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PK-PD and ANTIBIOTIC RESISTANCE Lessons Learned

24 September 2014

Paul G. Ambrose, Pharm.D, FIDSA Institute for Clinical Pharmacodynamics

Latham, New York

WHERE WE’RE GOING TODAY

Some Important Questions

• Does the presence or absence of a resistance determinant(s)

predict outcome?

• What is the relationship between drug exposure and resistance emergence?

• Can we alter the shape of drug exposure to increase our

chances of attaining positive outcomes?

• How big a challenge is effect site penetration and associated

variability?

• Is the answer simply the “not so simple” combination therapy?

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MIC DISTRIBUTION PATTERNS Cefepime versus Klebsiella pneumoniae

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Key Question: Does the

presence or absence of

a resistance determinant predict outcome?

Minimum inhibitory concentration distribution for cefepime against 1723 K. pneumoniae N. American clinical isolates

collected during 2005-2007 by the SENTRY Surveillance Program. Data provided as a courtesy by Ronald N. Jones.

EXPOSURE & RESPONSE IN MICE ESBL

Versus Non-ESBL Producing Strains

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The Answer: It is not the

presence or absence of

resistance determinants

that predict outcome,

but rather the drug

exposure indexed to MIC

Craig WA and Andes DR. Treatment of infections with ESBL-producing organisms: pharmacokinetic-

pharmacodynamic considerations. Clin Microbiol Infect. 2005;11:10-17.

CLINICAL DATA Bacteremic Patients with ESBL-Producing Isolates

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The Answer: Yes! Just like in animal infection models, drug

exposure indexed to MIC predicts outcome

Key Question: Are there clinical data to support this non-clinical observation?

MIC

(mg/L)

Success/Total

(n/N)

Percent Success

(n/N •100)

≤ 1 8/11 73

2 6/8 75

4 3/9 33

8 1/7 14

Clinical outcome with cephalosporin mono-therapy in 35 patients with bacteremia due to cephalosporin-susceptible ESBL-producing Klebsiella spp. or E. coli as defined by 2005 CLSI interpretive criteria

Craig WA, Bhavnani SM, Ambrose PG, Dudley MN, Jones RN. Evaluation of clinical outcome among patients with

ESBL-producing Enterobacteriaceae treated with cephalosporin mono-therapy. ICAAC 2005, Abstract K-1291

EXPOSURE & RESPONSE IN VITRO Fluoroquinolones and P. aeruginosa

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Tam VH, Louie A, Deziel MR, Weiguo L, Leary R, Drusano GL. Bacterial-population responses to drug-selective

pressure: examination of garenoxacin's effect on Pseudomonas aeruginosa. J Infect Dis. 2005;192:420-8.

Key Question: What is the relationship between drug

exposure and resistance emergence?

EXPOSURE & RESPONSE IN VITRO Fluoroquinolones and P. aeruginosa

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The Answer: In pre-

clinical infection

models, the shape of the relationship

between drug exposure

and response is that of

an inverted-U and the exposures that suppress

resistance are large

EXPOSURE & RESPONSE IN VITRO Cettolozane/Tazobactam and E. coli

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VanScoy B, Mendes RE, Castanherira M, McCauley J, Bhavnani SM, Forrest A, Okusanya OO, Jones RN, Friedrich LV, Steenbergen JN, Ambrose PG. Relationship between ceftolozane/tazobactam exposure and drug-resistance amplification in a hollow-fiber infection model. Antimicrob. Agents Chemother. 2013; 57:4134-4138.

U-SHAPED EXPOSURE & RESPONSE IN MAN Daptomycin in Bacteremia-Endocarditis

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Bhavnani SM, Rubino CM. Ambrose PG, Drusano GL. ICPD Study Report 00122. Data on file, Cubist

Pharmaceuticals.

The Answer: In patients, the shape of the relationship between

drug exposure and response can be that of an inverted-U

Key Question: Are there clinical data to support these non-clinical observation?

