How predictive is pk pd
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How predictive is PK/PD ?. Niels Frimodt-Møller, MD DrSci Microbiological R & D Antibiotic Resistance Surveillance Unit Statens Serum Institut Copenhagen, Denmark. NF-M 2001. Pharmacodynamic parameters. Pharmacokinetic parameters: Peak/MIC ratio AUC/MIC ratio Time > MIC

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How predictive is PK/PD ?

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How predictive is pk pd

How predictive is PK/PD ?

Niels Frimodt-Møller, MD DrSci

Microbiological R & D

Antibiotic Resistance Surveillance Unit

Statens Serum Institut

Copenhagen, Denmark

NF-M 2001


Pharmacodynamic parameters

Pharmacodynamic parameters

  • Pharmacokinetic parameters:

    • Peak/MIC ratio

    • AUC/MIC ratio

    • Time > MIC

  • Minimal inhibitory concentration (MIC)

    (minimal bactericidal concentration (MBC) (time kill activity)

MIC

NF-M 2001


Pharmacodynamics as related to time kill activity in vitro in vivo

Time-dependent, concentration-

independent:

Beta-lactams

Macrolides

Tmp/sulfa

Glycopeptides

-

Concentration dependent:

Aminoglycosides

Fluoroquinolones

Streptogramins

-

-

Pharmacodynamics as related to time-kill activity in vitro/in vivo

NF-M 2001


Auc vs peak

AUC vs. Peak

Bacterial growth curve

Peak,a

Peak,b

MIC

Tmax,a

Tmax,b

AUC/MIC,a = AUC/MIC,b

Peak,a = Peak,b

NF-M 2001


How predictive is the mic

How predictive is the MIC ?

NF-M 2001


Qualities of the mic minimal inhibitory concentration

Qualities of the MIC (Minimal Inhibitory Concentration)

  • ”Exact” measure of antibiotic activity vs. bacterium (variation: + one two-fold dilution step)

  • MIC as good measure of antibacterial activity/mechanism of resistance:

    1) linearly increasing resistance levels

    e.g. PBP changes in pneumococci,

    stepwise gyrA mutations

    2) resistance mechanisms expressed in whole

    bacterial population

    e.g. TEM-1 beta-lactamase in E. coli

    sulI and sulII in Enterobacteriaceae

NF-M 2001


How predictive is pk pd

MIC: Examples of incomplete measure of antibacterial activity; interpretative methods or gene detection needed

  • mecA gene in staphylococci (inoculum,salt,temp.)

  • Penicillinase in S. aureus (clover leaf, mecillinam)

  • ESBL in Enterobacteriaceae

  • Type-1 non-derepressed beta-lactamase in certain Enterobacteriaceae (species diagnosis)

  • Inducible resistance genes,

    e.g. vanB in E.faecium, certain erm genes

  • gyrA mutations in Salmonella (nalidixic acid)

NF-M 2001


Mic as pharmacodynamic parameter

MIC as pharmacodynamic parameter:

  • ”..while MICs and MBCs provide useful information regarding the intrinsic activity of antimicrobials against pathogens, the information is inadequate for designing dosing regimens aimed at optimizing drug effect in vivo”

    Steven C. Ebert

    Handbook of Pharmacokinetic/Pharmacodynamic Correlation, CRC Press 1995

NF-M 2001


How predictive is pk pd

Mouse protection test: Correlation between MIC and ED50 for pneumococci with varying penicillin susceptibility

Log ED50 mg/mouse

100

10

1

Log MIC

mg/l

0.01

0.1

1

10

Knudsen et.al. AAC 1995;39:1253-58.

NF-M 2001


Pharmacokinetics of penicillin in mice determined at the ed 50 for 10 pneumococci

Pharmacokinetics of penicillin in mice determined at the ED-50 for 10 pneumococci

Knudsen et.al. AAC 1995;39:1253-58.

NF-M 2001


How predictive is pk pd

Changes in CFU of S. pneumoniae in thighs of infected mice treated with CEFPROZIL for 24 h.Nicolau et.al. AAC 44: 1291-5, 2000

2.5

0.0

Change in log CFU

-2.5

-5.0

8

4

16

2

0

5

10

15

20

MIC (mg/l)

NF-M 2001


How predictive is pk pd

Effect of penicillin on S. pneumoniae infection in peritoneum (P), thigh (TH) and lung (L) of miceErlendsdottir et.al. AAC, 2001, 45: 1078-85.

