance Evaluation 1. Is it adequate to define a generalizable threshold of antimicrobial therapy, i.e. one PK/PD parameter for any agent of one drug class and any disease to be treated? a. Yes b. No 2. Are pharmacokinetics in healthy volunteers and patients, respectively, comparable? a. Yes b. No 3. Should once granted indications be revisited and revised, if indicated based on shifts in the susceptibility pattern of pathogens? a. Yes b. No 4. Are tissue penetration «activities (e.g. lung penetration) of any agent of one drug class comparable or different? a. Yes b. No Please find all correct answers at the back of your handout materials

8 Postgraduate Course PG9 How to optimise antibiotic use in respiratory infections. Pharmacokinetic and pharmacodynamic issues in respiratory infections. Axel Dalhoff, PhD., Prof. University Medical Center Schleswig Holstein Institute for Infection Medicine Brunswiker Str. 4 D Kiel adalhoff@t online.de PK/PD issues in RTI 1. Disclosures Employee of the pharmaceutical industry (Beecham, Bayer) till December Teaching and research at the Christian Albrechts University, Kiel, since Basics 3. Definitions 4. Theory 5. Reality PK/PD issues in RTI 2. Basics In vitro, ex vivo and in vivo infection models as well as in vitro pharmacokinetic models and in silico modelling have been developed to explore antibacterial pharmacodynamics. Any of the models used are indented simplifications of the clinical situation. Selection and justification of doses to be evaluated in phase II/III clinical trials is based first, on PK/PD surrogates derived from MICs for the relevant pathogens, and from both, in vitro and in vivo data, and second, on PK/PD parameters derived from pharmacokinetics in healthy volunteers (phase I) These models provide important information on clinical efficacy and risk for resistance development 8

9 PK/PD issues in RTI 2. Basics PK/PD issues in RTI 2. Basics Thus, the definition of PK/PD surrogates predicting clinical outcome is based on the microbiological parameter MIC, and the pharmacokinetic parameters like C max, AUC, and t 1/2 The question is, which species specific MIC value provides appropriate information general drug/bug, hospital unit, or disease specific MICs, and which population has been studied pharmacokinetically healthy volunteers in phase I or the target patient population? PK/PD issues in RTI 2. Basics 9

10 PK/PD issues in RTI 2. Basics Pattern of Activity Antibacterials Goal of Therapy PK/PD Parameter surrogates Type I Conc. depdt. killing and Aminoglycosides 24h AUC/MIC prolonged persistent effects Daptomycin Maximize conc. Peak/ MIC Fluoroquinolones Ketolides Type II Time dependent killing and Carbapenems Minimal persistent effects Cephalosporins Maximize duration T>MIC Penicillins of exposure Erythromycin Linezolid Type III Time dependent killing and Moderate to prolonged persistent effects. Azithromycin Clindamycin Oxazolidinones Maximize amount of drug 24h AUC/MIC Tetracyclines Vancomycin PK/PD issues in RTI 1. Disclosures 2. Basics 3. Definitions MIC, median/mean MIC, MIC 90 RTIs: CAP, HAP, HCAP, VAP, (CF, COPD) Epidemiological cut off value Clinical breakpoint Deterministic PK/PD methods Probalilistic PK/PD methods 3. Theory 4. Reality PK/PD issues in RTI 3. Definitions MIC, median/mean MIC, MIC 90 : minimal inhibitory concentration in mg/l Issues 1.The MIC is a discrete, static endpoint, so that its correlation to kinetics is a contradiction in itself 2.Its variability has a direct and inverse effect on AUC/MICand Cmax/MIC ratios, but a non proportional effect on T>MIC. 3.A variability of +/ one titration step, i.e. +100% and 50% are accepted to be within the normal range. 10

11 PK/PD issues in RTI 3. Definitions RTIs: CAP (community acquired pneumonia), HAP (hospital acquired pneumomia), HCAP (healthcare associated pneumonia), VAP (ventilator associated pneumonia), CF (cystic fibrosis), COPD (chronic obstructive pulmonary disease) Issues 1.Different bacterial species cause community or healthcare associated RTIs Thus, can a uniform, or has a species /disease specific PK/PD surrogate to be used? 2. Even if the bacterial species causing e.g. CAP as well as HAP are identical, their susceptibility patterns and thus MIC 90 are different; ciprofloxacin resistance (%): CF VAP +/ prev FQs HAP P. aeruginosa 53.8% 57.1% / 26% 18.4% 3. Susceptibility patterns vary geographically Epidemiological cut off value PK/PD issues in RTI 3. Definitions The epidemiological cut off value is the concentration separating the susceptible wild type from the resistant population and should be used as the most sensitive measure of resistance development. Clinical breakpoint The clinical breakpoint should be used in everyday clinical laboratory work to advise on therapy in the patient. A microorganism is defined either as susceptible by a level of antimicrobial activity associated with a high likelihood of therapeutic success or as resistant if the activity is associated with a high likelihood of therapeutic failure (EUCAST). The cut off value is a quantitative, the breakpoint a qualitative parameter Breakpoints can either be derived by deterministic or probabilistic methods (Dalhoff A. et al.: Infection 2009; 37: ) PK/PD issues in RTI 3. Definitions Deterministic PK/PD models use the means of PK parameters and the mean MIC or MIC 90 value: Moxifloxacin / AUIC as a function of MIC for a OD dose regimen susceptible (MIC < mg/l) borderline susceptible (M IC < 0.5 mg/l) 1000 AUIC 100 Gram negative Threshold Gram Positive Threshold mg 100 mg 200 mg 400 mg MIC [mg/l] 100 mg 50 mg 11

12 n mg p.o AUC - Range [mg*h/l] \PHSTS\PKPD MFX Modelmaker3 sts ppt n = Dalhoff, 2000 < PK/PD issues in RTI 3. Definitions Probabilistic PK/PD models factor in the variability of PK in the patient population to be treated and the variability of MICs within a population of pathogens to be targeted: PK PD 1.63% 0.99% 3.79% MIC (mg/l) AUIC<30 70>AUIC>30 125>AUIC>70 AUIC>125 PK/PD 93.60% Calculation of target hit rates for a 400mg once daily dosing of p.o. moxifloxacin for different AUC/MIC ratios against S. pneumoniae. (Stass H, Dalhoff A.: Infection 2005; 33 (Suppl 2): 29 35) PK/PD issue in RTI 3. Definitions Deterministic PK/PD models provide information on what is possible Probabilistic PK/PD models provide information on what is probable Thus, deterministic models are helpful during early phases of drug development, but probabilistic models should be used for breakpoint definitions and to support and safeguard clinical use. PK/PD issues in RTI 4. Theory Based on information derived from susceptibility distributions of the causative pathogens, and PK/PD targets derived from non clinical models of infection and clinical data, PK/PD surrogates have been defined predicting the statistical likelyhood of clinical outcome and/or emergence of resistance (see next two slides). These PK/PD surrogate indices should be attained with a probability of at least 90%, although an attainment rate of 95% would be ideal (DI = dosing interval) Drug class PK/PD parameter Magnitude for efficacy penicillins T > MIC (% of DI) 40% 50% for streptococci + Gram neg. cephalosporins T > MIC (% of DI) 25% 30% for staphylococci carbapenems T > MIC (% of DI) 25% 30% Macrolides + clindamycin T > MIC (% of DI) 40% 50% azithromycin 24h AUC/MIC 25 25h aminoglycosides fluoroquinolones 24h AUC/MIC Peak/MIC 24h AUC/MIC Peak/MIC 100h h for Gram neg. + staph/hap (CAVE!); 25 35h for pneumococci/cap 8 10 for Gram negatives and staphylococci (CAVE!) 12

13 PK/PD issues in RTI 4. Theory (Ambrose P, et al.: Clin Infect Dis 2007; 44:79 86) PK/PD issues in RTI 4. Theory ( Martinez MN et al., AAC 2012; 56: ) PK/PD issues in RTI Conclusions from 3. definitions and 4. theory The variability of mean MIC or MIC 90 values and mean PK parameters is high, so that there is a considerable room for manoevering by selecting the appropriate figures or the extreme values. This has a significant impact on the deterministic calculation of PK/PD surrogates for e.g. moxifloxacin; range of published data at the time of launch: S. pneumoniae MIC 50 = , MIC 90 = mg/l, C max = mg/l, AUC = mg. h/l following single p.o. dosing with 400mg low AUC/ high MIC lowauc/ low MIC high AUC/high MIC high AUC/ low MIC MIC MIC low C max / high MIC low C max / low MIC high C max / high MIC high C max / low MIC MIC MIC Thus, each and every value is mathematically correct but which one is representative and clinically relevant? Not anyone! State of the art calculations should be performed by using probabilistic methods, whenever feasable. 13

14 PK/PD issues in RTI 5. Reality Issues to be discussed: Use of PK/PD surrogates to safeguard therapy of RTIs with old agents, once for all Can one PK/PD surrgogate be used for each and every indication treated with a given agent; are PK/PD surrogates drug or disease specific? One size fits all Are serum PK and tissue penetration activities in healthy volunteers and RTI patients comparable and are the differences between the populations within acceptable limits? the tissue is the issue PK/PD issues in RTI 5. Reality once for all Probabilistic PK/PD analysis of in vitro S. pneumoniae susceptibilities (MICs in mg/l) and target attainment rates (attain rate, 40% T > MIC) of cephalosorins licenced for treatment of pneumococcal infections. (* cefpodoxime excl. pen r; the PK information needed for these calculations was obtained from the US package inserts; sus bp = susceptible breakpoint; res bp = resistant breakpoint) (Dalhoff A et al., Infection 2009; 37: ) agent sus bp res bp MIC MIC MIC attain rate attain rate attain rate (< X mg/l) (> X mg/l) pen s pen i pen r pen s pen i pen r cefaclor cefuroxime cefpodoxime * cefixime None of these cephalosporins attains the target for penicillin intermediate susceptible or resistant pneumococci, cefaclor and cefixime even not for penicillin susceptible pneumococci. Likewise, amongst all the ß lactams licenced for treatment of pneumococcal infections only high dose amoxicillin achieves (attain. rate = 95%) and ceftriaxone almost achieves (attain. rate = 88%) the target Thus, once a licence has been granted, the decision isn t revised anymore. PK/PD issues in RTI 5. Reality once for all MICs for a given strain do not change over time, but the susceptibility pattern of a population of clinical isolates changes over time (% susceptible etc., black = 1998, red = 2010): agent species susceptible intermediate resistant Amoxi clav E. coli ciprofloxacin E. coli Amoxi clav K. pneumoniae ciprofloxacin K. pneumoniae ciprofloxacin P. aeruginosa Resistance rates exceed the threshold (10% resistance) precluding the empirical use of agents, so that the authorities should change the categorisation to species for which acquired resistance may be a problem. However, the authorities do not revise the once accepted categorisation of bacterial species as active/inactive in vitro. 14

15 PK/PD issues in RTI 5. Reality once for all But more importantly, resistance acquisition may pass unnoticed: approximately 30% of S. pneumiae and approximately 10% of H. influenzae isolated from RTI patients contain mutations in the gyra and/or parc loci. (Dalhoff A. Infection 2012; 40: ) Treatment of the primed strains with standard doses of levofloxacin resulted in rapid development of high level quinolone resistance and clinical failures. Therefore, suspicious isolates should be retested by using ciprofloxacin (S. pneumoniae) and nalidixic acid (H. influenzae) as indicators for the acquisition of a first mutation. (Dalhoff A. Infection 2012; 40: ) the EUCAST qualified the levofloxacin breakpoint definition by stating that these breakpoints relate to high dose therapy only. However, a high dose, i.e. 750 mg qd or 500 mg bid is rarely administered. PK/PD issues in RTI 5. Reality once for all Many antibacterials select for resistance: Oral cephalosporins like cefaclor and cefixime are much better selectors of penicillin resistant pneumococci than amoxicillin. Fluoroquinolones (ciprofloxacin >levofloxacin>>moxifloxacin) are MRSA selectors (Dalhoff et al.: IJAA2010; 36: ) Macrolides and ketolides contain a basic sugar with a tertiary, ionizable amine group (azithromycin 2 groups), so that these agents are inonized at physiological ph; this effect increases resistance development and decreases antibacterial efficacy. Oral streptococci acquired macrolide resistance just following one dose; resistance remained stable over years (Dalhoff et al.: Infection 2005; 33 (Suppl 2): 36 43; Malhotra Kumar S. et al.: Lancet 2007; 369: ) Many bacterial species (at least those causing chronic infections) are heterogenously susceptible to antibacterials, so that any drug class rapidly eliminates the susceptible sub population but selects the resistant sub population Selection of resistant sub populations exhibits negative epidemiological effects and selects multi resistant pathogens, thus causing a collateral damage. Colateral damage is of particular concern in e.g. cystic fibrosis patients. Thus, antibacterials with a minimal selective potential should be used clinically 12 In vitro PK-simulation of fluctuating serum concentrations of levofloxacin following a 500 mg qd dose. Strain: S. aureus P8+ (MRSA, ß-lactamase positive) log 10 CFU/ml (Dalhoff A, Schubert S.: IJAA 2010; 36: ) Total 2xMIC 32 oxa 4xMIC 64 oxa 8xMIC 128 oxa Time (h) 15