EXPOSURE-RESPONSE IN MAN Time to Decreased Susceptibility1

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Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. ICPD Study Report 00122. Data on file, Cubist

Pharmaceuticals.

Potential confounder: Source control was an issue in all (N=7) patients with elevated MIC

categorized as daptomycin non-susceptible

1: Increased MIC was defined as ≥ 4 fold increase in MIC relative to baseline

U-SHAPED EXPOSURE & RESPONSE IN MAN Fluoroquinolones in Tuberculosis Meningitis

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Thwaites TE, Bhavnani SM, Chau TTH, Hammel JP, Torok E, Van Wart SA, Mai PP, Reynolds DK, Caws M, Dung NT, Hien TT, Kulawy R, Farrar J, Ambrose PG. Pharmacokinetics and pharmacodynamics of fluoroquinolones in patients with tuberculous

meningitis. Submitted.

EXPOSURE & RESPONSE IN VITRO The Sword of Time

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Key Question: How does the duration of treatment impact

the relationship between drug exposure and resistance emergence?



The Answer: In pre-clinical infection models,

as the duration of

therapy increases, so too

does the magnitude of

drug exposure needed to suppress resistance

IMPACT OF EXPOSURE SHAPE Same Exposure Administered Three Ways

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Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics

of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for

Clinical Pharmacology and Therapeutics, 2005

Key Question: Can we alter shape of drug exposure to increase our chances of attaining positive outcomes?

Azithromycin (500 mg load, then 250 mg/day or 500 mg QD X 3 days or 1500 mg X 1

dose) against H. influenzae in a Mongolian gerbil acute otitis media infection model

EXPOSURE AND RESPONSE IN VIVO Impact of Oritavancin Exposure Shape

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Okusanya et al. Pharmacokinetics and pharmacokinetics-pharmacodynamics of oritavancin against

Staphylococcus aureus using data from a neutropenic murine-thigh infection model. ICAAC 2008, Poster A1-1287.

The identical AUC was administered in two ways with

very different effect

A NEW ORITAVANCIN DOSE REGIMEN PK-PD Assessment of 200 & 1200 mg Regimens

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Box plots represent the median and interquartile range for daily average total-drug AUC:MIC ratios based on simulations of 2,000 patients. The associated whiskers represent the 5th and 95th percentile for the daily average total-drug AUC:MIC ratios. The horizontal solid and dashed lines represent the average total-drug AUC:MIC targets of 1078 and 1204 associated with net bacterial stasis and a 1 log10 CFU decline, respectively, based on data from a murine thigh-infection model for S. aureus after 48 hrs of study [Okusanya OO, et. al., ICAAC 2009. Abstract A1-1287]. Data on File, The Medicines Company.

ORITAVANCIN NOVEL DOSE REGIMENS A Phase 2 Study

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Dunbar LM, et al. Efficacy of oritavancin at single or infrequent doses for the treatment of complicated skin and skin structure infections. 19th European Congress of Clinical Microbiology and Infectious Diseases. Helsinki, Finland, May, 2009.

As early exposure intensity increases, so too does efficacy

PREVENTING RESISTANCE EMERGENCE Mission Impossible?

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1: Drusano GL, Preston SL, Gotfried MH, Danziger LH, Rodvold KA. Levofloxacin penetration into epithelial lining fluid

as determined by population pharmacokinetic modeling and Monte Carlo simulation. Antimicrob Agents

Chemother. 2002; 46:586-589.

2: Rubino CM, Ma L, Bhavnani SM, Korth-Bradley J, Speth J, Ellis-Grosse E, Rodvold KR, Ambrose PG, Drusano GL.

Evaluation of tigecycline penetration into colon wall tissue and epithelial lining fluid using a population

pharmacokinetic model and Monte Carlo simulation. Antimicrob Agents Chemother. 2007;51:4085-9.

