Intracellular Activity of Antibiotics: the knowns, the uncertainties and the failures

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Tulkens, MD, PhD * Emeritus Professor of Pharmacology Invited Lecturer

and Molecular Pharmacology Louvain Drug Research Institute Health Science

Chester, UK, 18-20 November 2015 * with slides borrowed from Françoise

1 Intracellular Activity of Antibiotics: the knowns, the uncertainties and the failures Paul M. Tulkens, MD, PhD * Emeritus Professor of Pharmacology Invited Lecturer (Drug Discovery & Development / Rational) therapeutic choices) Cellular and Molecular Pharmacology Louvain Drug Research Institute Health Science Sector Université catholique de Louvain Brussels, Belgium PKUK 2015, Chester, UK, November 2015 * with slides borrowed from Françoise Van Bambeke With approval of the Belgian Common Ethical Health Platform visa no. 15/V1/5450/ November 2015 PKUK - Chester, UK 1

2 Research grants Disclosures and slides availability Theravance, Astellas, Targanta, Cerexa/Forest, AstraZeneca, Bayer, GSK, Trius, Rib-X, Eumedica, Debiopharm Belgian Science Foundation (F.R.S.-FNRS), Ministry of Health (SPF), Walloon and Brussels Regions, European Union (FP7 programme) Speaking fees Bayer, GSK, Sanofi, Johnson & Johnson, OM-Pharma Decision-making and consultation bodies European Committee for Antimicrobial Susceptibility Testing [EUCAST] (General Assembly and steering committee ( )) European Medicines Agency (external ad-hoc expert) US National Institutes of Health (grant reviewing) Drive-AB [Driving reinvestment in R&D and responsible use for antibiotics] (governance) Slides: Lectures 19 November 2015 PKUK - Chester, UK 2

3 Chester extra and intra 19 November 2015 PKUK - Chester, UK 3

4 Why do we wish to look at intracellular activity of antibiotics? Beyond truly obligate intracellular parasites (e.g., Legionella, Chlamydia, Mycobacteriae, many more "common" bacteria are facultative (e.g. Listeria) or occasional (e.g. Staphylococci, Pseudomonas ) intracellular parasites These bacteria form a reservoir from where bacteria may escape causing relapses and recurrences of the infection Natural defenses often restrict their growth and decrease their persistence, but not always You may need to help host defenses with antibiotics 19 November 2015 PKUK - Chester, UK 4

5 Intracellular activity of antibiotics What has been know for long about pharmacokinetics What has surprised us Adding pharmacodynamics A renewed model? 19 November 2015 PKUK - Chester, UK 5

6 Intracellular activity of antibiotics What has been know for long about pharmacokinetics What has surprised us Adding pharmacodynamics A renewed model? 19 November 2015 PKUK - Chester, UK 6

7 A simple view in 1991 Tulkens PM. Intracellular distribution and activity of antibiotics. Eur J Clin Microbiol Infect Dis : PubMed PMID: November 2015 PKUK - Chester, UK 7

8 Which antibiotics accumulate in cells? beta-lactams: 1x aminoglycosides: <1 to 2 x ansamycins: 2-3 x tetracyclines: 2-4 x fluoroquinolones: 5-20 x macrolides: 4 to > 100 x * glycopeptides: 1 to 400 x!! ** * azithromycin, ketolides ** oritavancin 19 November PKUK - Chester, UK 8

9 How do antibiotics penetrate in cells? 1. diffusion macrolides fluoroquinolones tetracyclines ansamycines β-lactams, November PKUK - Chester, UK 9

10 How do antibiotics penetrate in cells? 1. diffusion Tyteca et al., EJCB, 2001, in press 19 November PKUK - Chester, UK 10

11 How do antibiotics penetrate in cells? 1. diffusion Ouadrhiri et al., AAC, November PKUK - Chester, UK 11

12 How do antibiotics penetrate in cells? 1. diffusion Ouadrhiri et al., AAC, November PKUK - Chester, UK 12

13 How do antibiotics penetrate in cells? 2. carrier-mediated influx specific structure (some energy-dependent) saturable competition by analogues highly variable rom on cell type to another 19 November PKUK - Chester, UK 13