16 PK/PD issues in RTI 5. Reality Selection of ciprofloxacin resistant sub populations in P. aeruginosa isolated from CF patients. (left: total viable counts and MICs for the entire population; right: population analysis. Dalhoff A.: Antibiot Chemother 1991; 44: ) PK/PD issues in RTI 5. Reality One size fits all Time (days of therapy) to bacterial eradication versus AUIC (=AUC/MIC) in hospitalized patients with RTIs maily caused by H. influenzae and Enterobacteriaceae treated with ciprofloxacin. (Forrest A. et al. AAC 1993; 37: ) PK/PD issues in RTI 5. Reality One size fits all Conclusions drawn by the authors: 1. A population based PK/PD analysis defined the adequacy of therapy and the probability of treatment failure. An AUIC value of >125 h was found to be a generalizable threshold of of antimicrobial therapy. 2. The difficulty (with this approach) lies in achieving an AUIC of 250 or even 125 with bacteria such as staphylococcus and Pseudomonas species 3. A further important point is that these patients, on average, had approximately half the ciprofloxacin clearance of volunteers Thus, the authors exclude explicitly S. aureus and P. aeruginosa from the concept of a generalizable PK/PD surrogate AUIC parameter of >125 (Forrest A. et al. AAC 1993; 37: ) In a subsequent publication an AUIC value of >350 was found to be predictive for microbiological cure and killing of P. aeruginosa (Hyatt et al., AAC 1994; 38: ) 16

17 PK/PD issues in RTI 5. Reality One size fits all (Preston S. et al., JAMA 1996; 279: ) Pharmacodynamics of levofloxacin. A new paradigm for early clinical trials. The prospective use of PK/PD modelling identified an optimal dose ensuring clinical efficacy. The site of infection modulates modulates the target attainment rate. PK in infected patients and young, healthy volunteers are not alike: patients volunteers Peak (mg/l) AUC (mg.h/l) The prospective PK/PD analysis shortens the time frame + reduces the No. of patients to be enrolled. PK/PD issues in RTI 5. Reality One size fits all PoP PK analysis and modelling of the clinical efficacy of linezolid in four different indications revealed that the probabilities of eradication differ. Data compiled from different sources: Meagher AK et al.: AAC 2003; 47: Craig R et al.: Clin PK 2003; 42: Forrest A et al.: 40 th ICAAC, Toronto, September 2000 PK/PD issues in RTI 5. Reality the tissue is the issue Adequate target site concentrations contribute to the clinical efficacy. But, indeed, the tissue is the issue Penetration of antibacterials into respiratory secretions: Lipid soluble, concentrate independent of inflammation, good penetration Quinolones New macrolides: azithromycin, clarithromycin Tetracyclines Clindamycin Trimethoprim/sulfamethoxazole Relatively lipid insoluble, inflammation dependent for concentration in the lung, poor penetration Aminoglycosides Beta lactams: Penicillins Cephalosporins Monobactams Carbapenems (Niederman MS: ACCP Critical Care Board Review 2003, ) 17

18 PK/PD issues in RTI 5. Reality the tissue is the issue Adequate target site concentrations contribute to the clinical efficacy. To penetrate the alveolar space the agents must cross the alveolar membrane which is relatively impermeable, so that there is a significant barrire between the epithelial lining fluid (ELF) and the capillary blood supply. Alveolar macrophages take up the antibacterial agents from the ELF and serum before they migrate into the alveolar space. ( Wiebel ER.: In Fishman AP, Hecht WW (Eds) The University of Chicago Press Chicago 1969, pp 67 83; Staehlin LA.: Int Rev Cytol 1974; 39: ) The concentration of an antibiotic in the lung depends on the permeability of the capillary bed at the site of infection (the bronchial circulation), the degree of protein binding of the drug, the presence or absence of an active transport site for the antibiotic in the lung. In the lung, the relevant site to consider for antibiotic penetration is controversial and not clearly defined. Sputum and bronchial concentrations are considered most relevant for bronchial infections, while concentrations in lung parenchyma, epithelial lining fluid, and in cells such as macrophages and neutrophils are probably more important for pneumonic infections. The localization of the pathogen may also be important, and intracellular organisms such as Legionella pneumophila and Chlamydia pneumoniae are probably best eradicated by agents that achieve high concentrations in macrophages. Although local concentration of an antibiotic is important, it is also necessary to consider the activity of an agent at the site that it reaches. For example, antibiotics can be inactivated by certain local conditions. Aminoglycosides have reduced activity at acidic ph levels, and some pneumonic areas of lung are acidic. (Niederman MS: ACCP Critical Care Board Review 2003, ) Polycationic agents liroxithromycinke aminoglycosides bind to DNA, so that they are inactivated (peripheral inactivation). (Vaudaux P.: JAC 1981; 8 (Suppl A): 17 25; Waldvogel FA.: JAC 1984; 13 (Suppl A): Quinolones bind to DNA and cell debris Biofilms protect bacteria from cellular immune defense and impair penetration of antibacterials PK/PD issues in RTI 5. Reality the tissue is the issue But penetration activities, even within one drug class, e.g. macrolides, are not uniform: agent Dose (mg) Serum (mg/l) ELF (mg/l) % penetration erythromycin clarithromycin azithromycin ,072 dirithromycin roxithromycin telithromycin PK/PD issues in RTI conclusions 5. Reality once for all No, once granted marketing authorizations should be revisited every two to five years. one size fits all No, PK/PD surrogates differ indication and species specifically both, the susceptibility pattern of pathogens and PK of the agents as well as the pathophysiology differ as the tissue is the issue Yes, penetration into the infectious foci differ within and between drug classes. 18

19 PK/PD issues in RTI conclusions 5. Reality In general, PK/PD is a powerful tool in drug development and postmarketing authrozation studies. Many pre clinical as well as clinical studies in RTIs have been performed demonstrating that PK/PD surrogates have to be defined species and indication specifically. The generalizing assumption one size fits all is too generous. In conclusion, consideration of disease and species specific factors will optimize the likelyhood of therapeutic success. 19

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21 Antibiotic use in special populations: renal failure and the obese patient Francesco Scaglione University of Milan Via vanvitelli Milan Italy Aims By the end of this session you should be able to: Appreciate the importance of prescribing antibiotics in a timely manner Understand the right dosing for major classes of antibiotics renal failure and in obese patients Summary Inappropriate antimicrobial dosing in patients with kidney impairment can cause toxicity or ineffective therapy. In particular, older patients are at a higher risk of developing advanced disease and related adverse events caused by age-related decline in renal function and the use of multiple medications to treat comorbid conditions. Kidney disease can affect glomerular blood flow and filtration, tubular secretion and reabsorption, and renal bioactivation and metabolism. Drug absorption, bioavailability, protein binding, distribution volume, and nonrenal clearance (metabolism) also can be altered in these patients. Physicians should pay careful attention when considering drug therapies with active or toxic metabolites that can accumulate and contribute to exaggerated pharmacologic effects or adverse drug reactions in patients with chronic kidney disease. Dosages of drugs cleared renally are based on renal function (calculated as GFR or creatinine clearance; Table 3). These calculations are valid only when renal function is stable and the serum creatinine level is constant. The K/DOQI clinical practice guideline advocates using the traditional Cockcroft- Gault equation or the Modification of Diet in Renal Disease (MDRD) study equation (full or abbreviated) for routine estimation of GFR. (1) However, in patients with a GFR lower than 60 ml per minute per 1.73 m2, the MDRD equation has been shown to be superior to the Cockcroft-Gault equation. (2) Because the production and excretion of creatinine declines with age, normal serum creatinine values may not represent normal renal function in older patients. The MDRD equation has been shown to be the best method for detecting a GFR lower than 90 ml per minute per 1.73 m2 in older patients. (3) Many antimicrobial agents are eliminated renally and require dosing adjustments in patients with chronic kidney disease; however, several commonly used agents do not require adjustments. (4) Excessive serum levels of injectable penicillin G or Piperacillin may be associated with neuromuscular toxicity, myoclonus, seizures, or coma. (5) Imipenem/cilastatin can accumulate in patients with chronic kidney disease, causing seizures if doses are not reduced.(6) Patients with advanced disease should receive a different carbapenem, such as meropenem.(7) Tetracyclines, with the exception of doxycycline, have an antianabolic effect that may significantly worsen the uremic state in patients with severe disease. Aminoglycosides and vancomycin should be avoided in patients with kidney disease when possible. If used, initial doses should be based on an accurate GFR estimate. Renal function and drug concentrations should be monitored and dosages adjusted accordingly. Obese patients have an increased risk of infection and a higher mortality rate. (8) Unfortunately, trials focusing on optimal dosing in obese patients are scarce. Underdosing antibiotics may increase the risk of treatment failure, unnecessary escalation to broader-spectrum antibiotics, resistance, and possibly death. 21

22 The current literature for vancomycin, aminoglycosides, beta-lactams, fluoroquinolones, linezolid, and macrolides was reviewed to evaluate appropriate dosing in obese patients. Due to the limited number of studies and various pharmacokinetic parameters of antibiotics, dosing should be based on both patient- and drug-specific factors. Pharmacokinetic studies show that the volume of distribution (VD) of lipophilic drugs and the clearance of hydrophilic drugs can be increased in obese patients. Water-soluble drugs may distribute to extracellular fluid in adipose tissue, slightly increasing the VD; however, this difference may not be significant.(9) Hydrophilic medications that are renally eliminated have increased clearance in obese patients.(10) Based on these kinetic findings, it can be difficult to ensure adequate drug concentrations or time above minimum inhibitory concentrations (MIC) in obese patients. References 1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39 (2 suppl 1):S Poggio ED, Wang X, Greene T, Van Lente F, Hall PM. Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease. J Am Soc Nephrol 2005; 16: Burkhardt H, Hahn T, Gretz N, Gladisch R. Bedside estimation of the glomerular filtration rate in hospitalized elderly patients. Nephron Clin Pract 2005; 101:c Livornese LL Jr, Slavin D, Gilbert B, Robbins P, Santoro J. Use of antibacterial agents in renal failure. Infect Dis Clin North Am 2004; 18: Marks MI, Hirshfeld S. Neurotoxicity of penicillin. N Engl J Med 1968; 279: Gibson TP, Demetriades JL, Bland JA. Imipenem/cilastatin: pharmacokinetic profile in renal insufficiency. Am J Med 1985; 78: Chimata M, Nagase M, Suzuki Y, Shimomura M, Kakuta S. Pharmacokinetics of meropenem in patients with various degrees of renal function, including patients with end-stage renal disease. Antimicrob Agents Chemother 1993; 37: Falagas ME, Athanasoulia AP, Peppas G, Karageorgopoulos DE. Effect of body mass index on the outcome of infections: a systematic review. Obes Rev. 2009; 10: Hanley MJ, Abernethy DR, Greenblat DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010; 49: Bauer LA. Chapter 3. Drug dosing in special populations: renal and hepatic disease, dialysis, heart failure, obesity, and drug interactions. In: Bauer LA, ed. Applied Clinical Pharmacokinetics. 2nd ed. New York: McGraw-Hill Evaluation 1. In obese patients the volume distribution of lipohilic drugs may: a. Increase b. Reduced c. does not change d. increases only for drugs eliminated by renal route e. increases only for drugs eliminated by the liver 2. In obese patients the clearance of hydrophilic drugs may: a. Reduced b. does not change c. increase d. increases only for drugs eliminated by renal route e. increases only for drugs eliminated by the liver 3. Kidney disease can affect: a. Drug absorption b. Bioavailability 22

23 c. protein binding d. distribution volume e. all the above 4. Excessive serum levels of injectable penicillin G may be associated with: a. Anaphylactic shock b. Diarrhoea c. Neuromuscular toxicity d. Kidney failure e. hives 5. Which of the following combinations is at high risk of kidney damage? a. Piperacillin amikacin b. Ciprofloxacin-ceftazidime c. Gentamicin vancomicin d. Vancomicin- fluconazole e. Amikacin-ceftazidime Please find all correct answers at the back of your handout materials 23

24 Antibiotic use in special populations: renal failure and the obese patient Speaker: Francesco Scaglione MD,PhD Director of Postgraduate School of Clinical Pharmacology Department of Medical Biotechnology and Translational Medicine University of Milan, Via Vanvitelli 32, Milan, Italy Introduction AIMS Appreciate the importance of prescribing antibiotics in a timely manner Understand the right dosing for major classes of antibiotics renal failure and in obese patients There are Three in this Relationship Drug Host Toxicity Pharmacokinetics (PK) Infection Pharmacodynamics(P D) Host defence Resistance Bacteria 24

25 Antibiotics, Renal Function and Hepatic Function Renal Function Estimated Creatinine clearance (Cockcroft-Gault formula) 140-AgexMass (Kg) x Constant Serum Creatinine in µmol/l Constant 1.04 for Women, 1.23 for Men Stage GFR(ml/min/1.73m²) Description I 90+ Normal II Mild reduction IIIa Moderate reduction IIIb Moderate reduction IV Severe reduction V <15 Very severe (End-stage) 25