Change in CFU

MIC = 1 mg/L

Th

P

L

Th P L

Th P L

Th P L

Th P L

Peak/MIC

T>MIC

7,4 x

13 %

3,7 x

16 %

105 x

65 %

47 x

71 %

15 x

100 %

NF-M 2001


How predictive is pk pd

Mouse thigh, lung, peritonitis - and rabbit cage models: Generation time of control vs. Max. Effect of Penicillin Dosing Regimen

  • log CFU/ml, 6h

Generation time,min

Yellow = mouse lung model

Erlendsdottir et.al., AAC, 2001, 45: 1078-85

NF-M 2001


How predictive is pk pd

Dose response experiment in mouse-peritonitis model: S.pneumoniae D39 and mutant,D39-T6(D39-T6 = D39 transformed with mosaic pbp2B gene from highly PRP)

NF-M 2000-01


How predictive is pk pd

Dose response experiment in mouse-peritonitis model: S.pneumoniae D39 and mutant,D39-T6(D39-T6 = D39 transformed with mosaic pbp2B gene from highly PRP)

NF-M 2000-01


How predictive is pk pd

Interaction of Beta-lactams with PBB´s of S. pneumoniaeWilliamson et.al. AAC 1980, 18: 629-37; Frimodt-Møller et.al JID 1986,154: 511-17

* IC50, nmol/ml

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Correlation between loged50 mg mouse and logpbp3 i 50 nmol ml for pneumococci

Correlation between logED50 (mg/mouse), and logPBP3(I-50,nmol/ml) for pneumococci

Multiple regr.

ED50 vs. MIC, PBP1a,1b,2a, 2b, 3 : logPBp3 only, p=0.0078

cefsulodin

cefalexin

cefoxitin

cefalothin

cefadroxil

cefotaxime

cefaloridin

Williamson et.al. AAC 1980, 18:629-37; Frimodt-Møller et.al JID 1986,154: 511-17

NF-M 2001


How predictive is pk pd

Correlation between logMIC and logED50 for cefepime, ceftriaxone, cefotaxime, cefuroxime and cephalothin against 3 pneumococci

LogED50,

mg/kg

2

1,5

1

0,5

0

-0,5

Cefepime

-1,5 -1 -0,5 0 0,5 1 1,5

Log MIC, mg/L

Knudsen et.al. JAC 40: 679, 1997

NF-M 2001


Ciprofloxacin resistance in salmonella clinical failures

Ciprofloxacin-resistance in Salmonella:Clinical failures

NB: NCCLS breakpoint < 4 mg/l

NFM/2001


How predictive is the time mic for effect of beta lactams and macrolides in clinical studies

How predictive is the Time>MIC for effect of beta-lactams (and macrolides) in clinical studies

NF-M 2001


How predictive is pk pd

Pharmacokinetic determinants of penicillin cure of gonococcal urethritisJaffe et.al. AAC, 1979, 15: 587-591

  • 47 male inmates of US Penitentiary, Atlanta, age > 21 years, received intraurethral inoculation with 2-mm platinum loop of 15 x 10-9 cfu of N. gonorrhoeae – 45 developed purulent discharge.

  • 2 days after inoculation subejcts were treated im with penicillin in following doses: Single doses of 0.9, 1.2, or 2.4 Mill. Units or 1.0 + 0.4 Mill.Units at 3 h .

  • Serum penicillin conc. measured in all subjects.

  • RESULTS:

    Cure was best predicted by the time the Se-Penicillin Conc. remained above 3-4 x MIC; those cured had Se-Penicillin Conc. in this range for 7-10 h.

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How predictive is pk pd

Treatment of gonorrhoeae in men: Comparison of Ampicillin with Penicillin-G Eriksson, Acta Dermatovener, 1970,50: 451

Treatment failure (%)

N= 833

341

329

343

3.4

8.8

3.0

1.7

2 g po

2 g po +

probenecid

1 g x 2 with

5 h interval

Pc-G

2.2 MIU i.m.

Ampicillin

NF-M 2001


How predictive is pk pd

Single injection treatment of meningococcal meningitisMacfarlane et.al. Transact Royal Trop Med Hygiene,1979,73

NF-M 2001

* mean, units/ml


How predictive is pk pd

Single injection treatment of meningococcal meningitisMacfarlane et.al. Transact Royal Trop Med Hygiene,1979,73

P = NS

NF-M 2001


How predictive is pk pd

Pharmacodynamics of beta-lactams, macrolides and TMP/SMZ in otitis mediaCraig & Andes Pediatr Infect Dis J 1996;15:255-9