14 Carrier-mediated transport Roth et al. Br J Pharmacol. 2012;165: PMID: November PKUK - Chester, UK 14

15 Carrier-mediated transport Roth et al. Br J Pharmacol. 2012;165: PMID: November PKUK - Chester, UK 15

16 How do antibiotics penetrate in cells? 3. pinocytosis aminoglycosides glycopeptides 19 November PKUK - Chester, UK 16

17 How do antibiotics penetrate in cells? aminoglycosides in fibroblasts Cc/Ce = 1 Ce = 1.3 mg/ml Ce = 0.65 mg/ml Ce = 0.35 mg/ml Slow (days ) ill-effective (2-4 fold) Tulkens & Trouet, November PKUK - Chester, UK 17

18 How do antibiotics penetrate in cells? receptor-mediated pinocytosis in kidney cortex binding to megalin (Moeströp et al., 1995) acidic phospholipids (Humes et al, 1983) Giuliano et al., J. Pharm. Exp. Ther., November PKUK - Chester, UK 18

19 How do antibiotics penetrate in cells? membrane binding and uptake of lipoglycopeptides Vna Bambeke et al. Antimicrob Agents Chemother (2004) 48: November PKUK - Chester, UK 19

20 How do antibiotics penetrate in cells? membrane binding and uptake of lipoglycopeptides Vna Bambeke et al. Antimicrob Agents Chemother (2004) 48: November PKUK - Chester, UK 20

21 How do antibiotics penetrate in cells? membrane binding and uptake of lipoglycopeptides Vna Bambeke et al. Antimicrob Agents Chemother (2004) 48: November PKUK - Chester, UK 21

22 Efflux main drug transporters Saier, November 2015 PKUK - Chester, UK 22

23 Efflux Saier, November 2015 PKUK - Chester, UK 23

24 Some transporters involved in the efflux of antibiotics from eukaryotic cells superfamily transporter physiol. antibiotics substrates ABC MDR1 phospholipids fluoroquinolones macrolides β-lactams tetracyclines streptogramins MRP1 phospholipids fluroquinolones leukotrienes macrolides conjugates rifamycins MRP2 / 4 conjugates fluoroquinolones β-lactams MFS NPT1 phosphates β-lactams OAT OATP1 bile salts β-lactams steroids 19 November 2015 PKUK - Chester, UK 24

25 Examples of efflux-mediated control of cellular accumulation 1. fluoroquinolones accumulation of ciprofloxacin in J774 macrophages Michot et al. Antimicrob Agents Chemother (2004) 48: November 2015 PKUK - Chester, UK 25

26 Evidencing active efflux... non linear accumulation kinetics... receptor mediated uptake Cc diffusion Ce apparent facilitated uptake 19 November 2015 PKUK - Chester, UK 26

27 Evidencing active efflux... non linear accumulation kinetics... Cc Ce apparent facilitated uptake by saturation of efflux! 19 November 2015 PKUK - Chester, UK 27

28 Influence of efflux inhibitors on fluoroquinolones and macrolide accumulation... Michot et al. Antimicrob Agents Chemother (2004) 48: November 2015 PKUK - Chester, UK 28

29 But once in cells, where are the drugs? cytosol endosomes?? phagolysososomes lysososomes? elsewhere 19 November 2015 PKUK - Chester, UK 29

30 Subcellular localization: a quick answer? cytosol fluoroquinolones beta-lactams ansamycins macrolides (1/3) endosomes?? phagolysososomes macrolides (2/3) phagosomes aminoglycosides lysososomes? 19 November 2015 PKUK - Chester, UK 30

$fractionation techniques 19 November 2015 PKUK -$

31 Subcellular localization is often studied by cell fractionation techniques 19 November 2015 PKUK - Chester, UK 31

32 A recent example with two novel oxazolidinones: 1. tedizolid (accumulation) O N N N N N N O OH F Comparative accumulation of linezolid (LZD) and of tedizolid (TR-700) in THP-1 macrophages (a) Uptake kinetics (b) Influence of the temperature (2 h incubation) Lemaire et al. J Antimicrob Chemother (2009) 64: November 2015 PKUK - Chester, UK 32