26 Effect of Creatinine Clearance on the Half Life of an Antibiotic with a Normal Half Life of 1 Hour Half Life in Hours Normal 50% Normal 25% Normal 5% Normal Creatinine Clearance Antibiotic Renal Handling Excretion Less than 15% in urine and Generally innocuous Examples Macrolides (erythromycin) Sodium fusidate Clindamycin Generally no dosage adjustment required Exception Chloramphenicol-not innocuous Major Renal Excretion i.e. 50% Generally innocuous Examples Penicillins Cephalosporins Carbapenems Tetracyclines Not Innocuous Examples Aminoglycosides Polymyxin B, Colistin Vancomycin Amphotericin Excretion Less than 15% in urine and Generally innocuous Dose adjustment required only at moderate to severe renal impairment Examples Antibiotic Creatinine Clearance Clindamycin Any None Dose adjustment Erythromycin Any None 26

27 Antibiotic Major Renal Excretion i.e. 50% Generally innocuous Creatinine Clearance (CrCl) Amoxicillin >30 Nil Co-amoxiclav >15 Nil Dose Adjustment Tazocin >40 Nil Ceftriaxone Any Nil Meropenem >50 Nil Doxycycline and Minocycline (All other tetracyclines to be avoided) Any Nil Major Renal Excretion i.e. 50% AND Poisonous Antibiotic Aminoglycosides (Gentamicin 5mg/Kg trough levels after 1 st dose) In all cases monitor levels Creatinine Clearance (CrCl) Reduced Severe <20 Dose Adjustment dose interval dose interval and dose Avoid Vancomycin (1g BD, trough levels before 4 th Dose) In all cases monitor levels Reduced Severe Monitor Trough levels Give only after trough levels known Amphotericin Reduced Avoid Gentamicin monitoring 1 Hartford Nomogram 7 mg/kg OD Precise Times of collection required Collection 6-12Hrs after dose 27

28 Gentamicin monitoring 2 Gentamicin 5-7mg/Kg OD Collect around 24Hrs post dose Aiming for <1mg/l Checking if patient is clearing gentamicin High levels Blood collected too early Patient not clearing Gentamicin Blood collected from lumen used to infuse Gentamicin earlier on Gentamicin monitoring 2 Corrective measures Re-check levels Stop, look for alternative antibiotic Omit dose and repeat levels after 12 Hrs Frequency 2-3x/week after steady state More frequently if renal function changing or concurrent nephrotoxic drugs Vancomycin Monitoring Glycopeptide ONLY active against Gram-positive bacteria including MRSA IV only except for Clostridium Difficile associated diarrhoea when oral route is used (NOT absorbed from GI and not enough levels get into GI by IV route) 1g BD IV standard dose Vancomycin trough level Collect serum specimen 30 minutes or less before next dose Frequency of collection: First level at steady state (3rd - 5th dose) Subsequent levels once or twice/week More frequently if renal function changing or concurrent nephrotoxic drugs 28

29 Therapy Trough Level (mg/l) Vancomycin <5 Vancomycin with Aminoglyco side Dosing Interval Adjustment On q24h, decrease interval by 12 hours On q12h, consult microbiology/pharmacist 5-15 No change Increase interval by 12 hours >20 Consult microbiologist/pharmacist/stop <5 On q24h, decrease interval by 12 hours On q12h, consult microbiology/pharmacist 5-10 No change Increase interval by 12 hours >20 Consult microbiologist/pharmacist/stop Hepatic failure Antibiotic Handling Comments Penicillins Kidneys Generally safe in liver failure, check individual drug for possible cholestatic jaundice Tetracyclines Concentrated in the Avoid or use with caution liver and excreted via bile and reabsorbed in the intestine. Eliminated in urine Aminoglycosides Kidneys Safe Macrolides Liver metabolism May worsen liver dysfunction, avoid Chloramphenicol 85-95% conjugated in the liver Glycopeptides Kidneys Safe Co-trimoxazole Significant metabolism Avoid by liver Avoid, increased probability of bone marrow toxicity 29

30 Key Message Aminoglycosides are toxic drugs and require monitoring Avoid use in renal failure but safe in liver failure Avoid concomitant use with other renal toxic drugs Check renal clearance, frequency according to renal function Vancomycin dosing should be BD dose and adjusted according to levels at steady state Frequency of monitoring depends on renal function Beta lactams are the safest antibiotics in renal and hepatic failure Adjustments to dose may still be required in severe failure And So! Patient Severe sepsis with septic shock Acute renal failure On Gentamicin, Clindamycin, co-amoxiclav Beta haemolytic Streptococcus group A klebsiella isolated from tracheoaspirate Sensitive to: meropenem, Clindamycin, levofloxacin Gentamicin, doxycycline, Vancomycin, Erythromycin, Gentamicin, oxacilline 30

31 What would you do? a. Stop Gentamicin b. Switch Co-amoxiclav to Oxacillin c. Continue with the same treatment d. Add meropenem to the current treatment What would you do? you are called by a nurse at 2300hrs to make a decision whether to give gentamicin or not since the level was not done that day. Previous Renal Function and Gentamicin Levels Date Urea (mmol/l) (Normal Ref ) Creatinine µmol/l ( Normal Ref 50-90) 09/05/ <1 07/05/ <1 04/05/ <1 30/04/ <1 Gent Levels How do you proceed? a) Send urgent Gentamicin levels before giving it b) Change to another antibiotic until you get levels back the following day c) Omit Gentamicin dose d) Give the Gentamicin and check levels the following day 31

32 Obesity Obesity is associated with an increased risk of infection. Unfortunately clinical trials examining the safety and efficacy of antibiotics in obese patients are deficient. Thus, clinicians predominately rely on pharmacokinetic and pharmacodynamic data for appropriate antibiotic dosing. VANCOMYCIN The Infectious Disease Society of America (IDSA) recommends a dosage of vancomycin of 15 to 20 mg/kg every 8 to 12 hours for most patients with normal renal function. Two studies found a shorter half-life and increased clearance in obese patients compared to non obese patients, with a direct correlation between total body weight (TBW) and both clearance and VD. Based on the high number of subtherapeutic troughs when using ideal body weight (IBW), TBW should be used to determine the appropriate dosage, with an interval based on the patient s renal function AMINOGLYCOSIDES Standardized approaches to weight-based aminoglycoside dosing have been derived from pharmacokinetic trials. Using TBW accepts that drug-specific pharmacokinetic parameters increase in proportion to body size; unfortunately, this tends to overshoot desired therapeutic concentrations and increases the risk for toxicities. Using IBW relies solely on a patient s gender and height and tends to underdose and increase risk for treatment failure. Utilizing protocols that emphasize dosing based on the patient s adjusted body weight (IBW [TBW IBW]), with a frequency based on the patient s renal function and adjusting regimens based on peaks and troughs for conventional dosing and midinterval for extended-interval dosing, may be useful in practice. 32

33 BETA-LACTAMS Beta-lactam antibiotics are hydrophilic and do not distribute well into adipose tissue. These antibiotics are time-dependent, and underdosing might yield concentrations below the MIC resulting in antibiotic failure. One study of preoperative cefazolin found a positive correlation with TBW and VD, but no correlation with clearance. A 2 g dose of cefazolin in morbidly obese patients achieved similar adipose and serum concentrations as did a 1 g dose in nonobese patients. In morbidly obese patients, the 2 g dose resulted in a significant decrease in postoperative infections compared to the 1 g dose (10.9%). A study examining cefepime in obese patients found that 2 g must be given every 8 hours to ensure that the percentage of time greater than the MIC (%t>mic) is at least 60%. Signs of toxicity were not observed. BETA-LACTAMS A 1 g dose of ertapenem yielded a higher area under the curve (AUC) in normal-weight patients compared to obese and morbidly obese patients. A nonsignificant decrease in clearance with an increased BMI was seen, suggesting a modest decrease in drug exposure in obese and morbidly obese patients. A post-hoc analysis found no difference in cure rates between obese and non-obese patients treated with ertapenem for a complicated intra-abdominal infection. However, another post-hoc analysis found an increased incidence of surgical-site infection in patients with a BMI 30 kg/m2 compared with those with BMI <30 kg/m2 (26.7% vs. 12.7%, respectively) after elective colorectal surgery. FLUOROQUINOLONES There are no specific recommendations for dosing fluoroquinolones in obese patients. A statistically significant decrease was noted in maximum plasma concentrations (Cmax) and AUC in obese patients compared to nonobese patients when administered 400 mg intravenous ciprofloxacin. Drug clearance and VD were significantly increased; however, no difference was noted in the half-life When dosing ciprofloxacin based on TBW, one study found higher Cmax and AUC in obese patients; however, interstitialspace fluid of skeletal muscle and subcutaneous adipose tissue Cmax and AUC were not significantly greater. 33

34 LINEZOLID Multiple small studies have examined linezolid use in obese patients. Although there appears to be a decrease in serum concentrations and increased clearance compared to nonobese patients, this does not appear to affect the efficacy of the drug. Based on the available data, it would be appropriate to continue using traditional 600 mg twice daily dosing in obese patients. 1. Weigh Patient: Weigh patient. If weighing is not possible, estimate weight using ideal body weight formulae (based on height and gender). For obese patients >120% ideal body weight use formula for dosing weight.-see below. Equations for Ideal Body weight and Obese dosing Imperial Ideal Body weight (Male) = 50 + (2.3 x inches over 5 feet) Ideal Body weight (Female) = (2.3 x inches over 5 feet) Or Metric Ideal Body weight (Male) = 50kg + 0.9kg for each cm above 150cm in height Ideal Body weight (Female) = 45.5Kg + 0.9kg for each cm above 150cm in height For Obese Patients (> 120% of ideal body weight) use obese dosing weight calculation5 : Obese Dosing Weight (in Kg) = ideal body weight (actual Body weight ideal body weight) 34

35 2. Calculate gentamicin Dose : Calculate the gentamicin dose using 5mg/Kg (maximum 400mg od) a)if normal body weight - use actual body weight value b)if Obese (> 120% of ideal body weight)- use obese dosing weight c) if weight unobtainable calculate ideal body weight 3. Calculate creatinine clearance (CrCl) : Calculate the creatinine clearance using Cockcroft and Gault equation Creatinine = (140-age in years) x weight in Kg(from step 1) x F clearance Serum Creatinine (in micromole/litre) F=1.04 (female) or F=1.23 (male) 4. Check dosing Interval and when levels need to be done : Work out the dosing interval and when levels should be checked Creatinine Clearance Dose Interval Pre-dose level check > 60ml/min 24 hourly Before 2 nd /3 rd dose 41-60ml/min 36 hourly Before 2 nd /3 rd dose 21-40ml/min 48 hourly Before 2 nd dose < 21ml/min > 48 hourly Check level after 48 hours 35

36 5. Check gentamicin serum level If pre-dose gentamicin level is 1mg/L or less continue the original dosing regime If pre-dose gentamicin level is greater than 1mg/L, consult Microbiology or Pharmacy for advice. Conclusion 36

37 Antibiotics in the critically ill and septic patient Federico Pea Institute of Clinical Pharmacology University Teaching Hospital Udine Udine Italy Aims To highlight how sepsis may alter the pharmacokinetic behaviour of antibiotics To understand how to appropriately manage antibiotic dosing in the critically ill and septic patient To understand how to optimise antibiotic use in the treatment of MDR Gram-negative infections Summary Patients with severe sepsis or with septic shock may have relevant patho-physiological changes which may significantly alter the pharmacokinetic behaviour of antibiotics [1-3]. This means that, if we don t take care of these changes, mortality rate in patients with severe sepsis could be at least partially due to underexposure to antibiotics [4-8]. When considering an antimicrobial therapy in septic patient, it s important not only choosing the right antibiotic in terms of spectrum of activity, but also considering the right dosage [2, 9]. In this regard, the antibiotics that are more significantly affected by the pathophysiology of sepsis are those with hydrophilic characteristics[10, 11], just because during sepsis there is an expansion of the extracellular fluids due to the capillary leakage and to a relevant change in renal function [12-14]. This means that for these antibiotics the dosages needed in septic patients are frequently higher than those needed in stable non-critically ill patients[1]. Conversely, there is non need to consider higher than standard dosages for those antibiotics with lipophilic characteristics, as for example linezolid [15], since sepsis does not affect neither their volume of distribution nor their non-renal elimination [11]. As far as hydrophilic antimicrobials is concerned, it has to be kept in mind that, as a general rule, the loading dose (that is the first dose when starting therapy) should be at least 50% higher in septic patients than the standard one administered to non-critically ill stable patients [1]. This has been clearly demonstrated for beta-lactams [16], glycopeptides [17, 18] and even for aminoglycosides [19-22]. All of these antimicrobials are renally cleared, and this means that, in order to calculate the right maintenance dose (that is the dose needed to continue therapy in the subsequent days), it is necessary to re-evaluate daily the creatinine clearance [23, 24], since renal function may significantly vary day by day in septic patients. Of note, it has been estimated that at least 15-20% of septic patients may have a hyperdynamic status with increased cardiac index, which may cause an augmented renal clearance [25-27]. This status is rather frequent in patients with traumatic brain injury, acute myeloid leukemia or extensive burns [28]. Additionally, it should be considered that hypoalbuminaemia, a rather frequent condition among septic patients, may further increase renal elimination of those antimicrobials that are highly bound to plasma proteins (i.e. ertapenem, teicoplanin) [29]. In these cases it s fundamental to consider higher dosages of hydrophilic antimicrobials and to adopt dosing strategies that could maximize efficacy [30-35]. In this regard, there is increasing evidence that administering time-dependent agents like beta-lactams by prolonged infusion or even better by continuous infusion may be worthwhile in this setting [36-41]. Although several user-friendly dosing nomograms have been developed recently with the intent of helping clinicians in choosing the right dosage of hydrophilic antimicrobials in septic patients [42-44], there is increasing evidence that therapeutic drug monitoring may represent a valuable tool in order to optimize drug exposure in these cases [45-49]. This is especially valuable when considering infection due to multi-drug resistant Gram-negative pathogens (i.e. Pseudomonas aeruginosa, Acinetobacter baumannii, carbapenemase-producing Enterobacteriaceae) [50], since it has been shown that 37

