1848. Daptomycin-Beta-lactam Combination Therapy of Experimental Methicillin Resistant Staphylococcus aureus Endocarditis
Session: Poster Abstract Session: Treatment of HAIs/Antimicrobial Resistant Infections
Saturday, October 10, 2015
Room: Poster Hall
Background:

Anti-staphylococcal penicillins enhance in vitro and in vivo activity of daptomycin (D) against methicillin-resistant (MR) D-non-susceptible (DNS) strains of Staphylococcus aureus(SA). Whether other beta-lactams (BL) also have this effect is unknown.

Methods:

Experiments were performed to determine if a cephalosporin, ceftriaxone (C) (MIC > 128 μg/ml) dosed IM at 100 mg/kg qd, or a carbapenem, ertapenem (E) (MIC 16 μg/ml) dosed IM at 40 mg/kg qd, improved efficacy of D (MIC = 4 μg/ml) dosed IV at 12 mg/kg qd in a rabbit model of aortic valve endocarditis due to a MR-DNS-SA strain, CB5054.  Untreated controls were sacrificed on infection day 1. Rabbits were treated for 4 days and sacrificed on day 5 ~24h after the last dose.  Vegetations (Veg), and samples of spleen (Spl) and kidney (Kid) were quantitatively cultured.

Results:

Table 1.  Plasma drug concentrations and half-life of antibiotics used for treatment.

Antibiotic

Mean (Range) Concentrations (μg/ml)*

Half-life (h)

1 h after dosing

Trough

D

140 (103-184) (n=8)

1.4 (0.7-2.4) (n=8)

3.3

C

300 (209-340) (n=5)

2.8 (0.7-8.3) (n=5)

3.4

E

214 (176-269) (n=4)

0.4 (0.1-0.6) (n=4)

2.5

* 1h samples obtained on day 1 or 2.  Trough samples obtained at the time of sacrifice.

Table 2. Number of rabbits per treatment group and tissue burden of organism in log10 cfu/g (mean + standard deviation).

 

Treatment Groups

Control

D

C

E

D+C

D+E

9

7

5

7

8

8

Veg

8.0+0.6

8.5+1.6

7.6+1.6

7.2+1.8

6.6+1.2

6.9+1.9

Spl§

6.4+0.4

5.8+0.9

4.7+0.7

5.0+1.0

3.4+1.9

3.5+0.7

Kid

6.9+0.5

5.01+0.8

4.6+2.2

5.0+1.5

3.7+2.4

2.6+1.4

§  Control vs D, p>0.1; C vs D+C, p>0.1; E vs D+E, p=0.004

¶   Control vs D, p<0.001; C vs D+C, p>0.1; E vs D+E, p=0.006

Conclusion:

D overall was ineffective.  C and E were numerically more effective than D in every instance, perhaps reflecting the see-saw effect. D+E out performed D+C in its ability to reduce tissue burdens of bacteria in Spl and Kid; neither was particularly effective in reducing bacterial counts in Veg compared to the better single agent. Drug exposures were less than those achievable in humans given that drug half-lives in rabbits were half or less of those in humans.  Bacterial burdens may have been lower with more frequent dosing (e.g., twice daily) of the BL and/or D to more closely simulate drug exposures in humans.

Henry Chambers, MD, FIDSA1, Li Basuino, MS1, Stephanie Hamilton, PhD1, Eun Ju Choo, MD, PhD1 and Pamela Moise, PharmD2, (1)Medicine, University of California San Francisco, San Francisco, CA, (2)Merck & Co., Inc., Kenilworth, NJ

Disclosures:

H. Chambers, Cubist: Grant Investigator , Grant recipient
AstraZeneca: Scientific Advisor , Consulting fee
Pfizer: Scientific Advisor , Consulting fee
Theravance: Scientific Advisor , Consulting fee
Merck: Shareholder , Stock holder
Genentech: Investigator and Scientific Advisor , Consulting fee and Research grant

L. Basuino, None

S. Hamilton, None

E. J. Choo, None

P. Moise, Merck & Co., Inc.: Employee , Salary

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