33 Subcellular localization of the accumulated tedizolid or redistribution? Tedizolid subcellular distribution in extract from J774 macrophages TDZ LDH NAB CytOx Q/ ρ density Das et al. Clin Infect Dis 2014;58 Suppl 1:S51-7. Flanagan et al. Antimicrob Agents Chemother 2015;59: November 2015 PKUK - Chester, UK 33

34 Mechanisms of localisation and accumulation in cytosol... cytosol β-lactams fluoroquinolones non ionic oxazolidinones Loose binding to cytosl soluble constituents? OR leakage from other sites? 19 November 2015 PKUK - Chester, UK 34

35 Accumulation of radezolid Lemaire et al. Antimicrob Agents Chemother (2010) 54: November 2015 PKUK - Chester, UK 35

36 Subcellular localization of radezolid Lemaire et al. Antimicrob Agents Chemother (2010) 54: November 2015 PKUK - Chester, UK 36

37 Mechanisms of localisation and accumulation... proton trapping (ML, OZ) binding to phospholipids? for aminoglycosides: inability to cross membranes macrolides aminoglycosides cationic oxazolidinones lysososomes 19 November 2015 PKUK - Chester, UK 37

38 Mechanisms of localisation and accumulation... Increase in phospholipid cellular content cellular concentration (mg/l) Azithromycin extracellular concentration (mg/l) Potential toxicity? Van Bambeke et al.,jac, November 2015 PKUK - Chester, UK 38

39 So, what we know in a nutshell... Adapted from Van Bambeke et al., Curr. Opin. Drug Discov. Devel (2006) 9: November 2015 PKUK - Chester, UK 39

40 But where does this lead us for activity? Ph. Geluck, with permission * taken from a slide presented at ECCMID in November 2015 PKUK - Chester, UK 40

41 Intracellular activity of antibiotics What has been know for long about pharmacokinetics What has surprised us Adding pharmacodynamics A renewed model? 19 November 2015 PKUK - Chester, UK 41

42 antibiotics: ampicillin azithromycin sparfloxacin Listeria monocytogenes hly+ 19 November 2015 PKUK - Chester, UK 42

43 Intracellular infection cycle of Listeria monocytogenes hly + from Portnoy et al. 19 November 2015 PKUK - Chester, UK 43

44 Following the intracellular fate of Listeria m. by EM phagocytosis escape from vacuole in cytosol 19 November 2015 PKUK - Chester, UK 44

45 MIC, accumulation and activity against cytosolic Listeria m.... MIC Accumulation Activity * AMPI AZ SP AMPI AZ SP AMPI AZ SP Ouadhriri et al., AAC,1999 * log CFU 5h Ce = 10 x MIC 19 November 2015 PKUK - Chester, UK 45

46 To make a long story short: can we predict intracellular activity as a function of the accumulation AMP=ampicillin; AZM=azithromycin; CIP=ciprofloxacin; ETP=ertapenem; GEN=gentamicin; GRN=garenoxacin; LNZ=linezolid; LVX=levofloxacin; MEM=meropenem; MXF=moxifloxacin; NAF=nafcillin; ORI=oritavancin; OXA=oxacillin; PEN V=penicillin V; RIF=rifampicin; TEC=teicoplanin; TEL=telithromycin; VAN=vancomycin Adapted from Van Bambeke et al., Curr. Opin. Drug Discov. Devel (2006) 9: November 2015 PKUK - Chester, UK 46

47 To make a long story short: can we predict intracellular activity as a function of the accumulation AMP=ampicillin; AZM=azithromycin; CIP=ciprofloxacin; ETP=ertapenem; GEN=gentamicin; GRN=garenoxacin; LNZ=linezolid; LVX=levofloxacin; MEM=meropenem; MXF=moxifloxacin; NAF=nafcillin; ORI=oritavancin; OXA=oxacillin; PEN V=penicillin V; RIF=rifampicin; TEC=teicoplanin; TEL=telithromycin; VAN=vancomycin Adapted from Van Bambeke et al., Curr. Opin. Drug Discov. Devel (2006) 9: November 2015 PKUK - Chester, UK 47

To make a long story short: can we predict intracellular activity as a function of the accumulation AMP=ampicillin; AZM=azithromycin; CIP=ciprofloxacin; ETP=ertapenem; GEN=gentamicin;