38 pharmacokinetic-pharmacodynamic optimization of beta-lactams with anti Gram-negative activity may overcome resistance associated with MDR Gram-negative bacteria [51, 52]. Of note, it should not be overlooked that when treating infections due to MDR Gram-negatives, combination therapy is considered mandatory to date [53, 54], and optimization of dosage and of the administration strategy are considered very important tools for minimizing the mortality rate in these occasions [52]. References 1. Pea F: Plasma pharmacokinetics of antimicrobial agents in critically ill patients. Current clinical pharmacology 2013, 8(1): Pea F, Viale P: Bench-to-bedside review: Appropriate antibiotic therapy in severe sepsis and septic shock--does the dose matter? Crit Care 2009, 13(3): Pea F, Viale P, Pavan F, Furlanut M: Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin Pharmacokinet 2007, 46(12): Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: Intensive Care Med 2008, 34(1): Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R et al: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: Crit Care Med 2013, 41(2): Pea F, Furlanut M, Viale P: Is antimicrobial underexposure due to glomerular hyperfiltration a possible cause of increased mortality rate from bacterial infections in critically ill patients? Anaesth Intensive Care 2009, 37(2): Udy AA, Roberts JA, De Waele JJ, Paterson DL, Lipman J: What's behind the failure of emerging antibiotics in the critically ill? Understanding the impact of altered pharmacokinetics and augmented renal clearance. Int J Antimicrob Agents 2012, 39(6): Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, Dodek P, Wood G, Simon D, Peters C et al: Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009, 136(5): Dryden M, Johnson AP, Ashiru-Oredope D, Sharland M: Using antibiotics responsibly: right drug, right time, right dose, right duration. J Antimicrob Chemother 2011, 66(11): Pea F, Viale P: The antimicrobial therapy puzzle: could pharmacokinetic-pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients? Clin Infect Dis 2006, 42(12): Pea F, Viale P, Furlanut M: Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005, 44(10): Lee WL, Slutsky AS: Sepsis and endothelial permeability. N Engl J Med 2010, 363(7): O'Brien JM, Jr., Ali NA, Aberegg SK, Abraham E: Sepsis. Am J Med 2007, 120(12): Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 2003, 348(2): Thallinger C, Buerger C, Plock N, Kljucar S, Wuenscher S, Sauermann R, Kloft C, Joukhadar C: Effect of severity of sepsis on tissue concentrations of linezolid. J Antimicrob Chemother 2008, 61(1): Taccone FS, Laterre PF, Dugernier T, Spapen H, Delattre I, Wittebole X, De Backer D, Layeux B, Wallemacq P, Vincent JL et al: Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care 2010, 14(4):R Roberts JA, Taccone FS, Udy AA, Vincent JL, Jacobs F, Lipman J: Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrob Agents Chemother 2011, 55(6): Mimoz O, Rolland D, Adoun M, Marchand S, Breilh D, Brumpt I, Debaene B, Couet W: Steady-state trough serum and epithelial lining fluid concentrations of teicoplanin 12 mg/kg 38

39 per day in patients with ventilator-associated pneumonia. Intensive Care Med 2006, 32(5): Galvez R, Luengo C, Cornejo R, Kosche J, Romero C, Tobar E, Illanes V, Llanos O, Castro J: Higher than recommended amikacin loading doses achieve pharmacokinetic targets without associated toxicity. Int J Antimicrob Agents 2011, 38(2): Taccone FS, Laterre PF, Spapen H, Dugernier T, Delattre I, Layeux B, De Backer D, Wittebole X, Wallemacq P, Vincent JL et al: Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock. Crit Care 2010, 14(2):R Delattre IK, Musuamba FT, Nyberg J, Taccone FS, Laterre PF, Verbeeck RK, Jacobs F, Wallemacq PE: Population pharmacokinetic modeling and optimal sampling strategy for Bayesian estimation of amikacin exposure in critically ill septic patients. Ther Drug Monit 2010, 32(6): Goncalves-Pereira J, Martins A, Povoa P: Pharmacokinetics of gentamicin in critically ill patients: pilot study evaluating the first dose. Clin Microbiol Infect 2010, 16(8): Grootaert V, Willems L, Debaveye Y, Meyfroidt G, Spriet I: Augmented Renal Clearance in the Critically Ill: How to Assess Kidney Function (July/August). Ann Pharmacother Herrera-Gutierrez ME, Seller-Perez G, Banderas-Bravo E, Munoz-Bono J, Lebron-Gallardo M, Fernandez-Ortega JF: Replacement of 24-h creatinine clearance by 2-h creatinine clearance in intensive care unit patients: a single-center study. Intensive Care Med 2007, 33(11): Udy AA, Roberts JA, Lipman J: Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol 2011, 7(9): Baptista JP, Udy AA, Sousa E, Pimentel J, Wang L, Roberts JA, Lipman J: A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Crit Care 2011, 15(3):R Udy AA, Putt MT, Shanmugathasan S, Roberts JA, Lipman J: Augmented renal clearance in the Intensive Care Unit: an illustrative case series. Int J Antimicrob Agents 2010, 35(6): Udy A, Boots R, Senthuran S, Stuart J, Deans R, Lassig-Smith M, Lipman J: Augmented creatinine clearance in traumatic brain injury. Anesth Analg 2010, 111(6): Roberts JA, Pea F, Lipman J: The clinical relevance of plasma protein binding changes. Clin Pharmacokinet 2013, 52(1): Pea F, Viale P, Damiani D, Pavan F, Cristini F, Fanin R, Furlanut M: Ceftazidime in acute myeloid leukemia patients with febrile neutropenia: helpfulness of continuous intravenous infusion in maximizing pharmacodynamic exposure. Antimicrob Agents Chemother 2005, 49(8): Conil JM, Georges B, Breden A, Segonds C, Lavit M, Seguin T, Coley N, Samii K, Chabanon G, Houin G et al: Increased amikacin dosage requirements in burn patients receiving a oncedaily regimen. Int J Antimicrob Agents 2006, 28(3): Lamoth F, Buclin T, Csajka C, Pascual A, Calandra T, Marchetti O: Reassessment of recommended imipenem doses in febrile neutropenic patients with hematological malignancies. Antimicrob Agents Chemother 2009, 53(2): Baptista JP, Sousa E, Martins PJ, Pimentel JM: Augmented renal clearance in septic patients and implications for vancomycin optimisation. Int J Antimicrob Agents 2012, 39(5): Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J: Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet 2010, 49(1): Udy AA, Varghese JM, Altukroni M, Briscoe S, McWhinney BC, Ungerer JP, Lipman J, Roberts JA: Subtherapeutic initial beta-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest 2012, 142(1): Roberts JA, Lipman J, Blot S, Rello J: Better outcomes through continuous infusion of timedependent antibiotics to critically ill patients? Curr Opin Crit Care 2008, 14(4): Mouton JW, Vinks AA: Continuous infusion of beta-lactams. Curr Opin Crit Care 2007, 13(5):

40 38. Lorente L, Jimenez A, Palmero S, Jimenez JJ, Iribarren JL, Santana M, Martin MM, Mora ML: Comparison of clinical cure rates in adults with ventilator-associated pneumonia treated with intravenous ceftazidime administered by continuous or intermittent infusion: a retrospective, nonrandomized, open-label, historical chart review. Clin Ther 2007, 29(11): Rafati MR, Rouini MR, Mojtahedzadeh M, Najafi A, Tavakoli H, Gholami K, Fazeli MR: Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients. Int J Antimicrob Agents 2006, 28(2): Lorente L, Lorenzo L, Martin MM, Jimenez A, Mora ML: Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Ann Pharmacother 2006, 40(2): Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, Shirwadkar C, Eastwood GM, Myburgh J, Paterson DL et al: Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis 2013, 56(2): Pea F, Furlanut M, Negri C, Pavan F, Crapis M, Cristini F, Viale P: Prospectively validated dosing nomograms for maximizing the pharmacodynamics of vancomycin administered by continuous infusion in critically ill patients. Antimicrob Agents Chemother 2009, 53(5): Pea F, Viale P, Cojutti P, Furlanut M: Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gram-negative infections: a pharmacokinetics/pharmacodynamics-based approach. Antimicrob Agents Chemother 2012, 56(12): Dailly E, Brun A, Kergueris MF, Victorri-Vignoli C, Milpied N, Jolliet P: A simple formula for individualising ceftazidime dosage administered by continuous infusion in patients with haematological malignancies. Int J Antimicrob Agents 2006, 27(6): Roberts JA, Norris R, Paterson DL, Martin JH: Therapeutic drug monitoring of antimicrobials. Br J Clin Pharmacol 2012, 73(1): Roberts JA, Ulldemolins M, Roberts MS, McWhinney B, Ungerer J, Paterson DL, Lipman J: Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents 2010, 36(4): Blondiaux N, Wallet F, Favory R, Onimus T, Nseir S, Courcol RJ, Durocher A, Roussel- Delvallez M: Daily serum piperacillin monitoring is advisable in critically ill patients. Int J Antimicrob Agents 2010, 35(5): Vazquez M, Fagiolino P, Boronat A, Buroni M, Maldonado C: Therapeutic drug monitoring of vancomycin in severe sepsis and septic shock. Int J Clin Pharmacol Ther 2008, 46(3): Pea F, Brollo L, Viale P, Pavan F, Furlanut M: Teicoplanin therapeutic drug monitoring in critically ill patients: a retrospective study emphasizing the importance of a loading dose. J Antimicrob Chemother 2003, 51(4): Taccone FS, Cotton F, Roisin S, Vincent JL, Jacobs F: Optimal meropenem concentrations to treat multidrug-resistant Pseudomonas aeruginosa septic shock. Antimicrob Agents Chemother 2012, 56(4): Moriyama B, Henning SA, Childs R, Holland SM, Anderson VL, Morris JC, Wilson WH, Drusano GL, Walsh TJ: High-dose continuous infusion beta-lactam antibiotics for the treatment of resistant Pseudomonas aeruginosa infections in immunocompromised patients. Ann Pharmacother 2010, 44(5): Cohen J: Confronting the threat of multidrug-resistant Gram-negative bacteria in critically ill patients. J Antimicrob Chemother 2013, 68(3): Daikos GL, Markogiannakis A: Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Clin Microbiol Infect 2011, 17(8): Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F et al: Predictors of mortality in bloodstream infections 40

41 caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012, 55(7): Evaluation 1. What do you mean with appropriate antibiotic therapy in patients with severe sepsis? a. correct choice in terms of spectrum of activity b. correct choice in terms of spectrum of activity plus optimal exposure at the infection site c. correct choice in terms of spectrum of activity plus optimal exposure at the infection site in a timely manner 2. Which antibiotics among the following are more significantly affected in their pharmacokinetics in septic patients? a. Gentamicin b. Linezolid c. Tigecycline d. Azithromicin 3. In patients with severe sepsis or septic shock and impaired renal function would you start antimicrobial therapy beta lactams with a: a. Standard loading dose b. Lower loading dose c. Higher loading dose d. I don I use a loading dose 4. How often should the dosing regimen of antimicrobials be reassessed in patients with severe sepsis or septic shock? a. Daily b. Every 2 days c. Every 3 days d. Once weekly Please find all correct answers at the back of your handout materials 41

42 HOW TO OPTIMISE ANTIBIOTIC USE IN RESPIRATORY INFECTIONS ANTIBIOTICS IN THE CRITICALLY ILL AND SEPTIC PATIENT FEDERICO PEA INSTITUTE OF CLINICAL PHARMACOLOGY UNIVERSITY TEACHING HOSPITAL OF UDINE ITALY Barcelona, September 7 th, 2013 INTRODUCTION AIMS To highglight how sepsis may alter the pharmacokinetic behavior of antibiotics To understand how to appropriately manage antibiotic dosing in the critically ill and septic patient To understand how to optimise antibiotic use in the treatment of MDR Gram-negative infections Faculty disclosure Speaker s bureau: Astra Zeneca, Gilead, MSD, Novartis, Pfizer, Teva Consultant: Astra Zeneca, Pfizer 42

