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Pharmacology

New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae

Zackery P. Bulman, Michael J. Satlin, Liang Chen, Barry N. Kreiswirth, Beom Soo Shin, Thomas J. Walsh, Patricia N. Holden, Alan Forrest, Roger L. Nation, Jian Li, Brian T. Tsuji
Zackery P. Bulman
aLaboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA
bSchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
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Michael J. Satlin
cWeill Cornell Medical College, Cornell University, New York, New York, USA
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Liang Chen
dPublic Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Barry N. Kreiswirth
dPublic Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Beom Soo Shin
eCatholic University of Daegu, Hayang, South Korea
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Thomas J. Walsh
cWeill Cornell Medical College, Cornell University, New York, New York, USA
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Patricia N. Holden
aLaboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA
bSchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
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Alan Forrest
fEshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
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Roger L. Nation
gDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
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Jian Li
gDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
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Brian T. Tsuji
aLaboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA
bSchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
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DOI: 10.1128/AAC.02023-16
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    FIG 1

    HFIM total bacterial population counts in log10 CFU/ml over 240 h following exposure to polymyxin B loading dose (2.22 mg/kg for 1 dose followed by 1.43 mg/kg q12h starting 12 h later), polymyxin B burst (5.53 mg/kg × 1 dose followed by no subsequent doses), meropenem (2 g q8h), and rifampin (600 mg q24h). Experiments were conducted at a starting inoculum of ∼108 CFU/ml for KPC-Kp 9A versus monotherapies (A), KPC-Kp 9A versus combination therapies (B), and KPC-Kp 27A versus combination therapy (C).

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    Population analysis profiles quantifying the growth of resistant KPC-Kp 9A (A to J) and KPC-Kp 27A (K to L) subpopulations on MHA plates containing the specified concentration of either polymyxin B (blue lines) or meropenem (red lines). Each panel represents a single antibiotic treatment regimen over 240 h in the HFIM and compares data from the antibiotic-resistant subpopulations, which are fractions of the respective total population (black lines). The black lines are displayed for comparison and represent the total population bacterial counts from Fig. 1 at time points when population analysis profiles were simultaneously performed (0, 24, 48, 72, 96, 144, 192, and 240 h). KPC-Kp 9A and KPC-Kp 27A polymyxin B MICs were initially 0.5 and 1 mg/liter, respectively. Polymyxin B MICs at the end of each experiment, following exposure for 240 h in the HFIM, were 0.5 mg/liter (A), >32 mg/liter (B), >32 mg/liter (C), 0.5 mg/liter (D), 0.5 mg/liter (E), >32 mg/liter (F), 0.5 mg/liter (G), 0.5 mg/liter (H), 32 mg/liter (I), 0.5 mg/liter (J), 0.5 mg/liter (K), and 0.5 mg/liter (L). KPC-Kp 9A and KPC-Kp 27A remained polymyxin susceptible following exposure to all combinations containing a polymyxin B burst plus rifampin.

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  • TABLE 1

    KPC-Kp isolate characteristics, including β-lactamases and MIC values, followed by the antibiotic regimens used in the time-kill experiments and mean changes in bacterial log10 CFU/ml from baseline after 4, 8, and 24 ha

