TY - JOUR
T1 - The potent bactericidal activity of streptomycin in the guinea pig model of tuberculosis ceases due to the presence of persisters
AU - Ahmad, Zahoor
AU - Pinn, Michael L.
AU - Nuermberger, Eric L.
AU - Peloquin, Charles A.
AU - Grosset, Jacques H.
AU - Karakousis, Petros C.
N1 - Funding Information:
This work was supported by The Bill and Melinda Gates Foundation (TB Accelerator grant #42851 to J. H. G., E. L. N. and P. C. K.) and the National Institutes of Health (AI064229 and AI083125 to P. C. K.).
PY - 2010/8/6
Y1 - 2010/8/6
N2 - Objectives: The biphasic kill curve of isoniazid against Mycobacterium tuberculosis in guinea pigs is due to the presence of persisters rather than selection of isoniazid-resistant mutants. To determine whether this phenomenon is common to other bactericidal drugs, we studied the activity of streptomycin and its ability to select for streptomycin-resistant mutants in the guinea pig model of tuberculosis. Methods: Pharmacokinetic studies were performed to establish the human-equivalent dose of streptomycin. Guinea pigs were aerosol-infected with M. tuberculosis and 2 weeks later streptomycin was given for 5 days/week via intramuscular injection. Bactericidal activity was assessed by homogenizing and plating lungs for cfu until 10 weeks of treatment. At each timepoint, cfu were isolated, suspended in normal saline and re-plated on plates containing 0.5, 1.0, 2.0 or 10.0 mg/L streptomycin. Results: The human-equivalent dose of streptomycin was determined to be 70 mg/kg. Streptomycin showed potent activity during the first 14 days of treatment, rescuing all animals from acute tuberculosis-related death and reducing lung cfu by ~4 log10. However, streptomycin activity was dramatically reduced thereafter, as lung cfu declined by only ~1 log10 over the next 56 days of treatment. Although streptomycin-resistant mutants were detectable, their frequency of isolation was identical at treatment initiation and after 70 days of treatment. Conclusions: The reduced activity of streptomycin during the second phase of monotherapy is not associated with the selection of streptomycin-resistant mutants but, rather, with the presence of phenotypically tolerant 'persisters'.
AB - Objectives: The biphasic kill curve of isoniazid against Mycobacterium tuberculosis in guinea pigs is due to the presence of persisters rather than selection of isoniazid-resistant mutants. To determine whether this phenomenon is common to other bactericidal drugs, we studied the activity of streptomycin and its ability to select for streptomycin-resistant mutants in the guinea pig model of tuberculosis. Methods: Pharmacokinetic studies were performed to establish the human-equivalent dose of streptomycin. Guinea pigs were aerosol-infected with M. tuberculosis and 2 weeks later streptomycin was given for 5 days/week via intramuscular injection. Bactericidal activity was assessed by homogenizing and plating lungs for cfu until 10 weeks of treatment. At each timepoint, cfu were isolated, suspended in normal saline and re-plated on plates containing 0.5, 1.0, 2.0 or 10.0 mg/L streptomycin. Results: The human-equivalent dose of streptomycin was determined to be 70 mg/kg. Streptomycin showed potent activity during the first 14 days of treatment, rescuing all animals from acute tuberculosis-related death and reducing lung cfu by ~4 log10. However, streptomycin activity was dramatically reduced thereafter, as lung cfu declined by only ~1 log10 over the next 56 days of treatment. Although streptomycin-resistant mutants were detectable, their frequency of isolation was identical at treatment initiation and after 70 days of treatment. Conclusions: The reduced activity of streptomycin during the second phase of monotherapy is not associated with the selection of streptomycin-resistant mutants but, rather, with the presence of phenotypically tolerant 'persisters'.
KW - Antibiotic chemotherapy
KW - Drug resistance
KW - Isoniazid
KW - Mycobacterium tuberculosis
KW - Persistence
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U2 - 10.1093/jac/dkq277
DO - 10.1093/jac/dkq277
M3 - Article
C2 - 20693172
AN - SCOPUS:77957229965
SN - 0305-7453
VL - 65
SP - 2172
EP - 2175
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 10
M1 - dkq277
ER -