43 Institute of Clinical Pharmacology - UniUD USE OF BROAD-SPECTRUM ANTIMICROBIALS FOR THE TREATMENT OF PNEUMONIA IN SERIOUSLY ILL PATIENTS: MAXIMIZING CLINICAL OUTCOMES AND MINIMIZING SELECTION OF RESISTANT ORGANISMS Niedermann MS, Clin Infect Dis 2006; 42:S INITIAL ADEQUATE THERAPY MORTALITY RATE (%) INITIAL INADEQUATE THERAPY 0 ALAVREZ LERMA 1996 RELLO 1997 LUNA KOLLEF KOLLEF IBRAHIM STUDY Istituto di Farmacologia Clinica UniUD APPROPRIATE ANTIBIOTIC THERAPY IN SEVERE SEPSIS AND SEPTIC SHOCK: DOES THE DOSE MATTER? Pea F and Viale P. Crit Care 2009; 13 (3) 214 CRITICAL ISSUES Appropriate antibiotic therapy in patients with severe sepsis and septic shock should mean prompt achievement and maintenance of optimal exposure at the infection site with broad-spectrum antimicrobial agents administered in a timely manner. Once that causative pathogens have been identified and tested for their in vitro susceptibility, subsequent de-escalation of antimicrobial therapy should be applied whenever feasible. The goal of appropriate antibiotic therapy must be pursued resolutely and with continuity in the light of the ongoing explosion of antibiotic-resistant infections which plague the ICU setting and of the continue decrease of antibiotic pipeline. Institute of Clinical Pharmacology & Toxicology University Hospital of Udine 43

44 Istituto di Farmacologia Clinica UniUD PATIENT S PATHOPHYSIOLOGY IDSA AND SEHA GUIDELINES FOR DEVELOPING AN INSTITUTIONAL PROGRAM TO ENHANCE ANTIMICROBIAL STEWARDSHIP Dellit TH et al. Clin Infect Dis 2007; 44: DOSE OPTIMIZATION Optimization of antimicrobial dosing based on individual patient characteristics, causative organism, site of infection, and pharmacokinetic and pharmacodynamic characteristics of the drug is an important part of antimicrobial stewardship (A-II). SOC Farmacologia Clinica AOUD MANAGING ANTIMICROBIAL RESISTANCE IN ICUs Ghandi TN et al. Crit Care Med 2010; 38 Suppl : S315 S323 STRATEGIES TO MANAGE ANTIMICROBIAL RESISTANCE IN THE ICU Istituto di Farmacologia Clinica - UniUD 44

45 DOES ONE SIZE FIT ALL in ICU PATIENTS? Institute of Clinical Pharmacology - UniUD IMIPENEM LEVELS ARE NOT PREDICTABLE IN THE CRITICALLY ILL PATIENT Belzberg H et al. J Trauma 2004; 56: Institute of Clinical Pharmacology - UniUD FACTORS POTENTIALLY ALTERING THE PHARMACOKINETICS OF ANTIMICROBIALS IN CRITICALLY ILL PATIENTS PATHOPHYSIOLOGICAL FACTORS Severe sepsis or septic shock Hypoalbuminaemia Abdominal, thoracic, and pericardial effusions Extensive burns Leukemia Trauma brain injury IATROGENIC FACTORS Fluid load Use of renal replacement therapies Use of haemodinamically active drugs (i.e. catecholamines) Pea F. Curr Clin Pharmacol 2013; 8:

46 Institute of Clinical Pharmacology - UniUD HYDROPHILIC ANTIBIOTICS LIPOPHILIC ANTIBIOTICS BETA-LACTAMS PENICILLINS CEPHALOSPORINS CARBAPENEMS MONOBACTAMS GLYCOPEPTIDES AMINOGLYCOSIDES MACROLIDES FLUOROQUINOLONES TETRACYCLINES CHLORAMPHENICOL RIFAMPICIN OXAZOLIDINONES LIMITED VOLUME OF DISTRIBUTION UNABLE TO PASSIVELY DIFFUSE THROUGH PLASMATIC MEMBRANE OF EUKARYOTIC CELLS INACTIVE AGAINST INTRACELLULAR PATHOGENS ELIMINATED RENALLY AS UNCHANGED DRUG LARGE VOLUME OF DISTRIBUTION FREELY DIFFUSE THROUGH PLASMATIC MEMBRANE OF EUKARYOTIC CELLS ACTIVE AGAINST INTRACELLULAR PATHOGENS ELIMINATED BY HEPATIC METABOLISM Pea F, Viale P, Furlanut M. Clin Pharmacokinet 2005; 44: Pea F & Viale P. Clin Infect Dis 2006; 42: PLASMA PK OF ANTIMICROBIAL AGENTS IN CRITICALLY ILL PATIENTS Pea F. Curr Clin Pharmacol 2013; 8: 5-12 SEPSIS AND PHYSICOCHEMICAL PROPERTIES OF ANTIBACTERIAL AGENTS SEPSIS SOC Farmacologia Clinica AOUD PLASMA PK OF ANTIMICROBIAL AGENTS IN CRITICALLY ILL PATIENTS Pea F. Curr Clin Pharmacol 2013; 8: 5-12 OVERVIEW OF THE PATHOPHYSIOLOGICAL MECHANISMS RELATED TO SEPSIS AND OF THEIR CONSEQUENCES ON ANTIMIBROBIAL DOSING SOC Farmacologia Clinica AOUD 46

47 PLASMA PK OF ANTIMICROBIAL AGENTS IN CRITICALLY ILL PATIENTS Pea F. Curr Clin Pharmacol 2013; 8: 5-12 PATHOPHYSIOLOGICAL MECHANISM RESPONSIBLE FOR THE NEED OF AN AUGMENTED LOADING DOSE (LD) OF HYDROPHILIC ANTIMICROBIALS STABLE PATIENT SEPTIC PATIENT LD = Vd x C TARGET LD = Vd x C TARGET VANCOMYCIN DOSING IN CRITICALLY ILL PATIENTS ROBUST METHODS FOR IMPROVED CONTINUOUS INFUSION REGIMENS Roberts J et al. Antimicrob Agents Chemother 2011 Jun; 55: DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF PATIENTS. SOC Farmacologia Clinica AOUD VANCOMYCIN DOSING IN CRITICALLY ILL PATIENTS ROBUST METHODS FOR IMPROVED CONTINUOUS INFUSION REGIMENS Roberts J et al. Antimicrob Agents Chemother 2011 Jun; 55: THE EFFECT OF LOADING DOSE ON RAPID ATTAINMENT OF TARGET VANCOMYCIN CONCENTRATIONS SOC Farmacologia Clinica AOUD 47

48 Istituto di Farmacologia Clinica - UniUD STEADY-STATE TROUGH SERUM AND ELF CONCENTRATIONS OF TEICOPLANIN 12 MG/KG/DAY IN PATIENTS WITH VAP Mimoz O et al. Intensive Care Med 2006; 32: TEICOPLANIN TROUGH CONCENTRATION (MG/L) PLASMA N=13 12 MG/KG BID DAY MG/KG OD FROM DAY 3 ON CL CR = 113 ml/min SAMPLING ON DAY 4-6 C MIN PLASMA = 10 MG/L EFFECT OF SEVERITY OF SEPSIS ON TISSUE CONCENTRATIONS OF LINEZOLID Thallinger C et al., J Antimicrob Chemother 2008; 61: PLASMA LINEZOLID 600 MG IV SINGLE DOSE 8 PTS WITH SEVERE SEPSIS 16 PTS WITH SEPTIC SHOCK Istituto di Farmacologia Clinica - UniUD LOADING DOSE IN SEPTIC PATIENTS HYDROPHYLIC ANTIBIOTICS LIPOPHILIC ANTIBIOTICS THE LD IN PTS WITH SEPSIS OR SEPTIC SHOCK MUST BE AT THE LD IN PTS WITH SEPSIS OR SEPTIC SHOCK MAY BE LEAST 50 % HIGHER THAN IN SIMILIAR TO THAT USED IN NON-CRITICALLY ILL PATIENTS NON-CRITICALLY ILL PATIENTS 48

49 SOC Farmacologia Clinica AOUD PLASMA PK OF ANTIMICROBIAL AGENTS IN CRITICALLY ILL PATIENTS Pea F. Curr Clin Pharmacol 2013; 8: 5-12 OVERVIEW OF THE PATHOPHYSIOLOGICAL MECHANISMS RELATED TO SEPSIS AND OF THEIR CONSEQUENCES ON ANTIMIBROBIAL DOSING IMPLICATIONS OF AUGMENTED RENAL CLEARANCE IN CRITICALLY ILL PATIENTS Udy AA et al. Nat Rev Nephrol Jul 19;7(9): MECHANISM UNDERLYING AUGMENTED RENAL CLEARANCE Institute of Clinical Pharmacology & Toxicology University Hospital of Udine IN WHICH TYPE OF CRITICALLY ILL PATIENTS IS AUGMENTED RENAL CLEARANCE HIGHLY FREQUENT? TRAUMATIC BRAIN INJURY ACUTE MYELOID LEUKEMIA EXTENSIVE BURNS Institute of Clinical Pharmacology & Toxicology University Hospital of Udine 49

50 Istituto di Farmacologia Clinica - UniUD THE CLINICAL RELEVANCE OF PLASMA PROTEIN BINDING CHANGES Roberts JA, Pea F, Lipman J. Clin Pharmacokinet 2013; 52: 1-8 CHANGES IN DRUG CLEARANCE FOR MODERATE-TO-HIGHLY BOUND ANTIBACTERIALS IN CRITICALLY ILL PATIENTS WITH HYPOALBUMINAEMIA COMPARED WITH HEALTHY VOLUNTEER DATA IS ANTIMICROBIAL UNDEREXPOSURE DUE TO GLOMERULAR HYPERFILTRATION A POSSIBLE CAUSE OF INCREASED MORTALITY RATE FROM BACTERIAL INFECTIONS IN THE CRITICALLY ILL PATIENTS? Pea F, Furlanut M, Viale P. Anaesth Intensive Care 2009; 37: It should not be overlooked that most of the antibacterial agents used to treat life-threatening bacterial infections in critically ill patients, namely betalactams, glycopeptides, aminoglycosides and levofloxacin, are hydrophilic or moderately liphophilic drugs which are almost completely cleared as unchanged moiety by the renal route. This means that marked underexposure at the infection site may be expected in GHF patients whenever standard dosages of these drugs are used, as recently shown for example with piperacillin, and this may obviously favour treatment failure. Institute of Clinical Pharmacology & Toxicology University Hospital of Udine MAINTENANCE DOSE IN SEPTIC PATIENTS HYDROPHYLIC ANTIBIOTICS THE MD IN PTS WITH SEPSIS OR SEPTIC SHOCK MUST BE LIPOPHILIC ANTIBIOTICS THE MD IN PTS WITH SEPSIS OR SEPTIC SHOCK MAY BE CALCULATED ON THE BASIS OF SIMILIAR TO THAT USED IN RENAL FUNCTION MEASURE OR ESTIMATE CL CR DAILY! NON-CRITICALLY ILL PATIENTS MOST OF THESE ANTIBIOTICS ARE CLEARED BY TH LIVER 50

51 Institute of Clinical Pharmacology & Toxicology University Hospital of Udine AUGMENTED RENAL CLEARANCE: IMPLICATIONS FOR ANTIBACTERIAL DOSING IN THE CRITICALLY ILL Udy AA et al. Clin Pharmacokinet 2010; 49: 1-16 CONCLUSIONS with increasing data supporting the concept, and many investigators demonstrating subtherapeutic concentrations of drugs in the critically ill, consideration of ARC and alternative dosing regimens is now mandatory, both to improve the likelihood of treatment success and to reduce the rate of development of antibacterial resistance. BETA-LACTAMS IN SEPTIC PATIENTS HYDROPHYLIC ANTIBIOTICS TIME-DEPENDENT BACTERICIDAL ACTIVITY PD DETERMINANT C MIN > MIC EXTENDED OR CONTINUOUS INFUSION IS THE BEST WAY TO MAXIMIZE THE BACTERICIDAL EFFECT OF BETA-LACTAMS UNDER THE SAME DAILY DOSE mg q12h 500 mg q6h 2000 mg CI 30 Plasma concentration (µg/ml) SAME DAILY DOSE MIC C min SOC Farmacologia Clinica AOUD 51

