Table 1.
Distribution of substitutions among TEM enzymes.
Table 2.
Variant Genotypes Created, Binary Codes, Substitutions and (Names of Genotypes Identified in Clinical Isolates).
Table 3.
β-lactam Antibiotics used for this study.
Table 4.
Average Growth Rates (x 10–3): the rows are the fitness landscapes.
Fig 1.
AMP: Ampicillin 256 μg/ml.
Fig 2.
AM: Amoxicillin 512 μg/ml.
Fig 3.
CEC: Cefaclor 1 μg/ml.
Fig 4.
CTX: Cefotaxime 0.05 μg/ml.
Fig 5.
ZOX: Ceftizoxime 0.03 μg/ml.
Fig 6.
CXM: Cefuroxime 1.5 μg/ml.
Fig 7.
CRO: Ceftriaxone 0.045 μg/ml.
Fig 8.
AMC: Amoxicillin/Clavulanate 512 μg/ml and 8μg/ml.
Fig 9.
CAZ: Cefazidime 0.1 μg/ml.
Fig 10.
CTT: Cefotetan 0.312 μg/ml.
Fig 11.
SAM: Ampicillin/Sulbactam 8 μg/ml and 8μg/ml.
Fig 12.
CPR: Cefprozil 100 μg/ml.
Fig 13.
CPD: Cefpodoxime 2 μg/ml.
Fig 14.
TZP: Pipercillin / Tazobactam 8.12μg/ml and 8 μg.ml.
Fig 15.
FEP: Cefepime 0.0156μg/ml.
Table 5.
Rank Order of Genotypes in Each β-Lactam Antibiotic (Derived From Table 4).
Fig 16.
Summary of CPM Substitutions with the Highest Probabilities.
Each arrow is labeled by the drug or drugs corresponding to the maximal transition probability, taken over all 15 drugs. Each arrow is also labeled by the maximal probability. The top panel shows which antibiotics selected the addition of substitutions and the bottom panel shows which antibiotics selected reversions. Unlabled arrows are those with low probabilities across all antibiotics.
Fig 17.
Summary of Optimal 6 Step CPM and EPM Treatment Paths beginning at genotype 1111 and ending at genotype 0000.
An arrow indicates that the substitution is included in a path that starts at 1111 and ends at 0000, where the pathway has non-zero probability. Black arrows show substitutions present in six step paths computed using both the CPM and the EPM. Red arrows signify substitutions found only in optimum paths computed using the CPM whereas blue signify substitutions only found using the EPM.
Table 6.
Maximum Probability and Number of Paths Using CPM.
Table 7.
Maximum Probability and Number of Paths Using EPM.
Table 8.
CPM Additions of Substitutions And Associated β-lactam Antibiotics From Optimal Six Step Treatment Plans (*Maximum Probability for Path).
Table 9.
CPM Reversions of Substitutions And Associated β-lactam Antibiotics From Optimal Six Step Treatment Plans (*Maximum Probability for Path).
Table 10.
EPM Additions of Substitutions and Associated β-lactam Antibiotics From Optimal Six Step Treatment Plans (*Maximum Probability for Path).
Table 11.
EPM Reversions of Substitutions and Associated β-lactam Antibiotics From Optimal Six Step Treatment Plans (*Maximum Probability for Path).
Fig 18.
Summary of Optimal CPM 2, 4, and 6 Step Antibiotic Cycles.
In this figure, cycles are distinguished from paths in that TEM-1 (0000) is the first and last genotype visited, thus creating circular paths. An arrow indicates a substitution included in a mutational pathway which starts and ends at 0000, where the mutational pathway has a non-zero probability for the optimal treatment cycle. The substitutions that are included in optimal two steps cycles are shown in red. Substitutions that are included in optimal four and six step cycles are shown in blue. Four and six step cycles differ only in the number of substitutions and reversions that occur within each cycle. Their probabilities are identical.
Table 12.
Cyclical Treatment Paths showing Substitutions and Associated β-lactam Antibiotics.