Bacte-

riolo-

gic

cure

(%)

Time > MIC (% of dosing interval)

NF-M 2001


How predictive is pk pd

Penicillin-resistant pneumococci: Treatment with beta-lactam antibiotics - Time>MIC in % of dosing interval (MIC)

NF-M 2001


Pharmacokinetic parameters for macrolides and mic s against h influenzae

Pharmacokinetic parameters for macrolidesand MIC´s against H. influenzae

NF-M 2001


Clarithromycin vs grepafloxacin in chronic bronchitis h influenzae tran et al jac 2000 45 9 17

Clarithromycin vs. Grepafloxacin in chronic bronchitis: H. influenzaeTran et.al., JAC, 2000, 45: 9-17

NF-M 2001


How predictive is pk pd

Treatment and outcome of S. aureus bacteremia: A prospective study of 278 casesA.G.Jensen et.al. Arch Intern Med in press.

NF-M 2001


Dicloxacillin dose vs time mic of free non proteinbound concentration

Dicloxacillin dose vs. Time > MIC of free (non-proteinbound) concentration

  • Dose Time > MIC

  • 1 g x 3 78 %

  • 1 g x 4 > 100 %

  • 2 g x 3 > 100 %

NF-M 2001


How predictive is pk pd

Continuous vs. Intermittent infusion of oxacillin in patients with staphylococcal infectionsRaber et.al. 36th ICAAC 1996 Abst, No. A104

a)

a)

Same effect in the two treatment groups

NF-M 2001


How predictive is pk pd

Experimental UTI in mice with E. coli

4 days treatment BID with 5 beta-lactams

NF-M 2001


How predictive is pk pd

Experimental UTI in mice:

Pharmacodynamics of Beta-lactams

NF-M 2001


Aminopenicillins for uncomplicated uti literature study

Aminopenicillins for uncomplicated UTI:Literature study

  • Criteria for evaluation

    Age > 14 years

    Female : male ratio > 4:1

    Uncomplicated, symptomatic UTI

    Urine culture before (> 100.000 cfu/ml) and

    after (4-10 days) = bacteriological cure(%)

    1)Susceptible – E. coli 2) all

    Normal renal function

    No attempts on localization studies e.g. ab-coated-bact.

NF-M 2001


Aminopenicillins for uncomplicated uti literature study1

Only female patients:

Charlton et.al. 1976

Eriksson et.al. 1981

Hoover et.al. 1982

Sutton et.al. 1983

Sigurdsson et.al. 1983

Kleinschmidt et.al. 1983

Morgan et.al. 1984

McAllister et.al. 1984

Nicolle et.al. 1993

Whitby et.al. 1993

Masterton et.al. 1995

Female and male patients:

Grüneberg et.al. 1967

Bresky 1977

Grob et.al. 1977

Rotschafer et.al. 1979

Leigh et.al. 1980

Iravani et.al. 1988

17 studies,

20 treatment groups with aminopenicillins

Aminopenicillins for uncomplicated UTI:Literature study

NF-M 2001


Aminopenicillins for uncomplicated uti calculation of t mic

Aminopenicillins for uncomplicated UTI:Calculation of T > MIC

  • T > MIC calculated from population pharmacokinetics:

    T>MIC = (ln (dose/Vd /fu) – ln MIC)/(0.693/T½)

    Vd = distribution vol. (amox 0,26 l/kg, ampi 0,24 l/kg)

    Patient weight = 60 kg

    fu = degree non-proteinbound (83%)

    T½ = 1 h

    MIC = 8 mg/l

NF-M 2001


Distribution of e coli mic s for ampicillin 100 strains 30 resistant

Distribution of E. coli MIC´s for ampicillin100 strains, 30 resistant

No. of strains

MIC, mg/l

NF-M 2001


Amoxicillin time serum mic calculated for mic 8 mg l

Amoxicillin Timeserum > MICcalculated for MIC=8 mg/L

NF-M 2001


Aminopenicillins for uncomplicated uti t mic in serum vs bacteriological cure

Aminopenicillins for uncomplicated UTI: T>MIC in serum vs. Bacteriological cure

NF-M 2001


How predictive is pk pd

NF-M 2001


Optimal dose of amoxicillin for uncomplicated uti t mic total 30 h

Optimal dose of amoxicillin for uncomplicated UTI (T>MIC(total) = 30 h)

NF-M 2001


How predictive is pk pd

Ciprofloxacin vs. Pondocillin for epididymitis in men > 40 years (prosp,rand,d-b): N=55 E. coliEickhoff et.al. Brit J Urol 1999, 84: 827-834

P = 0.001

NF-M 2001


Pharmacodynamics of beta lactams time mic

Pharmacodynamics of Beta-lactams: Time > MIC

Optimal time > MIC – const. infus

Intermittent dosing > 50% interval

Intermittent dosing < 50% interval

Bact./ml

Control

Time

NF-M 2001


How predictive is peak mic ratio or auc mic ratio for effect of aminoglycosides and quinolones

How predictive isPeak/MIC ratio or AUC/MIC ratio for effect of aminoglycosides and quinolones ?