52 Institute of Clinical Pharmacology & Toxicology University Hospital of Udine APPROPRIATE ANTIBIOTIC THERAPY IN SEVERE SEPSIS AND SEPTIC SHOCK: DOES THE DOSE MATTER? Pea F and Viale P. Crit Care 2009; 13 (3) 214 CONCLUSIONS Appropriateness of treatment is rarely assessed in terms of adequate dosing schedule regimens. Inadequate dosing schedules may lead to suboptimal exposure at the infection site, increasing the risk for therapeutic failure or selection of resistant bacteria. However, administration of higher antibiotic doses than are required increases the risk for adverse events. Therefore, TDM of plasma concentrations should be encouraged whenever possible, because these concentrations are difficult to predict in critically ill patients, even when their renal function is estimated using different formulae. THERAPEUTIC DRUG MONITORING OF BETA-LACTAMS IN CRITICALLY ILL PATIENTS: PROOF OF CONCEPT Roberts J et al. Int J Antimicrob Agents 2010; 36: EFFECT OF ANTIBIOTIC PRESCRIBED ON THE NEED FOR BETA-LACTAM ANTIBIOTIC DOSE ADJUSTMENT AT THE FIRST TDM Istituto di Farmacologia Clinica - UniUD THERAPEUTIC DRUG MONITORING OF β-lactams FOR CRITICALLY ILL PATIENTS: UNWARRANTED OR ESSENTIAL? Roberts J et al. Int J Antimicrob Agents 2010; 35: CONCLUSIONS It follows that although TDM of β-lactam antibiotics may appear unwarranted, persisting mortality and increasing antibiotic resistance may mean that it becomes an increasingly essential tool for securing favourable therapeutic outcomes in critically ill patients. The exact place and clinical utility of TDM unfortunately still need to be prospectively defined. Istituto di Farmacologia Clinica - UniUD 52

53 SOC Farmacologia Clinica AOUD HOSPITAL-ACQUIRED INFECTIONS DUE TO GRAM-NEGATIVE BACTERIA Peleg AJ and Hooper DC New Engl J Med 2010; 362: MECHANISMS OF RESISTANCE IN GRAM-NEGATIVE BACTERIA AND THE ANTIBIOTICS AFFECTED. MDR P. aeruginosa 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 May; 44 (5): CASE REPORTS Istituto di Farmacologia Clinica - UniUD 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) SOC Farmacologia Clinica AOUD 53

54 SOC Farmacologia Clinica AOUD CONTINUOUS INFUSION OF BETA-LACTAM ANTIBIOTICS IN SEVERE SEPSIS: A MULTICENTER DOUBLE-BLIND, RANDOMIZED CONTROLLED TRIAL Dulhunty JM et al. Clin Infect Dis 2013; 56(2): STUDY DESIGN CONTINUOUS INFUSION OF BETA-LACTAM ANTIBIOTICS IN SEVERE SEPSIS: A MULTICENTER DOUBLE-BLIND, RANDOMIZED CONTROLLED TRIAL Dulhunty JM et al. Clin Infect Dis 2013; 56(2): BASELINE AND STUDY CHARACTERISTICS SOC Farmacologia Clinica AOUD CONTINUOUS INFUSION OF BETA-LACTAM ANTIBIOTICS IN SEVERE SEPSIS: A MULTICENTER DOUBLE-BLIND, RANDOMIZED CONTROLLED TRIAL Dulhunty JM et al. Clin Infect Dis 2013; 56(2): FREE PLASMA ANTIBIOTIC CONCENTRATION BETWEEN TREATMENT GROUPS ON THE FIRST SAMPLE SOC Farmacologia Clinica AOUD 54

55 SOC Farmacologia Clinica AOUD CONTINUOUS INFUSION OF BETA-LACTAM ANTIBIOTICS IN SEVERE SEPSIS: A MULTICENTER DOUBLE-BLIND, RANDOMIZED CONTROLLED TRIAL Dulhunty JM et al. Clin Infect Dis 2013; 56(2): STUDY ENDPOINTS BY TREATMENT GROUP HOSPITAL-ACQUIRED INFECTIONS DUE TO GRAM-NEGATIVE BACTERIA Peleg AJ and Hooper DC New Engl J Med 2010; 362: MECHANISMS OF RESISTANCE IN GRAM-NEGATIVE BACTERIA AND THE ANTIBIOTICS AFFECTED. MBL and KPC + Enterobacteriaceae Istituto di Farmacologia Clinica - UniUD EMERGENCE OF A NEW ANTIBIOTIC RESISTANCE MECHANISM IN INDIA, PAKISTAN, AND THE UK: A MOLECULAR, BIOLOGICAL, AND EPIDEMIOLOGICAL STUDY Kumarasamy KK et al. Lancet Infect Dis 2010; 10: MIC 90 FOR Enterobacteriaceae SOC Farmacologia Clinica AOUD 55

56 SOC Farmacologia Clinica AOUD EMERGENCE OF A NEW ANTIBIOTIC RESISTANCE MECHANISM IN INDIA, PAKISTAN, AND THE UK: A MOLECULAR, BIOLOGICAL, AND EPIDEMIOLOGICAL STUDY Walsh TR et al. Lancet Infect Dis 2011; 11: MIC OF ANTIMICROBIALS AND GENETIC CHARACTERISTICS OF NDM-1-POSITIVE BACTERIA CLINICAL PK AND PD OF TIGECYCLINE Barbour A et al. Clin Pharmacokinet 2009; 48: COMPARISON OF DIFFERENT ANTIMICROBIAL CLASSES REGARDING THEIR VOLUME OF DISTRIBUTION AT STEADY STATE (VSS) SOC Farmacologia Clinica AOUD USE OF A CLINICALLY DERIVED EXPOSURE RESPONSE RELATIONSHIP TO EVALUATE POTENTIAL TIGECYCLINE - Enterobacteriaceae SUSCEPTIBILITY BPs Ambrose P et al. Diagn Microbiol Infect Dis 2009; 63: MEDIAN MICROBIOLOGIC RESPONSE EXPECTATION AND PROBABILITY OF PK-PD TARGET (AUC/MIC OF 6.96) ATTAINMENT OVERLAID ON THE MIC DISTRIBUTION AGAINST E. coli SOC Farmacologia Clinica AOUD 56

57 SOC Farmacologia Clinica AOUD PHARMACOLOGICAL AND PATIENT-SPECIFIC RESPONSE DETERMINANTS IN PATIENTS WITH HAP TREATED WITH TIGECYCLINE Bhavnani SM et al. Antimicrob Agents Chemother 2012; 56: TIGECYCLINE MIC DISTRIBUTION STRATIFIED BY VAP AND NON-VAP STATUS EMERGENCE OF A NEW ANTIBIOTIC RESISTANCE MECHANISM IN INDIA, PAKISTAN, AND THE UK: A MOLECULAR, BIOLOGICAL, AND EPIDEMIOLOGICAL STUDY Walsh TR et al. Lancet Infect Dis 2011; 11: MIC OF ANTIMICROBIALS AND GENETIC CHARACTERISTICS OF NDM-1-POSITIVE BACTERIA SOC Farmacologia Clinica AOUD POP PK ANALYSIS OF COLISTIN METHANESULFONATE AND COLISTIN AFTER IV ADMINISTRATION IN CRITICALLY ILL PATIENTS WITH INFECTIONS CAUSED BY GRAM-NEGATIVE BACTERIA Plachouras D et al. Antimicrob Agents Chemother 2009; 53: PREDICTED COLISTIN PLASMA LEVELS SOC Farmacologia Clinica AOUD 57

58 SOC Farmacologia Clinica AOUD HIGH-DOSE, EXTENDED-INTERVAL COLISTIN ADMINISTRATION IN CRITICALLY ILL PATIENTS: IS THIS THE RIGHT DOSING STRATEGY? A PRELIMINARY STUDY Dalfino L et al. Clin Infect Dis 2012; 54 (12): STUDY DESIGN Prospective, observational, cohort study All critically ill patients who had sepsis due to COS or minimally susceptible gramnegative bacteria and were administered intravenous colistimethate sodium (CMS) as a rescue therapy were enrolled. CMS 9M UI LD 4.5M UI Q12H HIGH-DOSE, EXTENDED-INTERVAL COLISTIN ADMINISTRATION IN CRITICALLY ILL PATIENTS: IS THIS THE RIGHT DOSING STRATEGY? A PRELIMINARY STUDY Dalfino L et al. Clin Infect Dis 2012; 54 (12): PATIENTS CHARACTERISTICS AND CLINICAL FEATURES (N = 23) (N = 5) SOC Farmacologia Clinica AOUD STEADY-STATE PK AND BRONCHOALVEOLAR LAVAGE CONCENTRATION OF COLISTIN IN CRITICALLY ILL PATIENTS AFTER IV COLISTIN METHANESULPHONATE Imberti R. et al. Chest 2010; 138: PLASMA CONCENTRATION VS TIME PROFILE ELF CONCENTRATION VS TIME PROFILE 2 MILLION IU Q8H SOC Farmacologia Clinica AOUD 58

59 Istituto di Farmacologia Clinica - UniUD CARBAPENEMASE-PRODUCING Klebsiella pneumoniae: (WHEN) MIGHT WE STILL CONSIDER TREATING WITH CARBAPENEMS? Daikos GL and Markogiannakis A. Clin Microbiol Infect 2011; 17: CONCLUSIONS The data analyses presented herein support the notion that carbapenems may be a reasonable treatment option against CPKP, provided that: (i)the carbapenem MIC for the infecting organism is 4 mg/l; (ii)a high-dose prolonged-infusion regimen is administered to drive the PK/PD profile to acceptable exposures; (iii) this class of agent is administered in combination with another active compound. DOSING NOMOGRAMS FOR ATTAINING OPTIMUM CONCENTRATIONS OF MEROPENEM BY CONTINUOUS INFUSION IN CRITICALLY ILL PATIENTS FOR SEVERE GRAM-NEGATIVE INFECTIONS: A PK/PD BASED APPROACH Pea F et al. Antimicrob Agents Chemother 2012 Dec; 56: PATIENT CHARACTERISTICS Istituto Farmacologia Clinica AOUD DOSING NOMOGRAMS FOR ATTAINING OPTIMUM CONCENTRATIONS OF MEROPENEM BY CONTINUOUS INFUSION IN CRITICALLY ILL PATIENTS FOR SEVERE GRAM-NEGATIVE INFECTIONS: A PK/PD BASED APPROACH Pea F et al. Antimicrob Agents Chemother 2012 Dec; 56: RELATIONSHIP BETWEEN INDIVIDUAL CL M AND CL CR ESTIMATED BY MEANS OF THE COCKCROFT AND GAULT FORMULA IN GROUP 1 (N = 67 PATIENTS AND 213 SAMPLES): Istituto Farmacologia Clinica AOUD 59

60 Istituto Farmacologia Clinica AOUD DOSING NOMOGRAMS FOR ATTAINING OPTIMUM CONCENTRATIONS OF MEROPENEM BY CONTINUOUS INFUSION IN CRITICALLY ILL PATIENTS FOR SEVERE GRAM-NEGATIVE INFECTIONS: A PK/PD BASED APPROACH Pea F et al. Antimicrob Agents Chemother 2012 Dec; 56: NOMOGRAMS FOR THE CALCULATION OF THE MEROPENEM DAILY DOSAGE A DMINISTERED BY CONTINUOUS INFUSION WHICH IS NECESSARY FOR THE ACHIEVEMENT OF TARGET CSS IN CRITICALLY ILL PATIENTS CONFRONTING THE THREAT OF MULTIDRUG-RESISTANT GRAM-NEGATIVE BACTERIA IN CRITICALLY ILL PATIENTS Cohen J. J Antimicrob Chemother 2013, 68(3): POSSIBLE STRATEGIES TO DEAL WITH THE PROBLEM OF MDR GRAM-NEGATIVE INFECTIONS IN CRITICALLY ILL PATIENTS SOC Farmacologia Clinica AOUD 60

61 Inhaled antibiotic therapy Michael Loebinger Host Defence Unit Royal Brompton Hospital London SW3 6NP United Kingdom Aims a. To understand the rationale for the use of inhaled antibiotics b. To be aware of the different delivery mechanisms c. To be familiar with the potential roles of inhaled antibiotics and the evidence for their use Summary Inhaled therapies are becoming more commonplace in respiratory infections. Their main role to date has been in chronic respiratory airway infection and cystic fibrosis in particular. As drug formulations and delivery devices become more sophisticated, this role is likely to expand, as highlighted by multiple randomised controlled studies presently ongoing. Introduction There has been a significant increase in interest in the inhaled route for antibiotic use in recent years. This route theoretically allows the delivery of high concentrations of antibiotics to the airways and lungs while significantly reducing systemic availability and hence toxicities. The increased interest from both researchers and the pharmaceutical industry has led to the development of increasingly sophisticated drug delivery systems and drug formulations. Role of inhaled antibiotics Inhaled antibiotics may have a role in both the long-term and short term treatment of infections. Long Term use Long term antibiotics have a role in chronic respiratory infection. This is exemplified by bronchiectasis which is characterised by permanently dilated airways. It clinically manifests as a cough productive of sputum with recurrent respiratory infections. A vicious cycle hypothesis (Fig 1) has been postulated to describe the relationships between airway infection, inflammation and host defence in bronchiectasis [1]. This has stood the test of time and has been supported by studies demonstrating an increase in bronchial lavage inflammatory markers in patients colonised with bacteria in bronchiectasis [2, 3]. The aim of long term antibiotics is to reduce the number of airway microbes, with the intention of improving inflammation and affecting clinical endpoints such as lung function, exacerbation rates and quality of life indicators. This hypothesis was tested in an early MRC study in 1950, where long term treatment with oral oxytetracycline or penicillin demonstrated improvement in sputum volume and a reduction in the number of days off work in bronchiectasis patients [4]. Long term oral antibiotics have continued to be studied and used in bronchiectasis, however there are limited oral compounds that are active against many of the resistant Gram negative microbes that colonise patients with chronic respiratory disease. In addition treatment may be limited by systemic toxicities. Inhaled therapies are attractive in potentially enabling high drug concentrations while limiting systemic toxicities. 61