48 To make a long story short: can we predict intracellular activity as a function of the accumulation AMP=ampicillin; AZM=azithromycin; CIP=ciprofloxacin; ETP=ertapenem; GEN=gentamicin; GRN=garenoxacin; LNZ=linezolid; LVX=levofloxacin; MEM=meropenem; MXF=moxifloxacin; NAF=nafcillin; ORI=oritavancin; OXA=oxacillin; PEN V=penicillin V; RIF=rifampicin; TEC=teicoplanin; TEL=telithromycin; VAN=vancomycin Adapted from Van Bambeke et al., Curr. Opin. Drug Discov. Devel (2006) 9: November 2015 PKUK - Chester, UK 48

49 Thus, there is now an obvious conclusion 19 November 2015 PKUK - Chester, UK 49

50 Subcellular bioavailability of antibiotics? High Fair Nil FQ / oxazolidinones / β-lactams ML / AG 19 November 2015 PKUK - Chester, UK 50

51 Subcellular bioavailability of antibiotics? Fluoroquinolones, β-lactams, oxazolidinones may move easily across membranes FQ 19 November 2015 PKUK - Chester, UK 51

52 Subcellular bioavailability of antibiotics? aminoglycosides, poorly diffusible drugs (oritavancin, e.g.) or subjected to protontrapping sequestration (macrolides, e.g.) may remained confined therein November 2015 PKUK - Chester, UK 52

53 Intracellular activity of antibiotics What has been know for long about pharmacokinetics What has surprised us Adding pharmacodynamics A renewed model? 19 November 2015 PKUK - Chester, UK 53

54 Second illustration: the 24h dose-effect model 1. Cell exposure to a a wide range of extracellular concentrations of the antibiotic Opsonization (45, 37 c) 9 ml RPMI + 1 ml human serum 500,000 THP-1 cells/ml 4 cfu/cell (MOI = 4) Phagocytosis (1 h) Extracellular Wash GEN 50 µg/ml (45 min) Typical post-phagocytosis inoculum: 5 to 7x10 5 CFU/mg prot. Incubation (with ATB) (T0, T24 h) This example is for S. aureus. Similar design for other bacteria Cell washing, collection, and lysis Cell-associated CFUs counting Cell Protein content determination 19 November 2015 PKUK - Chester, UK 54

55 Second illustration: the 24h dose-effect model 2. Analysis of the response 4 E min 3 E min : cfu increase (in log 10 units) at 24 h from the corresponding initial inoculum as extrapolated for an infinitely low antibiotic concentration Log10 cfu (24 h 0 h) Log 10 of extracellular concentration ( MIC) C stat Static concentration (C stat ): extracellular concentration resulting in no apparent bacterial growth (number of cfu identical to the initial inoculum) E max E max : cfu decrease (in log 10 units) at 24 h from the corresponding initial inoculum as extrapolated from infinitely large antibiotic concentration Reference: Barcia-Macay M, Seral C, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F. Pharmacodynamic evaluation of the intracellular activity of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. Antimicrobial Agents and Chemotherapy (2006) 50: November 2015 PKUK - Chester, UK 55

56 Second illustration: the 24h dose-effect model 2. the analysis of the response 4 E min 3 E min : cfu increase (in log 10 units) at 24 h from the corresponding initial inoculum as extrapolated for an infinitely low antibiotic concentration Log10 cfu (24 h 0 h) Log 10 of extracellular concentration ( MIC) C stat Static concentration (C stat ): extracellular concentration resulting in no apparent bacterial growth (number of cfu identical to the initial inoculum) E max E max : cfu decrease (in log 10 units) at 24 h from the corresponding initial inoculum as extrapolated from infinitely large antibiotic concentration Reference: Barcia-Macay M, Seral C, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F. Pharmacodynamic evaluation of the intracellular activity of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. Antimicrobial Agents and Chemotherapy (2006) 50: November 2015 PKUK - Chester, UK 56

57 Question #1: does increased accumulation of a given antibiotic results in its increased potency and maximal activity? cytosol azithromycin phagolysosomes gain in potency but not in max. activity gain in potency and max ciprofloxacin no gain the gain seems to depend on a common localization Seral et al; J. Antimicrob Chemother (2003) 47: November 2015 PKUK - Chester, UK 57

