How predictive is PK/PD ?

Table of Contents

Pharmacodynamic parameters

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

AUC vs. Peak

How predictive is the MIC ?

Qualities of the MIC (Minimal Inhibitory Concentration)

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

MIC as pharmacodynamic parameter:

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

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

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

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

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

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)

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)

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

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

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

Ciprofloxacin-resistance in Salmonella: Clinical failures 

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

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

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

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

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

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

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

Pharmacokinetic parameters for macrolides and MIC´s against H. influenzae

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

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

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

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Aminopenicillins for uncomplicated UTI: Literature study 

Aminopenicillins for uncomplicated UTI: Literature study

Aminopenicillins for uncomplicated UTI: Calculation of T > MIC

Distribution of E. coli MIC´s for ampicillin 100 strains, 30 resistant

Amoxicillin Timeserum > MIC calculated for MIC=8 mg/L

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

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

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

Pharmacodynamics of Beta-lactams: Time > MIC

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

Aminoglycosides: Pharmacodynamics in vivo Gram-negative bacteraemia Moore et.al. J Infect Dis 149: 443, 1984 

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

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

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

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

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

Pharmacodynamics of Antibiotics

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

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

Conclusion: Aminoglycosides/quinolones

How predictive is PK/PD ?

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