62 Inflammation Tissue damage Infection Host Defence Figure 1 Vicious circle hypothesis of bronchiectasis adapted from [1] The potential benefits of inhaled therapy were first demonstrated in bronchiectasis secondary to cystic fibrosis. Cystic fibrosis (CF) is an autosomal recessive condition due to mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which leads to abnormal chloride and sodium transport at the epithelial cell membrane. In the lung, this results in abnormal mucociliary clearance, bacterial colonisation, recurrent infection, bronchiectasis and respiratory failure. In 1981 Hodson et al compared inhaled gentamicin and carbenicillin against placebo in CF patients over a six month period. The inhaled antibiotic group demonstrated an improvement in respiratory function and a trend to reduced hospital admissions [5]. Further inhaled antibiotics were trialled in this condition. Inhaled colomycin demonstrated a reduction in the post intravenous antibiotic lung function decline [6] and a positive metaanlysis of several other small colomycin studies [7] led to the widespread use of this inhaled antibiotic therapy for CF patients with Pseudomonas aeruginosa (PSA). Despite a lack of good randomised controlled data, this is still first line treatment in many European centres. There was significant development in nebulised treatment with the formulation of tobramycin specifically designed for inhalation use (TOBI). Previous nebulised treatment had been based on the use of antibiotics manufactured for intravenous use. TOBI was used in a landmark randomised controlled trial (RCT) of 520 CF patients over six months with alternating monthly treatment cycles. A reduction in bacterial numbers was paralleled with clinical measures demonstrating an improvement in FEV1 and exacerbation number. There were no significant adverse events or resistance issues demonstrated in this study [8]. In CF this has become the gold standard study and new formulations and drugs have been compared against nebulised TOBI. The last few years have witnessed significant developments in this area. Nebulised aztreonam lysate has become available [9, 10] and was shown to be statistically superior to TOBI with respect to exacerbations number and FEV1, although patients were Aztreonam (but not TOBI) naïve [11]. Furthermore new delivery systems have been developed with the production of dry powder inhaler (DPI) formulations of tobramycin [12, 13] and colomycin [14], both of which have demonstrated non-inferiority to nebulised TOBI in randomised controlled studies and have been licensed for use. In addition to CF, inhaled antibiotic therapy has also been utilised in non-cf bronchiectasis. As yet, no inhaled therapies have a license for non-cf bronchiectasis, however evidence is also beginning to accumulate in this condition. A randomised controlled study of gentamicin in patients with non-cf bronchiectasis colonised by a variety of pathogens demonstrated improvements in bacterial density and eradication, exacerbations number and quality of life measures. Development of resistance was not a big feature of this study, however there were side effects in 30% of patients [15]. This has been replicated in several other studies and the non-cf bronchiectasis population do seem to be more prone to the side effects of inhaled therapies than CF patients [16, 17]. As with CF, in Europe, colomycin is the most common 62

63 inhaled therapy for non-cf bronchiectasis patients. The evidence for this was based on a few small uncontrolled studies with some improvement in microbiological and clinical endpoints [18], however provisional data from a recent multicentre RCT has demonstrated a reduced exacerbation number in bronchiectasis patients who were compliant with the medication (not in the intention to treat (ITT) population) [19]. Nebulised tobramycin has also been studied in non-cf bronchiectasis with the largest study of 74 patients demonstrating a reduction in microbial density after 4 weeks of inhaled tobramycin [16]. As with CF there is renewed interest and excitement in this area and multiple drugs are being developed with encouraging Phase 2 data from the use of ciprofloxacin DPI [20] and liposomal/dual release nebulised ciprofloxacin [21]. Short term use Microbe Eradication In CF, the isolation of Pseudomonas aeruginosa has been show to lead to a significant clinical deterioration with increased morbidity and more rapid deterioration of lung function and radiographic score [22]. Antibiotic treatment of initial PSA colonisation postpones colonisation [23] and when compared to historical controls has been shown to prevent deterioration of lung function [24]. As such, attempts are made to eradicate this microbe. In Europe inhaled colomycin is used in combination with oral ciprofloxacin, whereas 28 days of inhaled TOBI is the treatment of choice in the US following recent studies [25, 26]. In non- CF bronchiectasis, a potential causative relationship between PSA and deterioration is less clear although studies have demonstrated PSA as a determinant of mortality [27]. As such, practice for eradication varies between different centres with inhaled colomycin often used when eradication is attempted. Acute infection There is not much convincing data on the use of inhaled antibiotics for an acute exacerbation. In CF, a recent study showed that 24% of acute exacerbations were treated with inhaled in combination with other systemic antibiotics [28]. A study in non-cf bronchiectasis demonstrated that the addition of inhaled tobramycin to oral ciprofloxacin improved microbiological but not clinical endpoints, and as mentioned above, there was a high rate of intolerance with up to 50% of patients experiencing wheeze [29]. The use of inhaled antibiotics has also been investigated in ventilator associated pneumonia (VAP). This is a hospital acquired pneumonia associated with mechanical ventilation and has a high associated mortality. It is a common complication with a risk of 3%/day for the first five days [30, 31]. Often the responsible microbes can be difficult to treat and resistant to many antibiotics, providing rationale for the use of inhaled antibiotics. A metaanalysis of 5 small RCTs suggested an improvement in treatment success, but no change in microbiological, toxicity, or mortality outcomes [32]. Most subsequent studies that have been performed have been retrospective or non-comparative and so have been difficult to assess [33, 34]. The role of inhaled antibiotic therapy is likely to be as an add-on to systemic therapy as with bronchiectasis. A recent RCT however demonstrated a similar outcome in patients treated with either intravenous or nebulised combinations of ceftazidime and amikacin [35]. As with other conditions there is increasing interest in the possibility of inhaled antibiotics in VAP and a phase 3 study of nebulised amikacin is presently recruiting. Other possible avenues for inhaled antibiotic treatment is in other difficult to treat respiratory infections such as non-tuberculous mycobacteria (amikacin), complex fungal infections (amphotericin), and multi-drug resistant TB (capreomycin) [36]. Delivery systems Inhaled therapies need to be delivered to the lower airways. Particle size is important with sizes <5um needed for lower airway deposition. This has classically been delivered as a fine mist by nebuliser devices. Jet nebulisers function by directing a high flow of gas over a 63

64 capillary tube that is immersed into the fluid to be nebulised. These nebulisers are universal and of relatively low cost, however they can take a long time to nebulise and there is residual wasted drug at the end of nebulisation. Newer nebulisers rely on vibrating mesh technology whereby mechanical vibration of a piezoelectric element leads to vibration of a mesh with many laser holes to vibrate at the top of the liquid. This is much more efficient with significantly reduced nebuliser times and less liquid waste. Adaptive aerosol delivery systems have also been introduced whereby the inhaled drug is only delivered during the initial part of inspiration leading to reproducible dose delivery and less wastage. Dry powder inhalers have been developed which offer patients significantly more convenience with portability, no need for external power and reduced administration time, although some patients have found upper airway irritation with this form of antibiotic delivery. References 1. Cole, P.J., A new look at the pathogenesis and management of persistent bronchial sepsis: a vicious circle hypothesis and its logical therapeutic connatations.. Strategies for the management of chronic bronchial sepsis., ed. D.R. J. 1984, Oxford: Medicine Publishing Foundation Angrill, J., et al., Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med, (9): p Chalmers, J.D., et al., Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med, (7): p Prolonged antibiotic treatment of severe bronchiectasis; a report by a subcommittee of the Antibiotics Clinical Trials (non-tuberculous) Committee of the Medical Research Council. Br Med J, (5039): p Hodson, M.E., A.R. Penketh, and J.C. Batten, Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet, (8256): p Jensen, T., et al., Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J Antimicrob Chemother, (6): p Mukhopadhyay, S., et al., Nebulised antipseudomonal antibiotic therapy in cystic fibrosis: a meta-analysis of benefits and risks. Thorax, (4): p Ramsey, B.W., et al., Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med, (1): p McCoy, K.S., et al., Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med, (9): p Retsch-Bogart, G.Z., et al., Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest, (5): p Assael, B.M., et al., Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: A comparative efficacy trial. J Cyst Fibros, Konstan, M.W., et al., Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros, (1): p Konstan, M.W., et al., Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: The EVOLVE trial. Pediatr Pulmonol, Schuster, A., et al., Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax, (4): p Murray, M.P., et al., A randomized controlled trial of nebulized gentamicin in noncystic fibrosis bronchiectasis. Am J Respir Crit Care Med, (4): p Barker, A.F., et al., Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am J Respir Crit Care Med, (2 Pt 1): p

65 17. Drobnic, M.E., et al., Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Ann Pharmacother, (1): p Steinfort, D.P. and C. Steinfort, Effect of long-term nebulized colistin on lung function and quality of life in patients with chronic bronchial sepsis. Intern Med J, (7): p Haworth, C., et al., Multicenter randomised double blind placebo controlled trial of promixin (colistin) delivered through the i-neb in patients with non-cf bronchiectasis and chronic pseudomonas aeruginosa infection. Am J Respir Crit Care Med, : p. A Wilson, R., et al., Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study. Eur Respir J. 41(5): p Serisier, D.J., et al., Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial. Thorax, Kosorok, M.R., et al., Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol, (4): p Valerius, N.H., C. Koch, and N. Hoiby, Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. Lancet, (8769): p Frederiksen, B., C. Koch, and N. Hoiby, Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol, (5): p Gibson, R.L., et al., Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med, (6): p Ratjen, F., et al., Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax, (4): p Loebinger, M.R., et al., Mortality in bronchiectasis: a long-term study assessing the factors influencing survival. Eur Respir J, (4): p Wagener, J.S., et al., Oral, inhaled, and intravenous antibiotic choice for treating pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol, Bilton, D., et al., Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest, (5): p Chastre, J. and J.Y. Fagon, Ventilator-associated pneumonia. Am J Respir Crit Care Med, (7): p Masterton, R.G., et al., Guidelines for the management of hospital-acquired pneumonia in the UK: report of the working party on hospital-acquired pneumonia of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother, (1): p Ioannidou, E., Siempos, II, and M.E. Falagas, Administration of antimicrobials via the respiratory tract for the treatment of patients with nosocomial pneumonia: a metaanalysis. J Antimicrob Chemother, (6): p Korbila, I.P., et al., Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study. Clin Microbiol Infect, (8): p Michalopoulos, A., et al., Aerosolized colistin as adjunctive treatment of ventilatorassociated pneumonia due to multidrug-resistant Gram-negative bacteria: a prospective study. Respir Med, (3): p Lu, Q., et al., Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Am J Respir Crit Care Med, (1): p Dharmadhikari, A.S., et al., Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis. Antimicrob Agents Chemother, (6): p

66 Evaluation 1. Nebulisers with vibrating mesh technology have the following advantages over jet nebulisers: a. faster delivery of drug b. cost c. delivery of drug only during inhalation d. less need for cleaning 2. A patient with cystic fibrosis who is very well and has had no recent lung function decline starts culturing Pseudomonas aeruginosa from their sputum. Appropriate management may be: a. no specific treatment as they are well b. admission to hospital for intravenous antibiotics c. oral ciprofloxacin d. inhaled antibiotics +/- oral antibiotics 3. A patient with idiopathic, non-cf bronchiectasis has multiple infections per year and the plan is for long term antibiotic prophylaxis. Due to a lack of tolerance of oral prophylaxis, the aim is to try a long term inhaled antibiotic. Sputum cultures grow predominantly Haemophilus influenzae and Pseudomonas aeruginosa has not been previously cultured. The most appropriate choice may be: a. nebulised colomycin b. nebulised aztreonam lysate c. nebulised gentamicin d. TOBI podhaler 4. The benefits of inhaled antibiotics of systemic antibiotics are: a. high concentration of antibiotics at the site of infection b. minimal systemic side effects c. ability to use in the community d. all of the above Please find all correct answers at the back of your handout materials 66

67 Sept 2013 Inhaled antibiotics Michael Loebinger Royal Brompton Hospital Imperial College London, UK Faculty disclosure Bayer Site PI for Cipro DPI Phase 3 study Bayer Recipient of investigator led research funds Gilead Travel assistance Introduction AIMS Aim 1 To understand the rationale for the use of inhaled antibiotics Aim 2 To be aware of the different delivery mechanisms Aim 3 To be familiar with the potential roles of inhaled antibiotics and the evidence for their use 67