3: Rodvold KA, Nicolau DP, Lodise TP, Khashab M, Noel GJ, Kahn JB, Gotfried M, Murray SA, Nicholson S,

Laohavaleeson S, Tessier PR, Drusano GL. Identifying exposure targets for the treatment of Staphylococcal

pneumonia with ceftobiprole. Antimicrob Agents Chemother. 2009;53:3294-3301.

Key Question: How big a challenge is effect site penetration and associated variability?

AUCELF/AUCSERUM

Drug Median 5th – 95th Percentile

Levofloxacin1 1.43 0.14 – 19

Tigecycline2 1.15 0.56 – 5.2

Ceftobiprole3 0.153 0.035 – 7.87

PREVENTING RESISTANCE EMERGENCE Mission Impossible?

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• Combination therapy a must to push us “over the

hump” of the inverted U

The Answer: Effect site penetration and associated variability is likely a huge challenge

• Given the effect site penetration

lower margins and the high

exposures needed to prevent

resistance, it may be mission

impossible to prevent resistance

using mono-therapy with safe

dosing regimens



COMBINATION THERAPY Is The Answer as Simple as it Sounds?

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Key Question: Should we be simply administering drug

combinations that are synergistic or at least additive?

• Traditionally, we think of antimicrobial interactions as

synergistic, additive or antagonistic

o While interesting, these categories miss the point

o Synergistic agents can have horrible activity and visa versa

• Vancomycin and rifampin are often antagonistic

o Rifampin wildly active but resistance emerges rapidly;

o Vancomycin prevents rifampin resistance emergence; and

o Together are a more active regimen than either alone

The Answer: What makes or breaks a regimen is not the

presence or absence of synergy but is regimen activity

COMBINATION THERAPY Colistin Combinations Against A. baumannii

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Drug Total Log Kill (range)

Log Kill due to Synergy (range)

Doripenem (N =12) 8.8 (8-9) 5.8 (0-8)

Cefepime (N = 11) 8.3 (7-9) 7 (4.5-7)

Amikacin (N = 11) 7.8 (3-9) 1 (0-4)

Teicoplanin (N = 11) 7.5 (7-9) 5.5 (0-7)

Rifampin (N = 11) 6.9 (3-9) 0.1 (0-1)

Garonzik SM, Forrest A, Bulitta J Wisniewski W, Poudyal A, YU HH, KU C, LI J, Tsuji BT, Nation RL.

Pharmacodynamic interaction between colistin and other antimicrobials against Acinetobacter

baumannii. ISAP 2010.

TAKE HOME MESSAGES It’s About the Magnitude, Shape and Duration of Drug Exposure!

• Drug exposure indexed to MIC, rather than the presence or absence of resistance determinants,

predicts response

o Think about magnitude of drug exposure when designing regimens for drug-resistant pathogens

o The trade-off may be, but not necessarily, more toxicity

• Think about manipulating drug exposure shape to take advantage of each drug’s PK-PD profile to provide:

o Best chance to maximize bacterial kill,

o Best chance to maximize positive clinical outcomes,

o Best chance to reduce spontaneous mutation, and

o Best chance to eliminate a pre-existing resistant

subpopulations

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TAKE HOME MESSAGES It’s About the Magnitude, Shape and Duration of Drug Exposure!

• Relationships between drug exposure and resistance

emergence are U-shaped and time-dependent

o Just don’t think about magnitude and shape, but also

therapy duration

o Consider front-loading exposure and shortening therapy for

antibiotics with high resistance potential

• Effect site penetration variability is high and often will

necessitate the need for combination therapy

• Consider regimens, not simply drugs

o Consider multiple, combination administration routes

o Consider combining multiple new active drugs rather than

one new active drug with less active old ones

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THANK YOU FOR YOUR ATTENTION Questions, Comments or Wise Remarks?

Documents

PK-PD and ANTIBIOTIC RESISTANCE Lessons Learned 24 ... · PK-PD and ANTIBIOTIC RESISTANCE Lessons Learned 24 September ... examination of garenoxacin's effect on Pseudomonas ... advantage