The value of TDM

to curb antimicrobial resistance

Leonardo Pagani, MD

Former Lead, Antimicrobial Stewardship Program

Infectious Diseases Unit

Bolzano Central Hospital, Bolzano; Italy

Sibiu, 15.10.2016

• Early and effective appropriate antibacterial therapy is a significant determinant of clinical outcome

• Once correct antibacterial has been selected, dose selection

occurs

• The aims of antibiotic dosing are to:

• Maximise rate and extent of bacterial kill

• Minimise the development of antibacterial resistance

• Minimise possibility of drug toxicity

Effective antibacterial dosing

Enhances likelihood of positive clinical outcomes

• Lack of therapeutic response

• Toxic effects evident

• Potential for non-compliance

• Variability in relationship of dose and concentration

• Therapeutic/toxic actions not easily quantified by clinical endpoints

Why Measure Drug Concentrations?

Mug

Bug Drug

How to maximise positive outcomes?

The ‘players’ in this challenging

match

“One size fits all” policy is inappropriate

Significant variations in rate and pattern of resistance among centers:

• ESBL-producing pathogens

• Carbapenem-R pathogens

• MDR-pathogens

• C. difficile infection

ESBL vs. AmpC b-lactamases vs. MBL

AmpC ESBL MBL

Penicillins Resistant Resistant Resistant

Cephalosporins Resistant (except

cefepime) Resistant Resistant

Aztreonam Resistant Resistant Sensitive

b-lactamase inhibitors (tazobactam, clavulanic, etc)

Resistant Sensitive Resistant

Plasmids encoding resistance to several antibiotic classes

PD characteristics of antibacterials

Lodise TP, Butterfield J. J Hosp Med 2011;6: S16-S23

Time-dependent antimicrobials

Concentration-dependent antimicrobials

Cmax/MIC ≥ 10 or AUC24/MIC ≥ 100-125

• High level of sickness severity increases importance of achieving optimal therapy BUT also decreases the likelihood

• The pathophysiological status in ICU affecting antimicrobial disposition

Dosing complexities

Healthy volunteer Patient in ICU

Sources of PK variability

If dosing does not account for these changes – sub-optimal therapy!

Sub-optimal patient outcomes

RESISTANCE !!!

ABSORPTION

PROTEIN

BOUND FREE

PLASMA

PRESCRIBED DOSE

ELIMINATION

RENAL

EXCRETION

Hypoalbuminemia may greatly affect drug

disposition and active concentration for highly bound anti-microbials

(drug loss)

Ertapenem Ceftriaxone Teicoplanin

Beta-lactam PK/PD variability in ICU

Antibiotic data

Effect of indication on dosing

McKinnon et al (IJAA 2008; 31:345-51)

Critically ill patients receiving 3rd or 4th gen cephalosporin from 2 trials (n=76)

BSI, Pneumonia, cUTI

100% T>MIC vs <100% T>MIC

clinical cure (82% vs. 33%; P = 0.002) and

bacteriological eradication (97% vs. 44%; P < 0.001)

Is b-lactam exposure correlated with clinical outcome?

ARC is common in the critically ill and strongly predicts diminished b-lactam plasma concentrations. Whilst it seems intuitive that low or undetectable b-lactam trough levels would impact negatively on individual clinical outcome, their true effect require further examination via larger clinical studies. The ecological impact of diminished b-lactam concentrations in the ICU setting on antimicrobial resistance requires further exploration.

Low antibiotic exposures can lead to emergence of resistance

MIC...?

Minimal

Interest

for the Clinicians..!!

Labreche MJ, Frei CH. Am J Health-Syst Pharm 2012; 69:1863-1870

Fluoroquinolones

Resistance, dosing and target attainment

The Ciprofloxacin Target AUC/MIC Ratio Is Not Reached in Hospitalized Patients with the Recommended Dosing Regimens

Haeseker M et al. Br J Clin Pharmacol 2013; 75: 180-185

Mutant selection window (MSW) ??

Abdul-Aziz MH, et al. Semin Respir Crit Care Med 2015; 36: 136-153

The term “selective window” refers to a critical range of antibiotic concentrations in which drug-resistant bacterial mutants could be selectively enriched and amplified when exposed to concentrations in this zone.

Shape does matter: short high-concentration exposure minimizes

resistance emergence for fluoroquinolones in P. aeruginosa

• High CIP concentrations over 1–10 h yielded more rapid and extensive initial killing compared with 16 and 24 h exposures at the same fAUC/MIC. No resistance emerged for 1–10 h exposures, although regrowth of susceptible bacteria was extensive.

• CIP exposure over 24 h yielded less regrowth, but CIP-resistant bacteria at 5× MIC amplified by over 5 log10 and almost completely replaced the susceptible bacteria by 24 h

• Pre-existing resistant subpopulations amplified extensively with 24 and 16 h exposures, but not with shorter durations.

• The shape of the CIP concentration profile was critical to minimize resistance emergence.

Rees VE et al, J Antimicrob Chemother 2015; 70: 816-826

PK/PD indices and resistance

Recently proposed targets for TDM dose adjustments

Wong et al. BMC Infect Dis 2014, 14:288

• Aminoglycosides

• Glycopeptides

• Quinolones

• b-lactams

• Linezolid

• Colistin

• Daptomycin?

•No RCT has demonstrated a mortality benefit of TDM

Drugs subject to TDM?

• Critical aspects of “target-concentration” therapy • Know indications for monitoring serum concentrations

• AND when you do not need to monitor levels

• Know the appropriate time to measure the concentration

• If the serum concentration is low, know how to safely achieve the desired level

• Be sure the level is not drawn from the same line in which the drug is administered

• Be sure drug is administered over the appropriate time

• AND Treat the patient, not the drug level

Management of monitored-drug therapy

And if you don’t have TDM?

Do your best! Better outcome, less resistance…

• TZP 12-16 g/24h

• Ciprofloxacin 750 mg/d PO; 2 x 600 mg/d IV

• Gentamicin 5-7 mg/kg OD

• Amikacin 20-25 mg/kg OD

• Meropenem 3-4 g/24h

• Vancomycin 30 mg/kg/24h

• …and so on..

• Clear concentration-effect relationships exist for antibiotics

• Underdosing leads to resistance

• We are commonly underdosing our patients because we don’t understand the PK in individual patients

• One solution may be TDM

• Clinical utility of antibacterial TDM still being quantified

Conclusions

A mind is like a parachute:

It does not work if it is not open (Franck Zappa)

thanks for your attention