68 Plan Inhaled antibiotics Delivery systems When to use Practical examples and guide Challenges Advantages Increased drug concentrations locally Reduced systemic adverse effects C. difficile Home treatment Optimal characteristics of inhaled device Airway deposition Particle size important <5um lower airway deposition Reproducible dose-to-dose delivery Inexpensive Low burden Fast delivery Portable Minimal cleaning Easy to use Geller

69 Nebulisers Production of mist Jet compressed air >50% of drug wasted during exhalation Breathing pattern affects drug delivery Residual volume 0.8 mls Inexpensive Noisy Nebulisers VMT - mesh/membrane Aerosol is produced by horn vibrations pushing drug through a mesh (7000 2um holes) Uses a piezoelectric crystal that vibrates at speed Keller M

70 Nebulisers AAD Adapt aerosol delivery to patients breathing pattern Electronic sensors assess pressure changes continually I-neb TBM (Tidal breathing mode) TIM (Target inhalational mode) guides pt w feedback high resistance mouthpiece (<20l/min) slow and deep inhalation TIM may lung deposition and time Nebulised Drugs Adequate potency Lung retention IV medication used in nebulisers Specific nebulised formulations Liposomal delivery Reduced concentration of drug at airways at inhalation Longer half life od use Dual release drugs eg ciprofloxacin Dry powder inhaler Portable devices No need for power or fridge Short admin times Cleaning Traditional milling Strong cohesive forces Addition of carrier particles eg lactose limits dose quantity 70

71 Dry powder inhaler Pulmosphere Particles manufactured using emulsion based spray process High surface area, low density Highly dispersible and better flow Modest insp flow needed (30-40 l/min) Geller et al 2011 Dry powder inhaler Geller et al 2011 Role Long term management of chronic disease Short term eradication acute infection 71

72 Management of a chronic disease Chronic airways infection CF and bronchiectasis Shoemark et al

73 Cystic Fibrosis Autosomal recessive, multisystem Mutations in CFTR Encodes: 1480 amino-acid polypeptide Functions predominantly as a camp regulated chloride channel Most common mutation: ΔF508 >1800 mutations identified to date CF Trust 73

74 Bronchiectasis Angrill et al 2001 ARJCCM Bronchiectasis Chalmers et al 2012 ARJCCM 74

75 CF Evidence for chronic use Cystic Fibrosis 1981 Hodson et al compared 6/12 gent and carbenicillin vs placebo resp function and trend to admissions Potential benefits of nebulised therapy demonstrated Colomycin / Tobramycin / Aztreonam Colomycin Small Danish study decline lung function after IVs (Jensen Antimicrob Chemother 1987) Metaanalysis (Mukhopadhyay et al Thorax 1996) Colistin resistance rare Standard practice Many years of European clinical experience but lack of high quality RCTs Not licensed in the US Ramsey et al NEJM pt 6/12 study 28 day cycles FEV1 Exacerbations Bacterial numbers TOBI No signif adverse events or resistance TOBI gold standard therapy including for the regulatory bodies newer formulations have been compared against this. 75

76 Aztreonam Lysate AIR CF1 164 pts No recent antipsa drugs improved FEV1, symptom score and micro (Retsch- Bogart Chest 2009) AIR CF2 add on to TOBI 211 pts, 28/7 then 56/7 f/u improved FEV1, TTE, symptom score and micro (McCoy et al AJRCCM 2008) AIR CF3 18/12 study open label no placebo (Oermann Paed Pulm 2010 ) Comparisons Colomycin vs TOBI (Hodson ERJ 2002) 28/7 - FEV1 increase after TOBI only patients already had been on colomycin AZLI vs TOBI (Assael JCF 2012) Statistical superiority of AZLI wrt exacerbations and FEV1 patients already had been on TOBI Comparison Network metaanlysis similar effects of different inhaled abx (Littlewood KJ 2012) Evidence for effect but not 1 specific antibiotic or regimen (Cochrane (Ryan 2011)) TOBI DPI EVOLVE ( 105 pts vs placebo 28/7) signif FEV1 (Konstan Paed Pulm 2010) EAGER vs nebulised TOBI (553 pts 3 cycles) more mild adverse events, pt experience better, equivalent efficacy (Konstan JCF 2011) 76

77 Colomycin DPI FEV1 equivalence cf TOBI neb (380 pts after TOBI run in) (Schuster 2013 Thorax) = Colobreathe = tobramycin = CDPI completed patients; = TIS completed patients. Evidence for chronic use noncf Bronchiectasis Bronchiectasis Early studies on amoxycillin for Haemophilus but again mostly centred on PA, but others eg gent Colomycin Few small uncontrolled studies with some improvement in micro and clinical endpoints Recently presented multicentre study 144 pt exacerbation number in PP population (54 in each grp), better SGRQ and PSA CFU (Haworth et al ARJCCM 2013 A3511) 77

78 Tobramycin 4/52 RCT 74 pts (Barker 2000 AJRCCM) log CFU Adverse effects (not seen so much in CF) 12/12 cross over 30 patients (Drobnic 2005 Ann Pharm) hospitalisations BUT no effect on exacerbations or QoL open label 41 patients (Scheinberg 2005 Chest) Microbe eradication and QoL BUT significant 10% dropouts Some hospital, micro, but resistance and side effects Gentamicin 12/12 RCT vs HTS in 65 pts (Murray 2011 AJRCCM) Not just PA bacterial density and eradication exacerbations QoL No change in lung function No resistance but side effects in 30% Not sustained after therapy stopped Ciprofloxacin New Formulations for chronic use 78

79 New Formulations for chronic use Cipro DPI (Wilson 2013 ERJ) 124 pts 28/7 study followed by 56/7 follow up Reduction in bacterial load and increased eradication No effect on exacerbations Side effects low New Formulations for chronic use Cipro Dual Release (Serisier 2013 Thorax) 42 pts 3 cycles Reduction in bacterial load time to 1 st exacerbation (mitt) Well tolerated New Formulations for chronic use Ciprofloxacin Liposomal amikacin Promising phase 2 results PA density Also place in CF / NTM Levofloxacin Fosfamycin/Tobramycin (Trapnell 2012 AJRCCM) 119 pts Azli run in Abx use in the off month 79

80 Themes from chronic infection Which antibiotic Which regimen cyclical therapy Resistance patterns in vitro not appropriate to determine When stop therapy benefit not maintained (cf vicious cycle) Bacterial load reduction consistent feature Need clinical endpoints too Tailoring to populations side effect profiles seem worse in noncf Bx when to use prevention of deterioration and improvement of FEV1 in CF endpoints (eradication in noncf, lung function, exacerbation) PA or other microbes Practically Non CF Bx Chronic use Adapted from Loebinger et al 2007 Practically CF Chronic use PSA 1. Colomycin nebulised Continuous 2MU bd or promixin 1MU bd If not tolerated consider Colobreathe or TOBI If needs further treatment consider adding TOBI alt months 2. TOBI podhaler Alternate months If needs further treatment consider adding AZLI alt months 3. Aztreonam Lysate Alternate months 80

81 ? COPD 2/52 TOBI reduced I0 in COPD pt with PSA (Dal Negro 2008) Phase 2 inhaled levoflox 5/7 of each month for 1 year. No reduction in exacerbations (Sethi S AJRCCM Abs 2012) Role Long term management of chronic disease Short term eradication acute infection Pseudomonas Eradication CF Clinical state deteriorates after PA isolation Major predictor of mortality in children 2.6x risk of death over 8 years (Emerson Paediatr Pulmon 2002). Wisconsin CF Neonatal Screening Project (1/ neonates screened between pts) morbidity and more rapid of lung function and CXR score (Kosorok Paediatr Pulmon 2001) 81

82 Eradication Pseudomonas CF Clinical state deteriorates after PA isolation Major predictor of mortality in children 2.6x risk of death over 8 years (Emerson Paediatr Pulmon 2002). Wisconsin CF Neonatal Screening Project (1/ neonates screened between pts) morbidity and more rapid of lung function and CXR score (Kosorok Paediatr Pulmon 2001) Antibiotic treatment of initial colonisation postpones colonisation (Valerius et al Lancet 1991) Antibiotic treatment of initial colonisation prevent deterioration (Frederiksen et al Paediatr Pulmon 1997) historical controls Eradication po ciprofloxacin and neb colomycin for 3/52 (Valerius et al Lancet 1991) Increased duration to 3/12 (Frederiksen et al Pediatr Pulmon 1997) Nebulised tobramycin for 28/7 (Gibson et al AJRCCM 2003) ELITE trial for 28 vs 56/7 neb tobramycin (Ratjen et al Thorax 2010) Pseudomonas eradication in Bronchiectasis No studies to guide practice, but an attempt to eradicate seems pragmatic 82

83 Other eradications MRSA May involve inhaled vancomycin as part of certain regimens Role Long term management of chronic disease Short term eradication acute infection Acute infection CF / Bronchiectasis not much evidence CF - Used in exacerbations - 73% oral, 39% ivs, 24% inhaled (Wagener 2012) Cochrane 2 small studies not enough evidence to answer the question (Ryan 2012) Bx - oral cipro + inhaled tobra /placebo micro but not clinical endpoint met high rate 50% of wheeze (Bilton 2006) 83

84 Acute infection Ventilator associated pneumonia - Hospital acquited pneumonia associated with mechanical ventilation >48h after admission 0.5-1% inpatients Most common HCAI death stay 7-9/ % mortality (76% MDR) - Risk 3%/day during first 5/7 Gross et al AJM 1980; Chastre et al AJRCCM2002; BSAC Guidelines Pneumonia - VAP Study Study design N Medications Outcome Ioannidou 2007 Metaanalysis 5RCTs, 176pts Tobra, gent, sisamycin Improved cure, no mortality effect Michalopoulos 2008 Prospective, open-label 60 Nebulised colistin 83% bact and clinical response 57received iv Rx No control group Ghannam 2009 Retrospective 32 cancer and IV colistin/amino Increase complete resolution and VAP With Neb 16 micro eradication Without Neb 16 Korbila 2010 Retrospective 121 IV colistin With Neb 78 Without Neb 43 Cure rate 79.5% cf 60.5% Kofteridis 2010 Retrospective 86 IV colistin With Neb 43 Without Neb 43 No difference Arnold 2012 Retrospective 93 IV severity of illness in neb group With Col/Tob 19/9 but similar/crude mortality better Without Neb 74 Lu 2011 Phase 2 RT IV ceftaz/ami No difference in outcome, more 20 Neb ceftaz/ami resistance in IV group Others NTM amikacin Pneumocystis pentamidine Fungal infection amphotericin Pneumonia prophylaxis MDRTB capreomycin DPI phase 1 study (Dharmadhikari 2013) 84

85 Evidence Which patients Optimal regimen and delivery Resistance Patient Community Side Effects Bronchospasm Cost Challenges Burden Compliance Challenges Ineb data 80% self reported vs 36% (5-84%) actual (Daniels Chest 2011) In adolescents - 2 inhaled prescriptions 1.4 used 3 inhaled prescriptions 1.4 also (Ball et al JCF 2013) Conclusions Variable evidence Good rationale Established use in CF, bronchiectasis Less so in VAP Increasing interest Increasing number of products, studies, trials 85

86 Thank you Michael Loebinger 86

87 Faculty Disclosures Dr. Axel Dalhoff was an employee in the pharmaceutical industry (Beecham, Bayer) until December 2005 and has been involved in teaching and research at the Christian Albrechts University in Kiel since Dr. Federico Pea has received money for consulting from Astra Zeneca and Pfizer and for Speakers bureau from Astra Zeneca, Gilead, MSD, Novartis, Pfizer and Teva. Dr. Michael Loebinger has received money for research from Bayer in an unconnected area. 87

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89 Faculty Dr. Axel Dalhoff Institute for Infection Medicine University Hospital Schleswig-Holstein Campus Kiel Brunswiker Str Kiel GERMANY adalhoff@t-online.de Dr. Michael Loebinger Centre for Respiratory Research University College London Rayne Building, 5 University Street WC1E 6JJ London UNITED KINGDOM mloebinger@doctors.org.uk Dr. Federico Pea Institute of Clinical Pharmacology and Toxicology Medical School - University of Udine Udine ITALY pea.federico@aoud.sanita.fvg.it Prof. Francesco Scaglione Dept. of Pharmacology University of Milan Via Vanvitelli, Milan ITALY francesco.scaglione@unimi.it Prof. Hartmut Lode Pneumologie RCMS Universitatsmedezin Berlin Allergologie, Infektiologie (DGI) Hohenzollerndamm Berlin GERMANY haloheck@zedat.fu-berlin.de Dr. Stefano Aliberti Via Bergognone Milan ITALY stefano.aliberti@unimib.it 89

90 The EUROPEAN RESPIRATORY monograph A publication of the European Respiratory Society Editor in Chief: Tobias Welte COMPLEX PLEUROPULMONARY INFECTIONS Edited by Gernot Rohde and Dragan Subotic Monograph 61, Published September 2013 ISBN Each book-length issue of the European Respiratory Monograph covers a specific area of respiratory medicine, providing in-depth reviews that give clinicians at all levels a concise, comprehensive guide to symptoms, diagnosis and treatment. If you re an ERS member, you automatically have full online access to the Monographs. Find out more at erm.ersjournals.com 90