58 Question #2: does difference in accumulation of antibiotics of the same class results in commensurate differences in potency and maximal activity? 19 November 2015 PKUK - Chester, UK 58

59 Question #2: does difference in accumulation of antibiotics of the same class results in commensurate differences in potency and maximal activity? 1. accumulation (Ce = 20 mg/l) 19 November 2015 PKUK - Chester, UK 59

60 Question #2: does difference in accumulation of antibiotics of the same class results in commensurate differences in potency and maximal activity? 1. accumulation (Ce = 20 mg/l) 2. activity (MIC = mg/l) no difference in dose-effect relationship! 19 November 2015 PKUK - Chester, UK 60

Question #2: does difference in accumulation of antibiotics of the same class results in commensurate differences in potency and maximal activity? 1.

61 Question #2: does difference in accumulation of antibiotics of the same class results in commensurate differences in potency and maximal activity? 1. accumulation (Ce = 20 mg/l) 3. intracellular concentration to obtain a given effect you need more of the drug that accumulates more 19 November 2015 PKUK - Chester, UK 61

62 Question #3: are antibiotics that accumulate more effective (potency and maximal activity) than those which do not? S. aureus model low accumulation fair accumulation the answer is not obvious! low accumulation high accumulation Barcia-Macay et al. Antimicrob Agents Chemother (2006) 50: November 2015 PKUK - Chester, UK 62

63 Question #4: why are antibiotics unable eradicate the intracellular bacteria (viz. low maximal efficacy)? S. aureus model (ATCC25223) compare the extracellular and the intracellular E max Barcia-Macay et al. Antimicrob Agents Chemother (2006) 50: November 2015 PKUK - Chester, UK 63

64 Question #4: why are antibiotics unable eradicate the intracellular bacteria (viz. low maximal efficacy)? ceftaroline S. aureus model (ATCC33591 [MRSA]) - 5 log! - 1 log! compare the extracellular and the intracellular E max Melard et al. J Antimicrob Chemother (2013) 68: November 2015 PKUK - Chester, UK 64

65 about question #4 (eradication): some do (slightly) better than others (viz. maximal efficacy)? 5 4 ATCC Log10 cfu (24 h 0 h) daptomycin moxifloxacin oxacillin oxacillin daptomycin moxifloxacin Log 10 of extracellular concentration ( MICs) Peyrussoon et al. Antimicrob Agents Chemother (2015) 59: November 2015 PKUK - Chester, UK 65

66 about question #4 (eradication): some do (slightly) better than others (viz. maximal efficacy) but all do less than in broth a more systematic comparison with ATCC (S. aureus) and at human C max -5 From high to low intracellular activity: intracellular log CFU from time AZM LNZ TEL CIP RIF TEC ORI GRN MXF LVX NAF extracellular log CFU from time 0 AMP VAN PEN V GEN -5 ORI = oritvancin MXF =moxifloxacin GRN = garenoxacin LVX = levofloxacin CIP = ciprofloxacin AMP = ampicillin RIF = rifampincin TEC = teicoplann NAF = nafcillin VAN = vancomycin PEN V : penicillin V LNZ = linezolid TEL = telithromycin AZM = azithromycin Adapted from Barcia-Macay et al. Antimicrob Agents Chemother (2006) 50: November 2015 PKUK - Chester, UK 66

67 about question #4 (eradication): some do (slightly) better than others (viz. maximal efficacy) but all do less than in broth a more systematic comparison with ATCC (S. aureus) and at human C max intracellular log CFU from time but they all are below the equipotent line AZM LNZ TEL CIP RIF TEC ORI GRN MXF LVX NAF extracellular log CFU from time 0 AMP VAN PEN V GEN -5 From high to low intracellular activity: ORI = oritvancin MXF =moxifloxacin GRN = garenoxacin LVX = levofloxacin CIP = ciprofloxacin AMP = ampicillin RIF = rifampincin TEC = teicoplann NAF = nafcillin VAN = vancomycin PEN V : penicillin V LNZ = linezolid TEL = telithromycin AZM = azithromycin Adapted from Barcia-Macay et al. Antimicrob Agents Chemother (2006) 50: November 2015 PKUK - Chester, UK 67

