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Experimental Therapeutics

Adjunctive Clavulanic Acid Abolishes the Cefazolin Inoculum Effect in an Experimental Rat Model of Methicillin-Sensitive Staphylococcus aureus Endocarditis

William R. Miller, Kavindra V. Singh, Cesar A. Arias, Barbara E. Murray
William R. Miller
aCenter for Antimicrobial Resistance and Microbial Genomics, UTHealth, McGovern Medical School, Houston, Texas, USA
bDepartment of Internal Medicine, Division of Infectious Diseases, UTHealth, McGovern Medical School, Houston, Texas, USA
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Kavindra V. Singh
aCenter for Antimicrobial Resistance and Microbial Genomics, UTHealth, McGovern Medical School, Houston, Texas, USA
bDepartment of Internal Medicine, Division of Infectious Diseases, UTHealth, McGovern Medical School, Houston, Texas, USA
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Cesar A. Arias
aCenter for Antimicrobial Resistance and Microbial Genomics, UTHealth, McGovern Medical School, Houston, Texas, USA
bDepartment of Internal Medicine, Division of Infectious Diseases, UTHealth, McGovern Medical School, Houston, Texas, USA
cDepartment of Microbiology and Molecular Genetics, UTHealth, McGovern Medical School, Houston, Texas, USA
dCenter for Infectious Diseases, UTHealth, School of Public Health, Houston, Texas, USA
eMolecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia
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Barbara E. Murray
aCenter for Antimicrobial Resistance and Microbial Genomics, UTHealth, McGovern Medical School, Houston, Texas, USA
bDepartment of Internal Medicine, Division of Infectious Diseases, UTHealth, McGovern Medical School, Houston, Texas, USA
cDepartment of Microbiology and Molecular Genetics, UTHealth, McGovern Medical School, Houston, Texas, USA
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DOI: 10.1128/AAC.01158-18
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    FIG 1

    Time-kill curve of S. aureus strain TX0117 at standard and high inocula. At a standard inoculum, growth in the presence of CFZ 64 μg/ml resulted in an approximately (3.5 ± 0.8)-log10 reduction in CFU/ml at 24 h. At a high inoculum, growth in the presence of CFZ 64 μg/ml or AMC 1/0.25 μg/ml showed similar colony counts to the antibiotic-free control. The combination of CFZ 64 μg/ml plus AMC 1/0.25 μg/ml resulted in a reduction of 3 ± 0.4 log10 CFU/ml at 24 h. These results are geometric means from three independent experiments; error bars represent the standard deviations. AMC, amoxicillin-clavulanate; CFZ, cefazolin.

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    Clavulanic acid abolishes the cefazolin inoculum effect in a rat endocarditis model. (A) S. aureus TX0117 treated with CFZ plus CLA, CFZ alone, or untreated control animals (T = 0). Animals treated with CFZ plus CLA showed an additional mean reduction of 5 ± 0.7 log10 in CFU/g of vegetation compared to CFZ alone after 72 h of therapy. (B) S. aureus TX0117c without BlaZ activity, treated with cefazolin alone showed a mean reduction of 6.5 ± 0.6 log10 CFU/g compared to that of the untreated Bla-cured infected controls (T = 0), a decrease comparable to the parental strain treated with the cefazolin plus clavulanic acid combination (decrease of 7.1 ± 0.5 CFU/g). CLA, clavulanic acid; CFZ, cefazolin; βla+, β-lactamase positive; βla-cured, no β-lactamase activity; SD, standard deviation.

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  • TABLE 1

    S. aureus MICs at standard and high inocula

    TreatmentaMIC (μg/ml)
    ATCC 25923 (βla−, CIE−)ATCC 29213 (βla+, CIE−)TX0117 (βla+, CIE+)
    Standard inoculum (105 CFU/ml)
        AMC0.125/0.0310.25/0.0630.5/0.125
        SAMNDb0.125/0.0630.5/0.25
        TZPND1/0.1251/0.125
        Cefazolin0.50.51
    High inoculum (107 CFU/ml)
        AMC0.125/0.0311/0.258/2
        SAMND2/14/2
        TZPND1/0.1254/0.5
        Cefazolin0.54128
        Cefazolin combinations (μg/ml)c
            Cefazolin plus AMP (10)ND464
            Cefazolin plus AMC (10/2.5)ND<0.125<0.125
            Cefazolin plus AMC (1/0.25)ND<0.1250.5
            Cefazolin plus AMC (0.5/0.125)ND0.51
            Cefazolin plus AMC (0.25/0.063)ND0.51
            Cefazolin plus SAM (0.5/0.25)NDND2
            Cefazolin plus TZP (1/0.125)NDND1
    • ↵a AMC, amoxicillin-clavulanic acid; SAM, ampicillin-sulbactam; TZP, piperacillin-tazobactam; AMP, ampicillin.

    • ↵b ND, not done.

    • ↵c MICs for cefazolin combinations reported as MIC of cefazolin in the presence of specified concentrations of AMP, SAM, TZP, or AMC.

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Adjunctive Clavulanic Acid Abolishes the Cefazolin Inoculum Effect in an Experimental Rat Model of Methicillin-Sensitive Staphylococcus aureus Endocarditis
William R. Miller, Kavindra V. Singh, Cesar A. Arias, Barbara E. Murray
Antimicrobial Agents and Chemotherapy Oct 2018, 62 (11) e01158-18; DOI: 10.1128/AAC.01158-18

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Adjunctive Clavulanic Acid Abolishes the Cefazolin Inoculum Effect in an Experimental Rat Model of Methicillin-Sensitive Staphylococcus aureus Endocarditis
William R. Miller, Kavindra V. Singh, Cesar A. Arias, Barbara E. Murray
Antimicrobial Agents and Chemotherapy Oct 2018, 62 (11) e01158-18; DOI: 10.1128/AAC.01158-18
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KEYWORDS

Staphylococcus aureus
animal models
cefazolin
clavulanic acid
infective endocarditis
inoculum effect

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