Once-daily Dosing of Arbekacin Can Suppress the Formation of Small Colony Variants of Methicillin Resistant Staphylococcus aureus in an in vitro Pharmacodynamic Infection Model / 감염과화학요법

BACKGROUND: Small colony variants (SCVs) of Staphylococcus aureus have emerged to be commonly associated with persistent and relapsing infections. Arbekacin (ABK) is one of a few alternatives to vancomycin in intractable case of methicillin resistant S. aureus (MRSA) infection. However, it has not yet been defined whethter ABK tends to be efficacious to the MRSA SCVs. In this study, we employed an in vitro pharmacodynamic infection model (IVPDIM) to define efficacies of ABK against MRSA SCVs. MATERIALS AND METHODS: Using four strains of clinically isolated MRSA (MRSA122, MRSA160, MRSA18, MRSA123), we adopted IVPDIM comprised of two-compartment in which effective surface-to-volume ratio of 5.34 cm(-1). Human pharmacokinetic regimen simulations of ABK were as follows: 100 mg every 12 h (q12h), 200 mg q24h, 200 mg q12h, and 400 mg q24h. Samples were taken from each model at 0, 1, 2, 4, 6, 12, 24, and 30 h, and the bacterial colony counts were determined. The experiments were repeated twice with ABK-administered groups and control group. RESULTS: MICs of ABK for MRSA122, MRSA160, MRSA18, and MRSA123 were 2, 2, 2, and 1 microgram/mL, respectively. In case of MRSA122, MRSA160, MRSA18, C(max)/MIC were less than 9.0 except for ABK 400 mg q24h regimen. In MRSA123, C(max)/MIC were 8.9 on average at ABK 100 mg q12h regimen. But, other regimen showed C(max)/MIC >9. Four regimens for 4 strains showed statistically different colony counts at 30 h (P=0.000). The more dosage or less frequent dosing interval, the more colonies tended to reduce in all strains. In 100 mg q12h groups, SCVs were observed in all strains within 24 h. With increment of dosage or changing dosing interval from q12h to 24h, SCVs were reduced (P=0.000). Regimen of 400 mg q24h did not let SCVs appear in all strains of MIC 2 microgram/mL during the experiments. CONCLUSION: SCVs were observed when MIC of ABK against MRSA were 1-2 microgram/mL, especially in most cases of C(max)/MIC <9. Those findings were also associated with re-growth of colony during the experiments. Once-daily dosing of ABK could reduce or eliminate the appearance of SCV.

Once-daily Dosing of Arbekacin Can Suppress the Formation of Small Colony Variants of Methicillin Resistant Staphylococcus aureus in an in vitro Pharmacodynamic Infection Model / 감염과화학요법

BACKGROUND: Small colony variants (SCVs) of Staphylococcus aureus have emerged to be commonly associated with persistent and relapsing infections. Arbekacin (ABK) is one of a few alternatives to vancomycin in intractable case of methicillin resistant S. aureus (MRSA) infection. However, it has not yet been defined whethter ABK tends to be efficacious to the MRSA SCVs. In this study, we employed an in vitro pharmacodynamic infection model (IVPDIM) to define efficacies of ABK against MRSA SCVs. MATERIALS AND METHODS: Using four strains of clinically isolated MRSA (MRSA122, MRSA160, MRSA18, MRSA123), we adopted IVPDIM comprised of two-compartment in which effective surface-to-volume ratio of 5.34 cm(-1). Human pharmacokinetic regimen simulations of ABK were as follows: 100 mg every 12 h (q12h), 200 mg q24h, 200 mg q12h, and 400 mg q24h. Samples were taken from each model at 0, 1, 2, 4, 6, 12, 24, and 30 h, and the bacterial colony counts were determined. The experiments were repeated twice with ABK-administered groups and control group. RESULTS: MICs of ABK for MRSA122, MRSA160, MRSA18, and MRSA123 were 2, 2, 2, and 1 microgram/mL, respectively. In case of MRSA122, MRSA160, MRSA18, C(max)/MIC were less than 9.0 except for ABK 400 mg q24h regimen. In MRSA123, C(max)/MIC were 8.9 on average at ABK 100 mg q12h regimen. But, other regimen showed C(max)/MIC >9. Four regimens for 4 strains showed statistically different colony counts at 30 h (P=0.000). The more dosage or less frequent dosing interval, the more colonies tended to reduce in all strains. In 100 mg q12h groups, SCVs were observed in all strains within 24 h. With increment of dosage or changing dosing interval from q12h to 24h, SCVs were reduced (P=0.000). Regimen of 400 mg q24h did not let SCVs appear in all strains of MIC 2 microgram/mL during the experiments. CONCLUSION: SCVs were observed when MIC of ABK against MRSA were 1-2 microgram/mL, especially in most cases of C(max)/MIC <9. Those findings were also associated with re-growth of colony during the experiments. Once-daily dosing of ABK could reduce or eliminate the appearance of SCV.

A case of Small Colony Variants (SCVs) of Staphylococcus aureus from Sputum of a Patient with Chronic Renal Failure / 대한임상미생물학회지

Recently, small colony variants (SCVs) of Staphylococcus aureus causing fatal infections are increasing, but rarely reported in Korea. S. aureus, SCVs are slow growing subpopulation that cause persistent and relapsing infections. S. aureus, SCVs are frequently auxotrophic for hemin, menadione, and CO2, and are often disrupted in their electron transport activity. With S. aureus, SCVs virulence is altered by a decrease in -toxin production and susceptibility to various antibiotics, allowing their intracellular survival. We isolated S. aureus, SCVs from the sputum of a 67 year old male with pneumonia, chronic renal failure with hemodialysis and preventive antibiotic therapy. Because S. aureus, SCVs are easily missed or misdiagnosed as normal flora in routine culture due to their atypical growth behavior and biochemical reaction, the correct identification is very important, especially when no bacteria or unusual bacteria are found in patients with persistent or relapsing infections with long term antibiotic therapy.