68 Intracellular activity of antibiotics What has been know for long about pharmacokinetics What has surprised us Adding pharmacodynamics A renewed model? 19 November 2015 PKUK - Chester, UK 68

69 The seven pillars of intracellular activity? D 1 D 1. Penetration This is obvious: no penetration = no activity ex.: aminoglycosides in short term exposures 19 November 2015 PKUK - Chester, UK 69

70 The seven pillars of intracellular activity? D 1 D 2 1. Penetration 2. No efflux Also obvious: efflux decreases the intracellular concentration ex.: fluoroquinolones (MRP4), macrolides (Pgp) 19 November 2015 PKUK - Chester, UK 70

71 The seven pillars of intracellular activity? D 1 2 D 3 1. Penetration 2. No efflux 3. Accumulation Much less obvious no simple correlation accumulation-activity ex.: fluoroquinolones, macrolides, β-lactams 19 November 2015 PKUK - Chester, UK 71

72 The seven pillars of intracellular activity? D* D 1 D Penetration 2. No efflux 3. Accumulation 4. Subcell. bioavailability This is probably the most critical property ex.: fluoroquinolones, oxazolidinones vs macrolides and aminoglycosides 19 November 2015 PKUK - Chester, UK 72

73 The seven pillars of intracellular activity? D* D 1 D Interesting aspect but could vary for drugs and bugs one + example: intracellular MRSA and conventional β-lactams (not shown in this lecture) 1. Penetration 2. No efflux 3. Accumulation 4. Subcell. bioavailability 5. Expression of activity 19 November 2015 PKUK - Chester, UK 73

74 The seven pillars of intracellular activity? D* D 1 D Probably critical to explain the noneradication or part of the intracellular inoculum future therapeutic targets? 1. Penetration 2. No efflux 3. Accumulation 4. Subcell. bioavailability 5. Expression of activity 6. Bacterial responsiveness (population) 19 November 2015 PKUK - Chester, UK 74

75 The seven pillars of intracellular activity? D 1 D D* Penetration 2. No efflux 3. Accumulation Not addressed 4. Subcell. bioavailability 6 here but probably very important 7 5. Expression of activity 6. Bacterial responsiveness and pharmacodynamics 7. Cooper. with host def. 19 November 2015 PKUK - Chester, UK 75

76 The seven pillars of intracellular activity? D 1 D D* Penetration 2. No efflux 3. Accumulation 4. Subcell. bioavailability Expression of activity 6. Bacterial responsiveness and pharmacodynamics 7. Cooper. with host def. 19 November 2015 PKUK - Chester, UK 76

77 So, it a nutshell from ancient to contemporary but still a lot of unknowns 19 November 2015 PKUK - Chester, UK 77

But this work would not have been possible without The drugs β-lactams: penicillin V, oxacillin, cloxacililn, ceftaroline*, ceftobiprole* (+ avibactam*) aminoglycosides: gentamicin, amikacin

78 But this work would not have been possible without The drugs β-lactams: penicillin V, oxacillin, cloxacililn, ceftaroline*, ceftobiprole* (+ avibactam*) aminoglycosides: gentamicin, amikacin lincosamides: clindamycin, pirlimycin fluoroquinolones: ciprofloxacin, pefloxacin, lomefloxacin, sparfloxacin, moxifloxacin,, garenoxacin*, gemifloxacin, finafloxacin*, delafloxacin* oxazolidinones: linezolid, radezolid*, tedizolid* glycopeptides: vancomycin, telavancin*, oritavancin*, macrolides: clarithromycin, azithromycin, solithromycin*, other classes: daptomycin, GSK *, gepoditacin*, Debio1452* etc The people M.B. Carlier *,** A. Zenebergh ** B. Scorneaux * Y. Ouadrhiri * S. Caryn *,** C. Seral ** M. Barcia-Macay * H.A. Nguyen ** J.M. Michot * B. Marquez ** C. Vallet * S. Lemaire *,** A. Melard J. Buyck ** D. Das ** F. Peyrusson * F. Van Bambeke (current head of the group) Let us catch them * new molecules studied at preclinical level * doctoral fellow; ** post-doctoral fellow 19 November 2015 PKUK - Chester, UK 78

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