NF-M 2001


How predictive is pk pd

Aminoglycosides: Pharmacodynamics in vivoGram-negative bacteraemiaMoore et.al. J Infect Dis 149: 443, 1984

P < .01

NF-M 2001


How predictive is pk pd

Relationship between max. Peak/MIC ratio and the rate of clinical response for aminoglycosidesMoore et.al. J Infect Dis, 1987, 155: 93

Response rate, %

Maximum Peak/MIC ratio

NF-M 2001


How predictive is pk pd

Optimizing aminoglycoside therapy for nosocomial pneumonia (NP) caused by Gram-neg. BacteriaKashuba et.al. AAC, 1999, 43: 623-29

  • 78 patients with NP caused by Gram-neg. bacteria treated with gentamicin or tobramycin:

  • Cox hazard model of C(max), AUC, total dose, duration of therapy, MIC, age, ICU adm., nutritional status, Pseudomonas infection, concurrent therapy with beta-lactam:

  • 90% probability of temperature - and leucocyte count resolution by 7 days:

  • If Cmax/MIC > 10 mg/l within first 48 h

NF-M 2001


How predictive is pk pd

Pharmacodynamics of fluoroquinolones against Pseudomonas infection in neutropenic ratsDrusano et.al., AAC, 1993, 37: 483-90.

  • Survival linked to Peak/MIC when

    ratio > 10/1

  • Survival linked to AUC/MIC when

    ratio < 10/1

NF-M 2001


Pharmacodynamics of i v ciprofloxacin in seriously ill patients forrest et al aac 1993 37 1073 81

Pharmacodynamics of i.v. Ciprofloxacin in seriously ill patientsForrest et.al. AAC, 1993, 37: 1073-81.

NF-M 2001


Pharmacodynamics of iv ciprofloxacin in seriously ill patients forrest et al aac 1993 37 1073 81

Pharmacodynamics of iv ciprofloxacin in seriously ill patientsForrest et.al. AAC, 1993, 37: 1073-81.

* P < 0.005; ** P<0.001

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Pharmacodynamics of antibiotics

Pharmacodynamics of Antibiotics

AUIC >125

NF-M 2001


How predictive is pk pd

Pharmacodynamics of i.v. Ciprofloxacin in seriously ill patients: AUIC > 125Forrest et.al. AAC, 1993, 37: 1073-81.

  • MIC´s > 0.25 mg/l sign. worse for microbiologic cure and > 0.5 mg/l sign. worse for clinical cure (i.e. Pseudomonas and S. aureus)

  • Concomitant azlocillin improved likelihood of cure with Pseudomonas infections (P=0.028)

  • High correlation betwen Peak/MIC ratio and AUC/MIC ratio (R=0.92) prevented detection of Peak/MIC as important covariate.

  • Increase of AUC/MIC above 250 no further improvement

NF-M 2001


Pharmacodynamics of levofloxacin in clinical study preston et al jama 1998 279 125 9

Pharmacodynamics of levofloxacin in clinical studyPreston et.al. JAMA, 1998, 279: 125-9.

  • 313 ptts with bacterial infections of respiratory tract, skin or urinary tract

  • Clinical and microbiological outcome best predicted by Peak/MIC ratio > 12.2

NF-M 2001


Conclusion aminoglycosides quinolones

Conclusion: Aminoglycosides/quinolones

  • Peak/MIC ratio > 10-12 within first

    24 – 48 h predictive of good effect

  • Leads to shorter duration of treatment

NF-M 2001


How predictive is pk pd1

How predictive is PK/PD ?

  • MIC as predictive for antibacterial activity in vivo depends on drug/bacterial species/ type of resistance

  • For susceptible bacteria and selected types of resistance mechanisms:

  • Time>MIC (e.g. beta-lactams, macrolides) and Peak/MIC (AUC/MIC) ratio (e.g. aminogly-cosides, quinolones) are excellentpredictors of effect in vivo

NF-M 2001


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