    KPC-Kp isolateβ-Lactamase(s)MIC (mg/liter)Time-kill experiment antimicrobial(s)b,cTime-kill experiment Δ bacterial log10 CFU/ml ± SDd,e
    PMBMERORIF4 h8 h24 h
    9AKPC-2, SHV-11, TEM-10.51664PMB 2.41−2.93 ± 0.45−0.54 ± 0.090.86 ± 0.04
    PMB 6−4.19 ± 0.49−2.20 ± 0.150.82 ± 0.02
    PMB 2.41 + MERO−3.73 ± 0.05−0.67 ± 0.160.89 ± 0.05
    PMB 2.41 + RIF−3.16 ± 0.18 −3.78 ± 1.73 −0.98 ± 0.22*
    PMB 6 + MERO−4.87 ± 0.04−3.51 ± 0.780.82 ± 0.12
    PMB 6 + RIF−5.87 ± 3.20 −4.73 ± 1.55 −5.06 ± 0.26*
    PMB 2.41 + MERO + RIF−3.19 ± 0.19 −5.81 ± 0.44* −6.75 ± 1.91
    PMB 6 + MERO + RIF −8.13 ± 0.01 −8.13 ± 0.01* −8.13 ± 0.01*
    24AKPC-20.564>64PMB 2.41−0.55 ± 0.970.06 ± 0.750.90 ± 0.20
    PMB 6−5.85 ± 0.64−4.32 ± 0.78−0.28 ± 1.03
    PMB 2.41 + MERO−0.98 ± 1.25−0.15 ± 0.810.91 ± 0.14
    PMB 2.41 + RIF −3.27 ± 0.28 −3.16 ± 0.44 0.70 ± 0.17
    PMB 6 + MERO−6.11 ± 0.69−4.28 ± 0.99−0.33 ± 1.22
    PMB 6 + RIF −8.15 ± 0.06 −8.15 ± 0.06 −7.05 ± 1.50*
    PMB 2.41 + MERO + RIF −3.87 ± 0.40 −3.59 ± 0.44* 0.70 ± 0.12
    PMB 6 + MERO + RIF −8.23 ± 0.06 −8.23 ± 0.06 −8.23 ± 0.06
    27AKPC-2, SHV-11, TEM-1132>64PMB 2.41−3.34 ± 0.87−1.06 ± 0.570.74 ± 0.03
    PMB 6−5.14 ± 0.62−3.81 ± 0.960.20 ± 0.56
    PMB 2.41 + MERO−3.37 ± 0.47−1.42 ± 0.200.75 ± 0.05
    PMB 2.41 + RIF−0.93 ± 0.27−1.20 ± 0.50−0.46 ± 0.47
    PMB 6 + MERO−5.62 ± 0.21−5.40 ± 0.18 −3.57 ± 2.74
    PMB 6 + RIF−2.78 ± 0.22−4.14 ± 0.60 −3.92 ± 0.25*
    PMB 2.41 + MERO + RIF−1.34 ± 0.09−1.43 ± 0.23−1.25 ± 0.21*
    PMB 6 + MERO + RIF−2.92 ± 0.53−4.36 ± 0.75 −8.24 ± 0.07*
    • ↵a Baseline, 0 h.

    • ↵b PMB 2.41, polymyxin B at 2.41 mg/liter; PMB 6, polymyxin B at 6 mg/liter; MERO, meropenem at 49.6 mg/liter; RIF, rifampin at 3.5 mg/liter.

    • ↵c The MERO, RIF, and MERO + RIF experimental arms are not displayed and did not reduce bacterial counts at 4, 8, or 24 h.

    • ↵d Change from 0 h bacterial concentration in time-kill experiments [log10(CFUxh) − log10(CFU0h)], where x = 4, 8, or 24 h; mean starting inoculum, 8.19 ± 0.07 log10 CFU/ml.

    • ↵e Data from synergistic combinations (defined as those resulting in a >2 log10 CFU/ml mean reduction in viable counts over the results seen with the most active agent administered alone) are bolded; bacterial reductions for combinations whose results were significantly different from those seen with the most active agent alone are denoted with an asterisk (P < 0.05).

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New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae
Zackery P. Bulman, Michael J. Satlin, Liang Chen, Barry N. Kreiswirth, Beom Soo Shin, Thomas J. Walsh, Patricia N. Holden, Alan Forrest, Roger L. Nation, Jian Li, Brian T. Tsuji
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02023-16; DOI: 10.1128/AAC.02023-16

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New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae
Zackery P. Bulman, Michael J. Satlin, Liang Chen, Barry N. Kreiswirth, Beom Soo Shin, Thomas J. Walsh, Patricia N. Holden, Alan Forrest, Roger L. Nation, Jian Li, Brian T. Tsuji
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02023-16; DOI: 10.1128/AAC.02023-16
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KEYWORDS

Anti-Bacterial Agents
Klebsiella pneumoniae
Models, Statistical
polymyxin B
rifampin
Thienamycins
polymyxin B
meropenem
rifampin
PK/PD
KPC-producing K. pneumoniae

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